Inflammatory myopathies

The overall prevalence of IM varies between countries, ranging from 2.4 to 33.8 per 100,000.   

Classification of Inflammatory Myopathy

Idiopathic Inflammatory Myopathy:  Dermatomyositis (DM), (immune-mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis, OM) including anti-synthetase syndrome (AsyS) , inclusion body myositis (IBM), Polymyositis (PM).

Inflammatory myopathy (AANEM talk):

iRMD (Cavin-4) - immune mediated rippling muscle disease.

SLONM (HIV, MGUS)

GVHD

IMMM (immune mediated megaconial myopathy)

ICIM (immune check-point inhibitory associated myopathy)

GM (sarcoidosis)

AMA (mitochondrial)

Polymyositis and dermatomyositis in adults is often insidious in onset without any identifiable precipitating event.  Usually, the initial complaint is of a symmetrical weakness involving muscles in the shoulders and pelvic girdle.  Muscle pain and tenderness are noted frequently in the arms and less often in the legs.  As the disease progresses, dysphagia may develop, as well as weakness of neck muscles, particularly the flexors.  Even the respiratory muscles may eventually become affected.   The skin lesions of adult DM and childhood DM are similar.  In the acute stage, there is erythema accompanied by edema of the subcutaneous tissue, affecting particularly the periorbital, perioral, malar, anterior neck, and chest regions and extensor surfaces of the extremities.  Frequently, linear erythematous discolorations surround the nail beds.  These lesions subsequently result in scaling, pigmentation, and depigmentation of the skin, followed by zones of brawny induration.  

Dermatomyositis

First described by Wagner in 1863 and 1867 and by Jackson in 1887 was established as a clinical entity by Unverricht. 

• Dermatomyositis is an inflammatory disease characterized by muscle weakness and skin rash.

• Women > men.

• 0.-0.93 per 100,000 population.  

• Subacute onset of muscle weakness presents in children and adults with subacute onset and is accompanied or preceded by a distinct skin rash, a cardinal feature of dermatomyositis.  The skin involvement may precede the onset of weakness by weeks to months.  Early in the course, the rash and muscle enzyme elevations may be the sole manifestations of dermatomyositis.

• In children, it may manifest between 5 and 14 years of age.  It is an insidious onset of weakness and myalgia may be preceded by fatigue, low-grade fevers, and rash.  Some patients may develop the characteristic rash and never develop the weakness have normal CK levels for 2 years after the onset of the rash are thought to have dermatomyositis sine myositis or clinically amyopathic dermatomyositis.    However, in some of these patients, EMG and muscle biopsy studies do reveal features of myositis.  

• The erythematous skin lesions over the extensor surfaces of the joints, a malar rash, and muscle weakness  The muscle weakness and erythematous rash are always conjoined.  Initially, the rash appears in the periorbital region and over the extensor surfaces, particularly the knuckles, elbows, and knees.  Other areas of skin involvement include the anterior neck and upper chest (V sign), the shoulders (shawl) sign, the medial malleoli, and the buttocks.  The periorbital rash is violaceous, or heliotrope, in color and is often associated with edema and telangiectasia of the eyelids.  Subsequently, there is scaling accompanied by pigmentation and depigmentation of the affected skin.  Changes around the fingernails, consisting of cuticular overgrowth and nail-bed telangiectasia, and digital ulcerations are frequent findings.  As in SLE, exposure to sunlight worsens the rash and sometimes the myositis.  GI vasculitis with mucosal ulceration resulting in hemorrhage or perforation is more common in children than adults.  As in adults, pulmonary fibrosis can also appear in the course of the disease.  As a rule, symptoms of weakness, stiffness, and pain in the muscles follow the skin manifestations.  The muscle weakness is usually generalized but always most severe in the pectoral and pelvic girdle muscles.  The proximal muscles of the limbs are more severely affected than the distal ones; the abductors of the legs tend to be more affected than the adductors, and the extensors are more affected than the flexors.  A tip-toe gait, the result of flexion contracture at the ankles, is a common and early abnormality.  The tendon reflexes are depressed or abolished after a severe degree of muscle weakness has been attained.  As the disease progresses and in those who respond to treatment poorly, it can vary in degrees of progression from rapid over several months and involves all muscles, including those of chewing, swallowing, phonation, and respiration.  Flexion contractures at elbows, hips, knees, and ankles are frequent.  A brawny erythematous thickening of the skin with patches of pigmentation and depigmentation over the extensor surfaces of joints marks the more chronic stage of the disease.  Calcification in the subcutaneous tissues and muscles occurs in up to 50% of children.  Ulceration of the overlying skin with extrusion of calcific debris are observed in the more severely affected patients or in those who are treated incompletely.   Despite treatment advances in the management of childhood DM, some children do not recover completely and contractures, subcutaneous calcifications, and weakness may remain with sequelae pf heterotopic calcifications and ossifications.   

• Proximal weakness: Difficulty climbing stairs, lifting arms overhead, and arising from chairs.

• DM occurring in adulthood, especially in the elderly, should be considered as a possible paraneoplastic manifestation (much higher in Dermatomyositis, age > 40, and men). 

  • GI adenocarcinoma, SCLC, NSCLC, ovarian cancer.

  • In China the association of DM in 90% of cases is with nasopharyngeal carcinoma. 

  • Cutaneous vasculitis in adult-onset DM may be a marker for underlying malignancy.   

• Dysphagia occurs in ~30% of cases probably due to the involvement of oropharyngeal and esophageal muscles.  

• Speech, chewing, and swallowing difficulties can be due to the involvement of the masseter muscle.

• Muscle stretch reflexes are normal until a severe degree of weakness has developed.

• Rash is characteristic and most often precede the muscle syndrome, or may evolve together over period of 3 weeks or less.  It sometimes occurs long after muscle weakness leading to erroneous diagnosis of PM.

  • The rash generally occurs in photosensitive areas and is erythematous, edematous, and occasionally pruritic.  

  • A pathognomonic heliotrope (or violaceous discoloration) rash often involves the upper eyelids with or without periorbital edema. 

  • The cutaneous manifestations of the rash are characteristically seen over the extensor surfaces of the joints (metacarpophalangeal, proximal and dsital interphalangeal joints, on elbows and knees (Gottron sign).  

  • It may be raised papules or plaques (Gottron papules or plaques), on the elbows and knees.

  • Anterior chest (in a V sign), back and shoulders (in a “shawl Itching is bothersome and worsens when exposed to sunlight. 

    • V sign over sun-exposed areas of neck and upper shoulders

    • Shawl sign over sun-exposed areas of shoulders and upper arms - photosensitivity

  • A rough, cracking appearance of the skin of the fingertips may develop (most prominent on the lateral aspects of the index finger and thumb), known as mechanic’s hands. 

  • Telangiectasias, manifested by dilated capillary loops at the nailbeds (periungual abnormalities) with irregular thickened and distorted cuticles can be seen.

  • Poikiloderma, characterized by areas of hyperpigmentation and hypopigmentation, particularly over the upper back and extensor surfaces of the extremities, may be seen when active skin lesions in dermatomyositis resolve.

  • Itching and scaling lesions may develop on the scalp, resulting in alopecia.  

  • Calcium deposits within the skin (calcinosis cutis), may occur in juvenile-onset dermatomyositis but can also be found in adult dermatomyositis, albeit less commonly.

  • Extramuscular manifestations in dermatomyositis include involvement of cardiac, pulmonary, gastrointestinal, and joint systems, as well as malignancy.

  • Cardiac involvement can occur and has been described.  Symptoms, cardiac arrhythmias, or ejection fraction defects may be seen on ECGs and echocardiograms. Pericarditis, myocarditis, and congestive heart failure, while rare, can be lethal because of cardiac muscle involvement in dermatomyositis.

• DM may be difficult to distinguish from systemic lupus erythematosus with muscle involvement. 

• Cancer incidence increases at a range of between 6% and 45% among patients with adult dermatomyositis, but not juvenile dermatomyositis.

• Dyspnea and nonproductive cough are the clinical manifestations of interstitial lung disease, which can be a severe complication and the leading cause of death in patients with dermatomyositis—aspiration pneumonia from the weakness of the pharyngeal and upper esophageal muscles and ILD.  The frequency of ILD varies, ranging from 5-47% in the different series, and tends to increase with the duration of the muscle disease, overall frequency is close to 9%.  The symptoms of ILD may precede the muscle and skin manifestations or may occur later, as the disease progresses.  They may present with acute fever, non-productive cough, dyspnea, hypoxemia, and lung infiltrates, more chronically with dyspnea and interstitial fibrosis.  Chest imaging may reveal a diffuse reticulonodular pattern or a diffuse alveolar pattern with a ground-glass appearance seen in more severe pulmonary involvement.  

• Pathological studies of open lung biopsies of patients with ILD revealed three histological patterns: bronchiolitis obliterans with organizing pneumonia (BOOP), interstitial pneumonia,  or diffuse alveolar damage.  Those with BOOP have the best prognosis, and those with diffuse alveolar damage the worst.  

• ILD is present in 50% of the Jo-1-positive and in 13% of the Jo-1-negative patients.  

• It is of special interest to note that ILD can also occur in RA, SLE, progressive systemic sclerosis, MCTD, Sjogren's syndrome, and ankylosing spondylitis.

• Pulmonary function tests reveal a restrictive defect with a reduced diffusing capacity of the lungs for carbon monoxide (DLCO).

• Skeletal and smooth muscle involvement of the gastrointestinal tract in dermatomyositis can lead to dysphagia, impaired gastric motility, and aspiration pneumonia.  Vasculopathy of the gastrointestinal tract, a serious complication seen more commonly in juvenile dermatomyositis than in adult-onset dermatomyositis, can result in ulcers, perforations, and even gastrointestinal hemorrhages.

• Large-joint and small-joint arthralgias with or without an underlying arthritis can be a common symptom.  

• An increased incidence of malignancy is noted in adult-onset dermatomyositis patients, especially based on the autoantibody subtype.

• Poor prognostic indications in PM and DM: Malignancy, older age, cardiac disease, ILD, respiratory muscle weakness, dysphagia, acute onset, fever, high ESR, and late or inadequate therapy.  

Muscle biopsy is the definitive diagnostic test for DM. 

• Myopathologic features of DM are the most characteristic and reflect the primary involvement of microcirculation mediated by humoral processes with secondary ischemic changes of muscle fibers.

• Myofiber alterations include

  • Perifascicular atrophy that is preceded by local re-expression of MHC class 1 antigens.  MHC1 stain

  • Ischemic punched-out vacuoles that occur subsequent to focal myosin loss

  • Microinfarcts consisting of foci of contiguous necrotic or regenerating fibers

• Microvascular changes include

  • Early capillary deposition of the complement C5b-9 membrane attack complex (MAC).

  • Destruction of endothelial cells (free basement membranes), with focal loss of capillaries predominating in perifascicular areas

  • Endothelial hyperplasia with detection of tubuloreticular inclusions (interferon-gamma).

  • MxA stain

• Damage to the capillaries with capillary dropout may cause ischemia with subsequent atrophy and may be an explanation for the perifascicular atrophy pattern seen in dermatomyositis muscle biopsies.  Other histologic findings prominent in the perifascicular region include internalized nuclei, fiber necrosis, regeneration, basophilia, increased oxidative enzyme reactivity, endomysial fibrosis, and major histocompatibility complex class-1 upregulation.

• Inflammatory infiltrates include 

  • Septal perivascular infiltrates (without fibrinoid necrosis) and endomysial infiltrates predominating in peri fascicular areas

  • Mixture of mononuclear cells including B cells, plasmacytoid dendritic cells,T cells with CD4+ > CD8+, and macrophages

  • No CD8+ lymphocytic invasion of nonnecrotic myofibers.

    • Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialized in secreting high levels of type I interferons. pDCs play a crucial role in antiviral immunity and have been implicated in the initiation and development of many autoimmune and inflammatory diseases.  

• The combination of several immunogenetic risk factors, including class-2 human leukocyte antigen (HLA) alleles - HLA-B8 antigen (association with childhood DM and adult PM) and HLA-DR3, and environmental exposures, have been implicated in the pathogenesis of dermatomyositis.   Childhood DM is also associated with HLA-DQA1 allele DQA1*050 and non DR3 haplotypes.   HLA-B7 and HLA-DRw6 in blacks with PM.  HLA-B14 in adult DM associated with another connective tissue disease.  

• Interferon overproduction has been a proposed mechanism of the pathology seen in dermatomyositis because dermatomyositis muscle has been shown to contain abundant interferon-secreting plasmacytoid dendritic cells.  Additionally, interferon-inducible genes are highly upregulated in dermatomyositis, and the gene expression in the blood correlates with dermatomyositis disease activity; but the mechanism of interferon overproduction leading to the loss of capillaries and perifascicular atrophy still remains unclear.

• Interstitial lung disease occurs in 5% to 47% of patients but the overall frequency is probably close to 9%.  The symptoms of ILD may precede the muscle and skin manifestation in dermatomyositis especially anti-Jo positive (anti-synthetase ab) or may occur later as the disease progresses.  The pulmonary complications of polymyositis are similar.  Fever, nonproductive cough, dyspnea, hypoxemia, and lung infiltrates occur and more chronically, with dyspnea and interstitial fibrosis.  

  • Methotrexate should be avoided if patient have ILD and are anti-Jo positive as this medication is toxic to the lungs.

• Check for MG coexisting with DM (AChR-abs).

Electrodiagnostic Studies in Myositis (DM).

In patients with muscle weakness, electrodiagnostic studies are useful in confirming a myopathic process and ruling out neurogenic conditions with a predilection for proximal muscle weakness (including chronic inflammatory demyelinating polyradiculoneuropathy, spinal muscular atrophy, or other motor neuron disorders).  In patients with myositis, sensory and motor nerve conduction studies are typically normal; however, low-amplitude motor nerve responses can be seen when weakness in myositis is severe and diffuse.  Needle EMG may show abnormal spontaneous activity (fibrillation potentials, positive sharp waves) and short-duration, low-amplitude motor unit potentials with an early recruitment pattern consistent with a myopathic process with muscle membrane irritability.

Polymyositis

It is a HLA-restricted, antigen-specific, cell-mediated immune response directed against muscle fibers.  

Historically, polymyositis has been characterized by a subacute onset of proximal muscle weakness, CK elevation, myopathic EMG, and endomysial inflammation with CD8+ T cell infiltrates seen on muscle biopsy.  It has been increasingly recognized that polymyositis is a rare entity because many patients who were initially diagnosed with polymyositis are subsequently diagnosed with inclusion body myositis, antisynthetase syndrome without the rash, or an immune-mediated necrotizing myopathy based on further evaluation of characteristic clinical features, autoantibodies, and histopathology findings.  The diagnosis of polymyositis is seen now as a diagnosis of exclusion and patients should be followed closely to assess for the development of clinical findings that may indicate alternative diagnoses.

Although polymyositis (PM) is still a part of the 2017 EULAR/ACR classification of idiopathic inflammatory myopathies, it is now thought to be rare.  Using newer criteria based on clinical presentation, histopathology and the presence of autoantibodies, many cases originally diagnosed as PM are now being reclassified as NAM  (necrotozing autoimmune myopathy), antisynthetase syndrome or overlap myositis 

• Clinical features:

  • Inclusion criteria

    • Onset usually >18 years (post puberty)

    • Subacute or insidious onset

    • Pattern of weakness: symmetric proximal > distal weakness

  • Exclusion criteria

    • Clinical features of sIBM

      • Asymmetric weakness, wrist/finger flexors same or worse than deltoids

      • Knee extensors and/or ankle dorsiflexors same or worse than hip flexors.

      • Ocular weakness, isolated dysarthria, neck extensor > neck flexor weakness

  • Exposure to myotoxic drugs, active endocrinopathy (hyper- or hypothyroid and hyperparathyroid), amyloidosis, family history of muscular dystrophy or proximal motor neuropathies (e.g., SMA)

• Serum CK level must be elevated

• Other lab criteria (one of three): EMG criteria, skeletal muscle MRI, or presence of myositis specific antibodies (MSA)

  • EMG

    • Inclusion criteria

      • Increased insertional and spontaneous activity in the form fibrillation potentials, positive sharp waves, or CRD

      • Morphometric analysis reveals the presence of short-duration, small amplitude, polyphasic MUAPs

    • Exclusion criteria

      • Prominent myotonic discharges that would suggest proximal myotonic dystrophy or other channelopathy

      • Morphometric analysis reveals predominantly long-duration, large-amplitudes MUAPs

      • Decreased recruitment pattern of MUAPs.

  • Skeletal muscle MRI shows diffuse or patchy increased signal (edema) within muscle tissue on STIR images

  • Myositis-specific antibodies are detected in serum.

• Muscle biopsy:

  • Definite PM requires endomysial inflammatory cell infiltrates (CD8+ T cells) and macrophages surrounding and invading non-necrotic muscle fibers that express MHC-1 antigen.

  • Probable PM

    • Endomysial CD8+ T cells surrounding but no definite invasions of non-necrotic muscle fibers OR

    • Ubiquitous MHC-1 expression

    • Also requires exclusion of "necrotizing myopathies" and dystrophies with immunopathology/EM and clinical history/examination.

  • Exclusion criteria

    • Rimmed vacuoles, ragged red fibers, cytochrome oxidase-negative fibers that would suggest IBM

    • Perifascicular atrophy, deposition of MAC on small blood vessels, reduced capillary density, tubuloreticular inclusions in endothelial cells, or pipestem capillaries that would suggest dermatomyositis (DM) or another type of humorally mediated microangiopathy.

    • Dystrophic features of MAC deposition on non-necrotic muscle fibers that would suggest a muscular dystrophy

  • Dyferlinopathy and FSHD is in the DDx of PM histopathology. 25% of dysferlinopathy patients are initially misdiagnosed with PM as inflammatory infiltration can be prominent in muscle biopsy.

• Definite PM

  • All clinical criteria

  • Elevated serum CK

  • Muscle biopsy with features of histological features of definite PM

• Probable PM

  • All clinical criteria

  • Elevated CK

  • Other lab criteria (one of three)

  • Muscle biopsy with features of histological features of probable PM

• Cardiac involvement is the most common cause of death in polymyositis, and it can be the presenting feature.  Cardiac involvement usually is not reversible, but early detection may improve the prognosis.  

Bohan and Peter Criteria for Diagnosis of DM and PM

• Proximal muscle weakness, usually symmetrical

• Elevated serum muscle enzymes (CK, aldolase)

• Electromyographic abnormalities

  • Common – myopathic potential (low amplitude, short duration and polyphasic action potentials)

  • Characteristic triad – myopathic potentials, fibrillations, positive sharp waves, increased insertional activity, complex repetitive discharges

• Muscle biopsy findings typical of PM or DM – necrosis, phagocytosis, regeneration, inflammation

• Dermatological features of DM, Gottron’s sign or papules, or heliotrope rash

Definite diagnosis requires four criteria with rash for DM and without rash for PM

Probable diagnosis requires three criteria with rash for DM and without rash for PM

Bohan and Peter criteria tends to overdiagnose PM.

Autoantibodies associated with inflammatory myopathies:

Necrotizing autoimmune myopathy is an idiopathic inflammatory myopathy, characterized by myofiber necrosis and is often associated with myositis specific autoantibodies to signal recognition particle (SRP) and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the latter of which usually occurs in the setting of statin use.

ANA is a screening method to detect anti-nuclear antibodies.  It involves monitoring the binding of antibodies to the nuclei of Hep-2 (human epithelial tumor cell line) using an indirect immunofluorescence method.  The pattern of staining formed can provide clues about the type of anti-nuclear antibody present.  For instance, a discrete speckled pattern may suggest the presence of anti-centromere antibodies associated with CREST syndrome, whereas a fine speckled pattern may indicate the presence of antibodies against anti U1 RNP which is seen in inflammatory myopathy associated with MCTD.  

Myositis-Specific Antibodies:  

Found only in patients with myositis.  The MSAs have been shown to be highly specific for patients with PM, DM, anti-synthetase syndrome, necrotizing myositis, and overlap syndromes.

• Anti-Jo-1

• Anti-PL-12

• Anti-PL-7

• Anti-OJ

• Anti-EJ

• Anti-SRP

• Anti-Mi-2

• Anti-TIF-1gamma/TIF-1alpha  (formerly P155/140 kD)

• Anti-MDA5 (formerly part of P140 kD)

• Anti-MDA5 (formerly part of P140 kD), a.k.a CADM-140

• Anti-NXP-2 (MJ) (formerly part of P140 kD)

• anti-HMCR-ab

• anti-SRP

Myositis-Associated Antibodies

• Anti-PM/Scl: Found in 10% of IIM, 25% of scleroderma/myositis overlap and 2% of SSc; associated with myositis, arthritis, Raynaud's, SSc cutaneous changes and ILD.

• Anti-Ku: Found in about 20% of IIM; associated with overlap syndromes such as PM/SSc (most common), SLE/PM and other autoimmune disorders such as PM, SS, SSc, SLE, UCTD, MCTD, RA; common clinical features include arthralgias/arthritis, myositis, Raynaud's, esophageal dysmotility and ILD.

• Anti-SS-A (Ro52) 52 kD, IgG: Reported in a variety of autoimmune diseases such as IIM, SLE, SS, SSc, PBC, AIH, MCTD, and other overlap syndromes. Found in about 30% of IIM; 27% of  Anti-MDA5 positive patients; 40-58% of Anti-JO-1 positive patients.  Highly associated with ILD. May be paraneoplastic.

• Anti-U1 RNP:  10-15% of IIM; highly associated with MCTD.

• Anti-U2 RNP: <5% of IIM; scleroderma/myositis overlap syndrome

• Anti-Fibrillarin U3 RNP: 15% of IIM, mostly found in scleroderma/myositis overlap. Found in 4-10% of Diffuse SSc, <2% in Limited SSc; associated with isolated PAH,  myositis, cardiac & renal involvement. More prevalent in African-Americans.

Several myositis-associated antibodies that are nonspecific and seen in immune-mediated inflammatory myopathies and other connective tissue diseases have been identified, including antibodies to Ro52/TRIM21, PMScl, ribonucleoprotein complex (RNP; U1 RNP, U2 RNP, U4/U6 RNP, and U5 RNP), and Ku. The most common myositis-associated antibodies are anti-Ro52 antibodies, which are nonspecific and have been detected in approximately 25% of patients with all types of myositis.  Anti-PMScl antibodies (anti PM-1) have been observed in patients with myositis/systemic sclerosis overlap syndrome and have been associated with lung and esophageal involvement;  association with DR3, and DQw2 allele.  Anti-Ku antibodies have been identified in up to 55% of cases of myositis/systemic sclerosis overlap syndrome with frequent joint involvement, Raynaud syndrome, and a greater risk of interstitial lung disease.   Anti-U1 RNP antibodies have been described in patients with features of myositis, scleroderma, systemic lupus erythematosus, and glomerulonephritis.

Anti-Ro/SSA antibody, mostly directed against the Ro52 subunit, is the most prevalent MAA in myositis, found in more than 30 % of patients, frequently concomitant with anti-ARS antibodies or other MAA.  It has been recently reported that anti-Ro52 antibody could have a prognostic value in anti-Jo-1 positive patients, being associated with a higher risk of severe ILD, myositis, joint involvement, and cancer compared with anti-Jo1-positive patients without anti-Ro52 antibodies.  In addition, anti-Ro/SSA and/or anti-La/SSB antibodies are frequently encountered in PDM/Sjögren (SS) overlap syndrome, which is reported in 5.3 % of PDM patients, while myositis in primary SS is variably reported in 1–14 % of cases  

https://pubmed.ncbi.nlm.nih.gov/20188618/

Dermatomyositis specific Myositis-specific autoantibodies

• Anti-Mi-2:  10-20% of adult DM and <10% of JDM.  Classic DM features: mild to moderate weakness with shawl rash, heliotrope rash, V-sign and Gottron's papules (classic cutaneous features); good response to therapy and lower incidence of cancer compared to other DM.  Good prognosis.

  • Approximately 15% of patients have anti-Mi-2 autoantibodies, which are associated with especially severe initial skin manifestations; fortunately, these patients respond well to treatment with glucocorticoids.

  • DR7, DR253, and DQA1*0201 association.  

• Anti-MDA5 (formerly part of P140 kD), a.k.a CADM-140: Features consist of absent or mild muscle symptoms (CADM); associated with rapidly progressive ILD; specific mucocutaneous features of skin ulcerations and papules; higher risk of oral ulcerations and arthritis. ILD, palmar lesions, rash > myopathy

  • Patients with anti-melanoma differentiation associated protein 5 (anti-MDA5) autoantibodies often have palmar skin lesions and may develop a severe cardiopulmonary syndrome.  Unique cutaneous manifestations including ulcerations, tender palmar papules, and oral pain.

  • Autoantibodies against MDA-5 are reported in higher frequency in Asian patients with less muscle involvement (clinically amyopathic dermatomyositis) yet rapidly progressive interstitial lung disease and a poor prognosis.  Severe skin lesions, including skin ulcerations over interphalangeal joints, tender palmar papules, and oral ulcers, have also been described in patients with dermatomyositis who are anti–MDA-5–positive.

• Anti-TIF1gamma: 15-38% of adult DM and 20-30% in JDM. Highly associated with malignancy which is found in 50-75% of positive adults patients; 89% specificity and 78% sensitivity for diagnosing cancer-associated DM; no cancer association in children.

  • The anti–TIF-1γ antibody in dermatomyositis is highly associated with malignancy (in adult dermatomyositis but not in juvenile dermatomyositis) and severe skin manifestations, including diffuse photoerythema and “dusky red face” and unique characteristic cutaneous lesions of hypopigmented and telangiectatic (“red on white”) patches, distinctive palmar hyperkeratotic papules, psoriasis like lesions, and hypopigmented and telangiectatic (red on white) patches.

  • In terms of treatment, it has been recognized that the treatment for malignancies should be prioritized.  Corticosteroids are effective in TIF-1γ DM, but some cases show steroid resistance.  In these cases, a variety of non-steroid drugs, including methotrexate, antimalarial drugs, mycophenolate, AZT, and CyA, might be effective. The efficacy of immunoglobulins, rituximab, and tumor necrosis factor-α inhibitors has been described for patients with multiple drug resistance.  In our study, patients whose cancer was controlled showed a relatively good response in terms of dysphagia and cutaneous manifestations.  However, many patients required immunosuppressive therapy to control disease activity, especially those with cutaneous lesions and dysphagia.  One patient showed multiple drug resistance, but IVIG was effective.  We considered IVIG treatment when patients with TIF-1γ DM showed drug resistance. 

• Anti-NXP-2 (MJ) (formerly part of P140 kD): 1.6-30% of adult DM and 18-25% of JDM.  In JDM is associated with cutaneous calcinosis cutis.  In adult DM it is significantly associated with the presence of cancer (cancer found in 13.6% of Anti-NXP-2 positive DM patients).  

• Association of Dermatomyositis Sine Dermatitis With Anti–Nuclear Matrix Protein 2 Autoantibodies - PMC 

• Anti-SAE: rapidly progressive ILD, rash > myopathy

IMNM  (NAM) 

• Immune mediated necrotizing myopathy or necrotizing autoimmune myopathy or NAM , is a rare subtype of immune mediated myopathy (IM).  It typically presents with subacute progressive proximal weakness and marked elevated CK levels during adult-hood.  However, chronic forms reported as childhood onset weakness, mimicking muscular dystrophy has been increasingly recognized.  

• Rare extramuscular involvement and histopathologically there is myofiber necrosis with a lack of inflammatory cell infiltrates.  The presence of necrotic fibers and no or minimal lymphocytic inflammation are considered pathologically hallmarks of IM, but these findings are nonspecific as they can be seen in other myopathies.  

• Anti-SRP: SRP antibodies are present in approximately 27%–52% of cases of IMNM. There is a female predominance, with 61%–78% of patients being female. The usual age at disease onset is in the fourth to seventh decade, but rare pediatric cases have been described.  Compared to patients with HMGCR IMNM, patients with SRP IMNM typically present with more severe weakness and atrophy, and more commonly have dysphagia, although CK levels may not be substantially higher.  In one study, atrophy and fatty replacement of muscles on MRI were more extensive in SRP IMNM than HMGCR IMNM. Furthermore, SRP IMNM may be accompanied by cardiopulmonary manifestations. A subset of patients (13%–45%) develop interstitial lung disease, though symptoms are typically mild. Triggers for SRP IMNM are not known. In contrast to HMGCR and seronegative IMNM, SRP IMNM is not associated with cancer.  We typically order SRP antibodies in the evaluation of patients presenting with progressive, proximal predominant weakness and elevated CK, as we do for HMGCR antibodies. We also order the antibodies in patients that phenotypically look like they have limb girdle muscular dystrophy but in whom no genetic mutations are identified. Prognosis in SRP IMNM is generally poor. Longitudinal studies showed that even after at least 2 years of immunotherapy, only about one third to one half of patients returned to full or near-full strength, and many still had elevated CK.40,41 In one study, 12% continued to have progressive disease despite immunotherapy. Younger age was associated with a worse prognosis. Our approach to management is similar to that outlined in the 224th European Neuromuscular Centre consensus statement.  Although cardiopulmonary involvement may occur as mentioned above, we do not obtain routine screening unless symptoms are pre sent. For immunotherapy, we favor early, aggressive therapy to mini mize irreversible damage and fatty replacement of muscles. Although we typically initiate oral corticosteroids at 0.75–1 mg/kg daily along with IVIG and also an immunosuppressant, most often methotrexate or mycophenolate mofetil, these treatments are often not completely effective. Thus, we promptly initiate rituximab (usually within 3 months) in patients who do not respond quickly to these therapies or even start treatment with rituximab at the outset in those with severe disease. We give rituximab 1 g IV and repeat the dose 14 days later, followed by maintenance courses of the same regimen every 6 months. Retrospective case series showed that rituximab can be effective in patients with SRP IMNM 

• Anti-HMGCR: statin-associated myopathy accounts for 2/3rds of IMNM (NAM); often associated with statin-use, however, up to one-third may be statin naïve and may have a more resistant treatment response.

• The 2017 European Neuromuscular Centre criteria for immune-mediated necrotizing myopathy describe three subtypes: anti-SRP myopathy, anti–HMGCoA reductase myopathy, and antibody-negative immune-mediated necrotizing myopathy.

  • Antibody negative IMNM

• The risk of cancer in those patients with an immune-mediated necrotizing myopathy depends on the subtype (based on antibody status).  Those with anti-–HMG-CoA reductase myopathy have been described to have a relatively weak association with cancer, whereas anti-SRPmyopathy is not associated with malignancy.  However, autoantibody-negative immune-mediated necrotizing myopathy has been associated with a relatively high risk of fmalignancy, warranting aggressive cancer screening for up to 3 years from the onset of symptoms.

• An association of the class-2 HLA-allele DRB1*08:03, DR3, DRw52, and DQA1*0301 with anti-SRP myopathy.

• DRB1*11:01 as a risk factor for anti–HMG-CoA reductase myopathy.  DRB1*11:01 has been found in 70% of patients with anti–HMG-CoA reductase antibodies, but only in 15% of the general population, and may play a role in presenting the relevant HMG-CoA reductase peptides with exposure to statins that trigger an immune response.

IBM autoantibodies

• NT5C1A/anti-Mup44: IBM (30% to 70%) of IBM patients have the NT5C1a (anti-CN1A).

Treatment Link:  

Antisynthetase syndrome

This syndrome includes the following: myositis, interstitial lung disease, inflammatory polyarthritis, Raynaud phenomenon, fevers, or hyperkeratotic lesions along the radial and palmar surfaces of the fingers, known as mechanic’s hands.  In addition to these features, some patients who are antisynthetase positive also have erythematous rashes similar or identical to those seen in patients with dermatomyositis.  Patients with antisynthetase syndrome are often referred to as having dermatomyositis or polymyositis when such rashes are present or absent, respectively.  Myocarditis (42% of patients) is seen.  ILD  is frequently associated with anti-Jo1 antibodies, The Presence of interstitial lung disease is a major prognostic factor. 

Of the antisynthetase antibodies, anti–Jo-1 (the first to be discovered and most frequent antisynthetase autoantibody) is associated with the greatest risk of developing a myositis.   Up to 90% of patients with Jo-1 antibodies have a myositis; however, the risk of developing interstitial lung disease has been reported in up to 50% of patients with anti–PL-12 antibodies, but they have no muscle involvement.

Jo-1 antibody positive shows an association with B8, DR3, DRw52, and DQA1*0501.

There is considerable clinical heterogeneity, and one or other manifestation can predominate or can be the only expression of the syndrome. Furthermore, in the same patient, the individual features can prevail at different times and may develop years after onset of the disease. Therefore, in addition to patients with myositis, it would be important to suspect antisynthetase syndrome in patients presenting with isolated lung involvement (amyopathic interstitial lung disease), as there are therapeutic implications.  Histologically, the predominant pattern of lung injury in idiopathic pulmonary fibrosis is “usual interstitial pneumonia” which does not respond to immunosuppressive therapy, and hence lung transplantation is the only therapeutic option. On the other hand, in antisynthetase syndrome, the usual pattern of lung injury is “nonspecific interstitial pneumonia,” in which immunosuppressive therapy has a role.

Results and long‐term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: An open study with thirty‐five adult patients - Cherin - 2002 - Arthritis & Rheumatism - Wiley Online Library 

Clinical Features in ASyS

Fever:  About 20% of patients have a fever at disease onset or associated with relapses. Sometimes the fever can persist until treatment of antisynthetase syndrome is started. 

Myositis:  Muscle disease is seen in more than 90% of patients with anti-Jo-1 antisynthetase syndrome. It can be subclinical (in the absence of proximal myopathy), manifested by transient creatine kinase elevation only, which may normalize after therapy is initiated. However, more commonly, patients develop profound proximal muscle weakness and sometimes muscle pain. Weakness of the striated muscles of the upper esophagus, cricopharyngeus, and hypopharynx may cause dysphagia and makes these patients susceptible to aspiration pneumonia. Diaphragmatic and intercostal muscle weakness can contribute to shortness of breath in some patients. Myocarditis has also been reported. 

Pulmonary disease: Interstitial lung disease develops in most patients with anti-Jo-1 antisynthetase syndrome, with a reported prevalence of about 90% in one series.  Patients often present with acute, subacute, or insidious onset of exertional dyspnea. Sometimes there is an intractable nonproductive cough. At the outset of antisynthetase syndrome, if the patient is profoundly weak because of myopathy or has inflammatory polyarthritis, mobility is significantly compromised, and exertional dyspnea may not be experienced. However, as the interstitial lung disease progresses, shortness of breath becomes overt, more so when the patient’s level of activity improves with treatment of myositis. Inspiratory crackles on auscultation of the lung bases or changes on chest radiography are relatively insensitive findings and can miss early interstitial lung disease. Therefore, if antisynthetase syndrome is suspected or diagnosed, a baseline pulmonary function test (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease, and the diagnosis can then be confirmed with thoracic high-resolution computed tomography 

Pulmonary hypertension:  Recent studies indicate that, similar to patients with other autoimmune rheumatic diseases, pulmonary hypertension can develop in patients with antisynthetase syndrome, with or without concomitant interstitial lung disease.  This complication occurred in the case presented here. It has been found that when pulmonary hypertension coexists with interstitial lung disease, its degree may not correlate with the severity of the latter. Additionally, pulmonary hypertension, when present, has been found to contribute independently to prognosis and survival.

Mechanic’s hands:  In about 30% of patients, the skin of the tips and margins of the fingers becomes thickened, hyperkeratotic, and fissured, the appearance of which is classically described as mechanic’s hands. It is a common manifestation of antisynthetase syndrome and is particularly prominent on the radial side of the index fingers. Biopsy of affected skin shows an interface psoriasiform dermatitis. In addition, some dermatomyositis patients with Gottron papules and a heliotrope rash have antisynthetase antibodies. 

Raynaud phenomenon:  Raynaud phenomenon develops in about 40% of patients. Some have nailfold capillary abnormalities. However, persistent or severe digital ischemia leading to digital ulceration or infarction is uncommon.

Inflammatory arthritis:  Arthralgias and arthritis are common (50%), the most common form being a symmetric polyarthritis of the small joints of the hands and feet. It is typically nonerosive but can sometimes be erosive and destructive.  Because inflammatory arthritis mimics rheumatoid arthritis, antisynthetase syndrome should be considered in rheumatoid factor-negative patients presenting with polyarthritis. 

Antisynthetase autoantibodies:

Myositis specific antibodies seen in 30-40% of adult IIM and 1-3% of JM.   Myositis, interstitial lung disease, mechanic’s hands, arthritis, and Raynaud phenomenon are associated with all types of antisynthetase autoantibodies.

Synthetases play a central role in protein synthesis by catalyzing the acetylation of tRNAs.  Aminoacyl transfer RNA (tRNA) synthetases are a group of enzymes that catalyze the binding of a specific amino acid to their cognate tRNA; currently eight antisynthetase myositis-specific autoantibodies (anti–Jo-1, anti–PL-7, anti–PL-12, anti-EJ, anti-OJ, anti-KS, anti-Zo, anti-YRS, and anti-Wa) directed against different tRNA synthetases have been recognized.  

The propensity of organ involvement in antisynthetase syndrome suggests that tissue-specific changes in muscle or lung lead to the production of unique forms of target autoantigens, the aminoacyl-tRNA synthetases. There is evidence that these enzymes themselves may be nvolved in recruiting both antigen-presenting and inflammatory cells to the site of muscle or lung injury. However, the molecular pathway that initiates and propagates this autoimmune response and the specific role of the antisynthetase antibodies in the pathogenesis of this syndrome are presently unknown. 

Anti-Jo-1 antibody (anti-histidyl-tRNA synthetase) is the most common of the antibodies and also was the first one to be identified. It was named after John P, a patient with polymyositis and interstitial lung disease, in whom it was first detected in 1980. The onset of the syndrome associated with anti-Jo-1 antibody is often acute, and the myositis is usually steroid-responsive. However, not uncommonly,  severe disease can develop over time, with a tendency to relapse and with a poor long-term prognosis.

Often, anti-Ro52 SS-A antibodies are present concurrently in patients with antiJo-1 syndrome. In observational studies in patients with anti-Jo-1 antibody-associated interstitial lung disease, coexistence of antiRo52 SS-A antibody tended to predict a worse pulmonary outcome than in those with anti-Jo-1 antibody alone.

• Anti-Jo-1

  • Antigen: Histidyl-tRNA synthetase 

  • Prevalence: 25% - 30%

  • 90% with muscle involvement; 50-75% with interstitial lung disease.  May have a mild skin rash and mechanic’s hands. Arthritis and Raynaud's phenomenon.

• https://www.ccjm.org/content/ccjom/80/10/655.full.pdf 

• Anti-PL-7: 

  • Antigen: Threonyl-tRNA synthetase

  • Prevalence: 2%–5%

  • PM, DM, ILD.  Severe interstitial lung disease, may have moderate muscle involvement. Severe arthritis.

• Anti-PL-12: 

  • Antigen: Alanyl-tRNA synthetase

  • Prevalence: 2%–5%

  • 52% with muscle involvement; 90% with interstitial lung disease.  Severe interstitial lung disease, may have mild or no muscle involvement. Pulmonary HTN.  Esophageal involvement. 

• Anti-OJ

  • Antigen:  Isoleucyl-tRNA synthetase

  • Prevalence: 1%

  • ILD is seen in all patients.  Some myositis

• Anti-EJ:

  • Antigen: Glycyl-tRNA synthetase

  • Prevalence: 1%

  • ILD and dermatomyositis

• Anti-KS:

  • Antigen: Asparaginyl-tRNA synthetase

  • Prevalence: 1%

  • ILD, fever, UIP in 40% of cases. 

• Anti-Wa:

  • Antigen: Autoantibody to a 48-kDa transfer RNA-related protein 

  • Prevalence: 1%

• Anti–glycyl-transfer RNA synthetase (EJ), anti-OJ, anti-KS:  PM > DM + ILD.  High association with interstitial lung disease

• Anti-YRS:

  • Antigen: Tyrosyl-tRNA synthetase 

  • Prevalence;  NA

  • Rash and arthritis

• Anti-Zo:

  • Antigen: Phenylalanyl-tRNA synthetase 

  • Prevalence: NA

  • ILD and myositis.  NSIP on biopsy, Raynaud's phenomenon, and arthrlagia. 

Clinical Vignette ASyS.

A 66-year-old man was initially seen in March 2004 clinic with a 5-month history of polyarthritis (affecting the finger joints, wrists, and knees) and several hours of morning stiffness. He also had significant proximal muscle weakness, progressive exertional dyspnea, and a nonproductive cough. There was no history of fever, chills, rash, dysphagia, or sicca symptoms. 

Findings on initial tests: • 

• CPK: 2200 U/L

• ANA: positive

• Anti-Jo-1 ab: positive

• EMG: disfugurative myopathy

• Left quadriceps muscle biopsy:  Revealed scattered degenerating and regenerating muscle fibers but no evidence of endomysial inflammation. 

• PFT: FVC: 80% of predicted, DLCO: 67% of predicted. 

• High-resolution computed tomography revealed evidence of interstitial lung disease, characterized by bilateral patchy groundglass opacities suggestive of active alveolitis, most extensive at the lung bases.

• Bronchoalveolar lavage indicated alveolitis, and transbronchial biopsy revealed pathologic changes consistent with cryptogenic organizing pneumonia. All cultures were negative. 

This constellation of clinical manifestations, including myositis, interstitial lung disease, and polyarthritis, along with positive anti-Jo-1 antibody, confirmed the diagnosis of antisynthetase syndrome.

In June 2004, for his interstitial lung disease, he was started on daily oral cyclophosphamide along with high-dose foral prednisone. Three months later the skin of the tips and radial margins of his fingers started thickening and cracking, the appearance of which is classically described as “mechanic’s hands,” a well-described manifestation of antisynthetase syndrome.

Cyclophosphamide was continued for about a year. Subsequently, along with prednisone, he sequentially received various other immunosuppressive medications (tacrolimus, mycophenolate mofetil, and rituximab) over the next few years in an attempt to control his progressive interstitial lung disease. Methotrexate was not tried due to ILD.  All of these agents were only partially and temporarily effective. Ultimately, despite all of these therapies, as his interstitial lung disease progressed, he needed supplemental oxygen and enrollment in a pulmonary rehabilitation program.

In March 2010, he was admitted with worsening dyspnea and significant peripheral edema and was found to have severe pulmonary arterial hypertension. He was started on bosentan. Eight months later sildenafil was added for progressive pulmonary arterial hypertension. However, his oxygenation status continued to decline.

In July 2011, he presented with chills, increasing shortness of breath, and a mild productive cough. As he was severely hypoxic, he was admitted to the intensive care unit and started on mechanical ventilation and broad spectrum antibiotics. Despite escalation of oxygen therapy, his respiratory status rapidly deteriorated, and he developed hypotension requiring vasopressors. He ultimately died of cardiac arrest secondary to respiratory failure.

Association of ASyS with malignancy:

Traditional teaching has been that antisynthetase antibody is protective against an underlying malignancy. However, several recently published case studies have reported various malignancies occurring within 6 to 12 months of the diagnosis of antisynthetase syndrome. The debate as to whether these are chance associations or causal (a paraneoplastic phenomenon) has not been resolved at this time. It is now recommended that patients with antisynthetase syndrome be screened for malignancies as appropriate for the patient’s age and sex. Screening should include a careful history and physical examination, complete blood cell count, comprehensive metabolic panel, chest radiography, mammography, and a gynecologic examination for women. If abnormalities are found, a more thorough evaluation for cancer is appropriate.

Diagnosis of ASyS:

Muscle enzymes (creatine kinase and aldolase) are often elevated. Serum creatine kinase  levels can range between 5 to 50 times the upper limit of normal. In an established case, creatine kinase levels along with careful manual muscle strength testing may help evaluate myositis activity. However, in chronic and advanced disease, creatine kinase may be within the normal range despite active myositis, partly because of extensive loss of muscle mass. In myositis, it may be prudent to check both creatine kinase and aldolase; sometimes only serum aldolase level rises, when immune-mediated injury predominantly affects the early regenerative myocytes.

If a myositis patient is also found to have interstitial lung disease or develops mechanic’s hands, the likely diagnosis is antisynthetase syndrome, which can be confirmed by serologic testing for antisynthetase antibodies. Interstitial lung disease in antisynthetase syndrome is often from “nonspecific interstitial pneumonitis”; therefore, medications tested and proven effective for this condition should be approved and reimbursed by payers.

Electromyography not only helps differentiate between myopathic and neuropathic weakness, but it may also support the diagnosis of “inflammatory” myopathy as suggested by prominent muscle membrane irritability (fibrillations, positive sharp waves) and abnormal motor unit action potentials (spontaneous activity showing small, short, polyphasic potentials and early recruitment). However, the findings can be nonspecific, and may even be normal in 10% to 15% of patients. Electromyographic abnormalities are most consistently observed in weak proximal muscles, and electromyography is also helpful in selecting a muscle for biopsy. Although no single electromyographic pattern is considered diagnostic for inflammatory myopathy, abnormalities are present in around 90% of patients.

Magnetic resonance imaging Magnetic resonance imaging may show increased signal intensity in the affected muscles and surrounding tissues, Because it lacks sensitivity and specificity, magnetic resonance imaging is not helpful in diagnosing the disease. However, in the correct clinical setting, it may be used to guide muscle biopsy, and it can help in monitoring the disease progress

Pulmonary function testing in ASyS.

If antisynthetase syndrome is suspected or diagnosed, baseline pulmonary function testing (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease (reduced forced vital capacity and carbon monoxide diffusion capacity), and the diagnosis will be substantiated on thoracic high-resolution computed tomography. Respiratory muscle weakness can be detected with upright and supine spirometry. Weakness of these muscles contributes to shortness of breath, and patients may need ventilatory support. 

Thoracic high-resolution  computed tomography

Different patterns of lung injury can be seen in antisynthetase syndrome. Diffuse groundglass opacification may suggest a nonspecific interstitial pneumonitis pattern, which is the most common form of interstitial lung disease, whereas coarse reticulation or honeycombing correlates with a usual interstitial pneumonitis pattern. Patchy consolidation or air-space disease can occur if cryptogenic organizing pneumonia is the predominant pattern of lung injury.

Lung histopathology 

If necessary, a surgical lung biopsy is needed to document the pathologic pattern of injury, including the amount of fibrosis in the lung. Historically, in idiopathic inflammatory myopathy patients in general, this has taken the form of usual interstitial pneumonia, organizing pneumonia, or diffuse alveolar damage. With the emergence of the definition of nonspecific interstitial pneumonitis and fibrosis as a documented and accepted pattern, more studies have found this to be the most common pattern of lung injury. It is characterized by diffuse involvement of the lung by an interstitial chronic inflammatory infiltrate, a cellular type of nonspecific interstitial pneumonitis that progresses in a uniform pattern to a fibrotic type. This form of fibrosis rarely results in significant remodeling, so-called honeycomb changes. In addition, anti-Jo-1 antibody patients may also have an increased incidence of acute lung injury, including acute diffuse alveolar damage that is often superimposed on the underlying chronic lung disease. In patients with pulmonary hypertension, histopathologic studies of the muscular pulmonary arteries often show moderate intimal fibroplasia, suggesting that a pulmonary arteriopathy with intimal thickening and luminal narrowing develops in some of these patients, independent of chronic hypoxic pulmonary vasoconstriction or vascular obstruction due to its entrapment within fibrotic lung tissue.

Swallowing evaluation 

A comprehensive swallowing evaluation by a speech therapist may be necessary for evaluation of dysphagia (from oropharyngeal and striated esophageal muscle weakness) and determination of aspiration risk.

Muscle histopathology in ASyS. 

Muscle biopsy, though often helpful, is not always diagnostic, and antisynthetase syndrome should still be suspected in the right clinical context, even in the absence of characteristic pathologic changes. Biopsy of sites recently studied by electromyography should be avoided, and if the patient has undergone electromyography recently, the contralateral side should be selected for biopsy.

Reports of histopathologic findings in muscle biopsies in patients with antisynthetase syndrome document inflammatory myopathic feature. In a series of patients with anti-Jo-1 syndrome, inflammation was noted in all cases, predominantly perimysial in location, with occasional endomysial and perivascular inflammation. Many of the inflammatory cells seen were macrophages and lymphocytes, in contrast to the predominantly lymphocytic infiltrates described in classic polymyositis and dermatomyositis. Perifascicular atrophy, similar to what is seen in dermatomyositis, was encountered; however, vascular changes, typical of dermatomyositis, were absent. Occasional degenerating and regenerating muscle fibers were also observed in most cases. Additionally, a characteristic perimysial connective tissue fragmentation was described, a feature less often seen in classic polymyositis and dermatomyositis

Distinct histopathology features described in muscle biopsies from patients with anti–Jo-1 antibodies include necrosis in the perifascicular region, fragmentation of the perimysium, and increased perimysial alkaline phosphatase activity.  On electron microscopy, aggregation of nuclear actin is seen, a unique feature that is not seen in other inflammatory myopathies.

Treatment of ASyS:

• Glucocorticoids are mainstay of treatment.

  • Standard practice is to initiate treatment with high doses for the first 4 to 6 weeks to achieve disease control, followed by a slow taper over the next 9 to 12 months to the lowest effective dose to maintain remission. 

  • If the patient is profoundly weak, especially with respiratory muscle weakness or significant dysphagia and aspiration risk, hospital admission for intravenous methylprednisolone 1,000 mg daily for 3 to 5 days may be necessary. Otherwise, oral prednisone 1 mg/kg/day would be the usual starting dose.

  • If the patient’s muscle strength initially improves and then declines weeks to months later despite adequate therapy, glucocorticoidinduced myopathy should be suspected, especially if the muscle enzymes are within the reference range. This is more likely to occur if high-dose prednisone is continued for more than 6 to 8 weeks.

  • Improvement in muscle strength, which can take several weeks to several months, is a more reliable indicator of response to therapy than the serum creatine kinase level, which may take much longer to normalize.

  • Relying on normalization of the creatine kinase level alone may lead to unnecessary prolongation of high-dose glucocorticoid therapy. It may take several months for the muscle enzymes to normalize, and there is usually a time lag between normalization of muscle enzymes and complete recovery of muscle strength. 

  • Physical therapy and rehabilitation should begin early if the patient is  profoundly weak  

  • Long-term use of high-dose prednisone leads to glucocorticoid-induced osteoporosis. Therefore, patients should receive osteoporosis prophylaxis including antiresorptive therapy with a bisphosphonate. 

  • In addition, prophylaxis against Pneumocystis jirovecii is indicated for patients treated with high-dose glucocorticoids.

• Azathioprine or methotrexate are often required as steroid-sparing agents and also to achieve disease control.

  • Addition of such agents from the outset is particularly necessary in patients with profound muscle weakness or those who have concomitant symptomatic interstitial lung disease.

  • No randomized controlled trial comparing azathioprine and methotrexate has been conducted to date. Therefore, the choice is based on patient preference, presence of coexisting interstitial lung disease or liver disease, commitment to limit alcohol consumption, and thiopurine methyltransferase status. Most patients need prolonged therapy.

  • Avoid methotrexate in anti-Jo1 due to ILD.

  • In a randomized clinical trial, concomitant therapy with prednisone and azathioprine resulted in better functional outcomes and a significantly lower prednisone dose requirement for maintenance therapy at 3 years than with prednisone alone. Although no such randomized study has been conducted using methotrexate, several retrospective studies have demonstrated 70% to 80% response rates, including those for whom monotherapy with glucocorticoids had failed. The combination of methotrexate and azathioprine may be beneficial in patients who previously had inadequate responses to either of these agents alone.

• Cyclophosphamide is recommended for severe pulmonary involvement associated with antisynthetase syndrome,

  • Monthly intravenous infusion of cyclophosphamide has been shown to be effective.

• Some recent studies established the role of tacrolimus in the treatment of both interstitial lung disease and myositis associated with antisynthetase syndrome.

• Cyclosporine has also been successfully used in a case of interstitial lung disease associated with anti Jo-1 syndrome.

• Rituximab, a monoclonal antibody to Blymphocyte antigen CD20, can also be used successfully in refractory disease, including refractory interstitial lung disease.

• In an open-label prospective study, polymyositis refractory to glucocorticoids and multiple conventional immunosuppressive agents responded well to high-dose intravenous immune globulin in the short term. However, the antisynthetase antibody status in this cohort was unknown; therefore, no definite conclusion could be drawn about the efficacy of intravenous immune globulin specifically in antisynthetase syndrome.[Cherin P, Pelletier S, Teixeira A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002; 46:467–474.]

General measures in ASyS

 In patients with profound muscle weakness, physical therapy and rehabilitation should begin early. The goal is to reduce further muscle wasting from disuse and prevent muscle contractures. Patients with oropharyngeal and esophageal dysmotility should be advised about aspiration precautions and may need a swallow evaluation by a speech therapist; some may need temporary parenteral hyperalimentation or J-tube insertion.

Prognosis in ASyS

If skeletal muscle involvement is the sole manifestation of antisynthetase syndrome, patients usually respond to glucocorticoids and immunosuppressive therapy and do fairly well. However, the outcome is not so promising when patients also develop interstitial lung disease, and the severity and type of lung injury usually determine the prognosis. As expected, patients with a progressive course of interstitial lung disease fare poorly, whereas those with a nonprogressive course tend to do relatively better. Older age at onset (> 60 years), presence of a malignancy, and a negative antinuclear antibody test are associated with a poor prognosis.

Inclusion body myositis (IBM)

• Inclusion body myositis is the most common myopathy with onset after 50 years (mean age of onset 61 - 66 years) of age.

• Second most common myopathy (apart from sarcopenia of aging) in patients over the age of 50 years. 

• Insidious onset of slowly progressive proximal and distal weakness

• Men > women

• Diagnostic delay typically averages 6 - 7 years after the onset of symptoms.

• CK is usually < 1000 (differentiating features from DM and PM where CK is much higher), ANA +ve in 20%.  MSA are absent.  There is a significant incidence of the HLA DR3 phenotype (*0301/0302) in IBM.  Skeletal muscle scans demonstrate atrophy and signal abnormalities in affected muscle . 

• A B cell antigen, NT5C1A to which serum autoantibodies are present is identified in 60–76% of patients with IBM.  The identification of a B-cell pathway has resulted in the first identification of an IBM autoantigen and emphasized its status as an autoimmune disease. 

• A characteristic feature of IBM muscle pathology is the presence of large numbers of clonally expanded CD8+ cytotoxic T cells infiltrating and destroying muscle  groups (patchy areas of increased signal in VL and VM with relative sparing of the rectus femoris).   Proliferation of T cells within muscle, given their expression of the proliferation marker Ki-67, denotes intramuscular T cell expansion which may be antigen-driven, though no specific T cell antigen has been identified.  The recognition that large granular lymphocyte CD8+ T-cell expansions are present in both blood and muscle provides additional biomarkers for IBM and suggests a mechanistic relationship to the neoplastic disease T-cell large granular lymphocytic leukemia.  

  • Decrease in CD4/CD8 ratio

  • Increase in blood CD8 coount

  • Lymphocytosis

  • Myofiber invading cells express CD57+ a natural killer marker on CD8+ T-cells indicate persistent T cell exposure to antigen and T cell aggressiveness. CD8+ CD57+ T cells secrete higher levels of cytokines and have higher cytotoxic potential than CD8+ T cells lacking CD57 expression.  IBM muscle contains large numbers of myofiber invading CD57+ cells and that in most patients expanded numbers of these cells could also be found in blood. 

• Antibodies directed against cytosolic 5'-nucleotidase 1A (NT5C1A antibody) is reported in 37% to 76% of patients with IBM.  These are associated with greater motor and functional disability in sIBM.  It has sensitivity of 70% and is highly specific 92% and when positive in a patient with a typical clinical phenotype of sIBM, has high diagnostic significance.  This is detected in research studies in as many as two-thirds of patients with inclusion body myositis, whereas they are much less prevalent in dermatomyositis, polymyositis, and other neuromuscular disorders.

  • 15-20% of patients with Sjogren's, lupus, and DM also have these antibodies

  • While NT5c1A can be elevated in IBM, it can also be elevated (even without a myopathy) in up to one third of patients with connective tissue disease. One needs to consider this in the presence of positive ANA and ENA.

  • anti-NT5C1A autoantibodies are also found in about 10-15% of adult DM patients and in 4-36% of adult patients with lupus or Sjogren's syndrome.[8, 9, 12] Given that they are found in myositis as well as in other autoimmune diseases, anti-NT5C1A can be defined as an adult MAA. 

  • Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis - PMC 

• The presence of slowly progressive, asymmetric, involvement of wrist and finger flexor, quadriceps (knee extensors), and later ankle dorsiflexors in a patient >50 years of age strongly suggest the diagnosis of IBM even in the absence of histological confirmation.

  • Knee extensors are weaker than hip flexors.  A preferential, but not exclusive, pattern of muscle involvement is a highly distinctive feature of IBM, involving quadriceps, finger flexors, and ankle dorsiflexors. The muscle involvement is asymmetric and focal, recognizable by clinical examination and MRI. Finger flexor weakness may be extremely focal, with complete paralysis of flexor digitorum profundus for one particular finger but good strength for other fingers.  Relative preservation of flexion at the metacarpophalangeal joints and of the adductor pollicis, allowing limited grip between the thumb and second finger, is typical.

  • Patients generally relate early symptoms to weakness of quadriceps (difficulty arising from a chair, knee buckling, falling), finger flexion weakness (grip weakness, difficulty opening jars and manipulating objects), or swallowing.  Tripping from ankle dorsiflexion weakness is a less common presenting symptoms. It can be helpful to palpate the VL and VM during knee extension to fully appreciate their involvement.  Other commonly involved muscles include biceps brachii, triceps, and wrist flexors.  The last affected muscles are hip adductors, neck extensors, and lumbricals.  Facial weakness is common but it is often underrecognized.

• Muscle atrophy and weakness are often markedly asymmetrical and may lead to an erroneous diagnosis of motor neuron disease (ALS). However, unlike amyotrophic lateral sclerosis, no significant atrophy of the hand intrinsics occurs; forearm flexors are involved; fasciculations are absent, and deep tendon reflexes are normal or reduced. The muscle groups affected early are different in IBM compared to ALS.  The progression is gradual but relentless, and disability may be severe. Myalgia is absent. 

• 40% of patients develop swallowing difficulties due to esophageal and pharyngeal muscle involvement.  This can lead to weight loss or aspiration.  In severe cases, cricopharyngeal myotomy may be beneficial.  Mild facial weakness, neck weakness usually occurs.

• Most patients have no sensory symptoms, but as many as 30% have evidence of a generalized sensory peripheral neuropathy on clinical examination and electrophysiological testing.

• Muscle stretch reflexes are normal or slightly decreased.  Patellar reflexes are lost early.

• Associated manifestations:  Unlike DM, PM, IBM is not associated with myocarditis, lung disease, or an increased risk of malignancy (Is there a link between IBM and T-cell large granular lymphocytic leukemia?).  15% of patients with IBM have an underlying autoimmune disorder such as SLE, Sjogren syndrome, scleroderma, sarcoidosis, variable immunoglobulin deficiency, or thrombocytopenia.  

Diagnostic Criteria (Griggs et al.) for Inclusion Body Myositis

• • I.  Characteristic features - inclusion criteria

    • A.  Clinical features:

      • 1.  Duration of illness >6 months

      • 2.  Age of onset > 30 years

      • 3.  Muscle weakness

      • 4.  Must predominantly affect proximal and distal muscles of the arms and legs and the patient muscle exhibit at least one of the following features:

        • a.  Finger flexor weakness

        • b.  Wrist flexor > wrist extensor weakness

        • c.  Quadriceps muscle weakness (+ or < MRC grade 4)

    • B.  Laboratory features

      • 1.  Serum CK <12 times normal

      • 2.  Muscle biopsy

        • a.  Inflammatory myopathy characterized by mononuclear cell invasion of non-necrotic fibers

        • b.  Vacuolated muscle fibers

        • c.  Either

          • i.  Intracellular amyloid deposits (must use fluorescent method of identification before amyloid excluded) or

          • ii. 15 - 1 nm tubulofilaments by EM

      • 3.  EMG must be consistent with features of inflammatory myopathy (however, long-duration potentials are commonly observed and do not exclude the diagnosis of IBM)

        • Fibrillation potentials and positive sharp waves are seen on needle EMG. Motor units shows both myopathic and neurogenic features (large).  Examination of FDP, especially 4th and 5th fingers, can be very helpful.  

    • C.  Family history:  Rarely, IBM may be observed in families.  This condition is different from hereditary inclusion boy myopathy without inflammation.  The diagnosis of familial IBM requires specific documentation of mononuclear inflammatory cells invading non-necrotic muscle fibers by muscle biopsy in addition to vacuolated muscle fibers and intracellular amyloid deposits or 15-18 nm tubulofilaments. 

  • II.  Associated disorders:  IBM occurs with a variety of other, especially immune-mediated conditions.  An associated condition does not preclude a diagnosis of IBM if the diagnostic criteria are fulfilled.

  • III.  Diagnostic criteria for IBM

    • A.  Definite IBM

      • 1.  Patient's muscle exhibit all muscle biopsy features including invasion of non-necrotic muscle fibers by mononuclear cells, vacuolated muscle fibers, and intracellular amyloid deposits or 15 -1 8 nm tubulofilaments.

      • 2.  None of the other clinical or laboratory features are mandatory if the muscle biopsy features are diagnostic.

    • B.  Possible IBM:  If the muscle biopsy shows only inflammation (invasion of non-necrotic muscle fibers by mononuclear cells) without other pathological features of IBM, then a diagnosis of possible IBM can be made if the patient exhibits the characteristic clinical (A1,2,3,4) and laboratory (B1,3) features. 

  • Rimmed vacuoles are seen in 25% - 30% of muscle biopsies.

Lloyd and Greenberg criteria require all three of the following features:

• Finger flexion OR knee extension weakness

• Endomysial inflammation

• Invasion of non-necrotic muscle fibers OR rimmed vacuoles on biopsy

Sensitivity: 90% and specificity: 96%

Testing required: Exam and muscle biopsy.

IBM functional rating scale

1. Swallowing

– 4 Normal

– 3 Early eating problems—occasional choking

– 2 Dietary consistency changes

– 1 Frequent choking

– 0 Needs tube feeding

2. Handwriting (with dominant hand prior to IBM onset)

– 4 Normal

– 3 Slow or sloppy; all words are legible

– 2 Not all words are legible

– 1 Able to grip pen but unable to write

– 0 unable to grip pen

3. Cutting food and handling utensils

– 4 Normal

– 3 Somewhat slow and clumsy, but no help needed

– 2 Can cut most foods, although clumsy and slow; some help needed

– 1 Food must be cut by someone, but can still feed slowly

– 0 Needs to be fed

4. Fine motor tasks (opening doors, using keys, picking up small objects)

– 4 Independent

– 3 Slow or clumsy in completing task

– 2 Independent but requires modified techniques or assistive devices

– 1 Frequently requires assistance from caregiver

– 0 Unable

5. Dressing

– 4 Normal

– 3 Independent but with increased effort or decreased efficiency

– 2 Independent but requires assistive devices or modified techniques (Velcro snaps, shirts without buttons, etc)

– 1 Requires assistance from caregiver for some clothing items

– 0 total dependence

6. Hygiene (bathing and toileting)

– 4 Normal

– 3 Independent but with increased effort or decreased activity

– 2 Independent but requires use of assistive devices (shower chair, raised toilet seat, etc)

– 1 Requires occasional assistance from caregiver

– 0 Completely dependent

7. Turning in bed and adjusting covers

– 4 Normal

– 3 Somewhat slow and clumsy but no help needed

– 2 Can turn alone or adjust sheets, but with great difficulty

– 1 Can initiate, but not turn or adjust sheets alone

– 0 Unable or requires total assistance

8. Sit to stand

– 4 Independent (without use of arms)

– 3 Performs with substitute motions (leaning forward, rocking) but without use of arms

– 2 Requires use of arms

– 1 requires assistance from a device or person

– 0 Unable to stand

9. Walking

– 4 Normal

– 3 Slow or mild unsteadiness

– 2 Intermittent use of an assistive device (ankle–foot orthosis, cane, walker)

– 1 Dependent on assistive device

– 0 Wheelchair dependent

10. Climbing stairs

– 4 Normal

– 3 Slow with hesitation or increased effort; uses hand rail intermittently

– 2 Dependent on hand rail

– 1 Dependent on hand rail and additional support (cane or person)

– 0 Cannot climb stairs

Reference: “INCLUSION BODY MYOSITIS FUNCTIONAL RATING SCALE: A RELIABLE AND VALID MEASURE OF DISEASE SEVERITY” Muscle Nerve 37: 473–476, 2008

Alemtuzumab and sIBM

Treatment regimens for Immune-Mediated Myopathies

Standardized consensus guidelines for the treatment of inflammatory myopathies do not exist. Instead, treatment approaches have predominantly been based on anecdotal experience, case series, and the opinions of experts in the field.

Prednisone: 0.5 - 1 mg/kg/day to start.  The most common dose to start is 40 mg PO daily and upto a maximum of 60 mg PO morning dose with breakfast. It is first line treatment of choice for DM, PM and IMNM.  In severe cases, start methylprednisolone 1 gm IVPB daily for 3 days, followed by oral dose.  Noticeable clinical improvement begins within 3-6 months of starting prednisone in DM and PM.  IMNM may be refractory and often requires additional agents.  When no response occurs after an adequate trial of prednisone, consider alternate diagnosis such as sIBM, dysferlinopathy, and a repeat biopsy should be considered.   Treat with prednisone 40-60 mg daily for 4-6 weeks or until patients show stability.  A very slow rate of taper is recommended: 5 mg to 10 mg every 2 to 3 months when the prednisone dose is greater than 20 mg/d and even slower tapers, 2.5 mg to 5 mg every 2 to 3 months with prednisone doses of less than 20 mg/d with clinical evaluations performed before each taper and a halt in tapering if subtle signs of worsening of disease appear.  If CK level declines and the exam is stable, taper prednisone.  However, if CK levels rise and exam appears stable, hold on to the same dose of prednisone and do not taper further.  

In patients who have no evidence of active disease for 6 to 12 months after steroids have been discontinued, consideration may be given to tapering any other therapeutic agents the patient may be taking.  This should be done slowly, often over the course of a year, during which time patients should undergo careful monitoring of strength and CK levels.  At the first sign of a disease flare, more aggressive treatment should be reinstated. 

Relapse of the myositis needs to be distinguished from steroid myopathy.  This quandary may occur in patients who initially improved but then start developing progressive muscle weakness following long-term corticosteroid use because it can cause type 2 muscle fiber atrophy leading to steroid myopathy.  Features that would suggest a steroid myopathy as opposed to relapse of myositis would be that the serum CK would be normal, Cushingoid features, ecchymoses, striae, and absence of muscle membrane irritability on needdle EMG.  In contrast, patients who myositis relapse during prednisone taper, have increasing serum CK levels, and abnormal spontaneous activity on EMG. 

Of note, a few treated patients recover full strength even though CK levels remain markedly elevated, suggesting that some underlying disease activity still exists. This may be especially true in patients with anti-HMG-CoA reductase myopathy. Whether therapy should be escalated in this situation has not been established. Other patients have persistent muscle weakness even after muscle enzyme levels have normalized. This may occur in patients with an active disease process in which no muscle necrosis and, therefore, no release of muscle enzymes into the bloodstream is present (often in those with dermatomyositis). This may also occur in patients who have developed fatty replacement of muscle tissue due to a chronic or especially severe myopathic process. Muscle MRI can verify extensive permanent muscle damage that, in the absence of active edema, should discourage the futile escalation of immunosuppressive therapy. 

Side Effects: Hypertension, fluid and weight gain, hyperglycemia, hypokalemia, cataracts, gastric irritation, osteoporosis, infection, avascular necrosis 

Check hepatitis panel (Hep-B/C), HIV, TB quantiferon gold.  Consider Bactrim DS thrice a week for Pneumocystis. jirovecii infection prophylaxis, especially if patient has ILD and hast to remain on steroids for the long-term.  DEXA at baseline and yearly.  Calcium 1 gm daily, vitamin D 400-800 IU daily for prophylaxis to avert steroid-induce osteoporosis.  PPI for GI prophylaxis.  Postmenopausal women are also started on biphosphonates: alendronate 35 mg per week.  In those with osteoporosis given 70 mg per week.  Alendronate can cause severe esophagitis, and absorption is impaired when taken with meals.  Patients must take this mediation standing upright  and not eat or lay down for at least 30 minutes, following the dose of alendronate in the morning.  Diet should be low sodium, low-carbohydrate, high-protein diet to prevent excessive weight gain.  PT, aerobic exercise are helpful to avoid preventing weight gain.  BP monitoring.  Patients with scleroderma and MCTD on steroids may develop renal failure (renal crisis). Eye-exam for cataracts and glaucoma.  Check blood glucose, potassium (for hypokalemia).  Potassium supplementation may be need if patient becomes hypokalemia. 

Monitor: Weight, blood pressure, serum glucose/potassium, bone density, cataract formation, glaucoma 

Methylprednisolone: 1 gram IV daily for 3–5 doses.  Side-Effects: Arrhythmia, flushing, dysgeusia, anxiety, insomnia, fluid and weight gain, hyperglycemia, hypokalemia,  Monitor: Heart rate, blood pressure, serum glucose/potassium  infection  

Methotrexate:  7.5–20 mg weekly; in single or divided doses within 1 day a week. Folate 5 mg weekly on a separate day. Begin with 2.5 mg/week increments up to 20 mg/week  It should be used cautiously in patients with renal insufficiency.  If no improvement with PO methotrexate at 20 mg/wk after a month of therapy,  switch to parenteral form, usually subcutaneous, and increase dose by 5 mg qwk up to 20–50 mg 1-day a week.  Caution for stomatitis, alopecia, ILD, teratogenecity, oncogenicity, risk of infections, pulmonary fibrosis, bone marrow, renal and liver toxicity. Doses over 50 mg/wk (rarely needed) need leukovorin rescue, otherwise supplement folate 400 mcg - 800 mcg daily, or 5 gm weekly given 48 hours after weekly dose of methotrexate.  Avoid MTX in myositis patients with ILD and especially those with positive Jo1 antibodies. 

Side Effects: Hepatotoxicity, pulmonary fibrosis, infection, neoplasia, infertility, leukopenia, alopecia, gastric irritation, stomatitis, teratogenicity 

Monitor: CXR, PPD, DEXA baseline and q6 mo, anti-Jo1, PFT, CBC with differential, LFTs, GGT q2 wks until stable on methotrexate then q1-3 mo

Azathioprine, 2-3 mg/kg PO daily or bid. Ideally, give as a single does in the morning after breakfast. Begin with a low initial dose. Onset of action: 4-10 mo, max effect: 1-2 years

• • Advantage: steroid-paring immunosuppressant. Beneficial if used with prednisone.

  • Flu-like illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, neoplasia, infection, teratogenicity 

  • Disadvantages neoplasia risk, immunosuppression, pancytopenia, pancreatitis, hepatotoxicity. Not to be used in pregnancy.

    • 10% do not tolerate. Flu-like sx, bone marrow suppression, LFTs abnormalities. 

    • Not to be used with allopurinol - bone marrow suppression

    • Weekly CBC to check WBC for the first few months of starting treatment.  If the WBC count falls below 4,000/mm3, reduce the dose.  If the WBC count declines to 2,000/mm3 or the absolute neutrophil count falls to 1,000/mm3.  Leukopenia can develop as early as 1 week or as late as 2 years after initiating azathioprine. The leukopenia usually reverses within a month of discontinuing azathioprine.  It is possible to rechallenge the patient with azathioprine without recurrence of the severe leukopenia.  

    • CBCwith diff, liver enzymes 

    • Check TPMT (thiopurine methyltransferase) enzyme activity.  If an individual is homozygous for TPMT (1:300), do not give azathioprine.  If individual is heterozygous for TPMT, given azathioprine in smaller doses and monitored carefully. 

    • Not to be used with allopurinol - bone marrow suppression

  • Improvement may be slow, seen after 6 months, and full effect occurs after 1-2 years.

  •  The usual dosage is 2 to 3 mg/kg/day. Approximately 5% to 10% of individuals have an idiosyncratic reaction with fever, nausea, and vomiting, sometimes accompanied by eosinophilia or increased hepatocellular enzymes at the initiating dose.  Obtain a baseline complete blood count (CBC) and differential, platelet count, and LFTs. If the patient is not already receiving corticosteroids, also obtain an anergy panel, including a PPD, and check that a recent x-ray film has been taken. 

  • Therapy starts with 50 mg/day for 2 weeks, blood tests are checked weekly, and the dosage is increased by 50 mg/day every 2 weeks with blood tests checked before each increase. After reaching 150 mg/day, generally increase at 25 mg/day every 5 days, checking the blood studies. At 2 to 2.5 mg/kg/day, observe the patient for 3 to 4 months. If the patient has not started to show clinical improvement and an increase in red blood cell (RBC) mean cell volume (MCV; increase in MCV is a useful indicator of a therapeutic dose, in the absence of concomitant iron deficiency), increase again by 2.5 mg/day to 3 mg/kg/day. Blood should be checked weekly for the first 2 to 4 months, then every 2 weeks for several months, then monthly for several months, and then 4 times per year. Patients who have been receiving a stable dose for greater than 2 years and who have shown no signs of toxicity can be monitored 2 to 3 times per year. Upward adjustment of dose or signs of toxicity require returning to weekly monitoring and going through the same cycle. Side effects that may respond to lowering of the dose or dividing the daily dose to twice or three times a day include a queasy feeling, nausea and vomiting, stomatitis, oral thrush, increased susceptibility to infections, marrow suppression, or increase in hepatocellular or obstructive liver chemistries. Some patients may develop gallstones.  The majority of patients benefit from the drug and tolerate it long term (years). Very little evidence has shown an increased incidence of neoplasm from azathioprine in doses used for PM and MG. The major disadvantage of azathioprine is the delay in therapeutic effect; it takes 3 to 4 months to see a clinical effect, and it may take 6-18 months for maximal effect.

Mycophenolate mofetil 500 mg to 1 g BID to 1.5 g BID. Children: 600 mg/m2 per dose BID (limit to 1 g BID in patients with renal failure).

Side-effects: Bone marrow suppression, hypertension, tremor, diarrhea, nausea, vomiting, headache, sinusitis, confusion, amblyopia, cough, teratogenicity, infection, neoplasia, reduced efficacy of COVID-19 vaccinations. 

Monitor: CBC with diff 

IVIg in those who develop very severe weakness at the outset or do not respond to the initial combination of medications after 6 to 8 weeks : 2 gm/kg over 2-5 days, then 1 gm/kg every 4-8 weeks as needed.  Effective in anti-HMG-CoA reductase myopathy, DM and IMNM as monotherapy; not very effective in PM.  Not effective in sIBM. It is given in a patient who is on prednisone.   Patients with diabetes need renal function monitoring as it can induce renal failure.  Other SE: HA, myalgias, fever, chills, back pain, nausea, pompholyx of palms, aseptic meningitis, VTE, MI, hemolytic anemia, thrombocytopenia, transaminitis, and stroke. 

Side-effects:  Hypotension, arrhythmia, diaphoresis, flushing, rash, anaphylaxis, nephrotoxicity, headache, aseptic meningitis, thromboembolic events (DVT, PE, stroke), hemolytic anemia 

Monitor: Heart rate, blood pressure, creatinine/BUN 

Rituximab may be added to IVIg in severe cases that are refractory to IVIg or show only modest improvement.  It is preferred in refractory anti-SRP: 750 mg/m2 (1 gm) IV and repeat dose (1 gm) IV in two weeks.  Repeat infusion 6 months later.  Alternatively, 375 mg/m2 per week for 4 weeks.  Repeat 6-18 months depending on the patient's clinical exam.  

Side-effects: Infusion reactions (as per IVIG), infection, progressive multifocal leukoencephalopathy, reduced efficacy of vaccinations.

Monitor: Hepatitis B serology and TB screening prior to 1st dose; CBC with diff (some check B-cell count prior to subsequent courses but this may not be warranted), heart rate, blood pressure 

Cyclophosphamide: Used in refractory cases, as a last resort.  0.5 - 1 gm/m2 IV qmonthly for 6-12 months. 

Treatment Strategy 

Although many patients have at least a partial, if not robust, response to prednisone, treatment with prednisone is limited by the potentially serious long-term side effects such as osteoporosis, weight gain, hypertension, and elevation of blood sugars. Thus, prednisone monotherapy is rarely used long-term, and it is recommended that a second immunosuppressive steroid-sparing agent should be started early in the course in patients with moderate-to-severe disease.  These immunosuppressive agents include methotrexate (10 mg/wk to 25 mg/wk orally or subcutaneously), azathioprine (2 mg/kg/d to 3 mg/kg/d), mycophenolate mofetil (total daily dose of 2 g/d to 3 g/d divided into 2 daily doses), or IV immunoglobulin (IVIg) (1 g/kg/mo to 2 g/kg/mo administered over 2 to 5 consecutive days).  

Although methotrexate and azathioprine are agents commonly used in conjunction with prednisone, little evidence exists to support the superiority in efficacy of one of these immunosuppressive agents over another in the treatment of autoimmune myopathies. Methotrexate, although beneficial for muscle, skin, and joint involvement, should be cautiously used in patients with myositis with interstitial lung disease because of potential lung toxicity.  For severe or refractory cases, other options include rituximab (an anti-monoclonal CD20 antibody targeting B cells leading to selective peripheral B-cell depletion), which is a well-established biologic agent used in refractory inflammatory myopathy; calcineurin inhibitors, such as cyclosporine and tacrolimus (should be used with caution in the elderly with hypertension because of potential renal toxicity); and cyclophosphamide (can be used in severe or rapidly progressive interstitial lung disease but can cause infertility).

Recent evidence has suggested that particular subtypes of autoimmune myopathies (based on autoantibodies) may have a robust response to particular immunotherapies. IVIg has shown efficacy in a randomized controlled trial for the management of refractory dermatomyositis and is effective in immune-mediated necrotizing myopathy, particularly in patients with anti–HMG-CoA reductase antibodies, even as monotherapy.  Rituximab has been shown to have beneficial effects in patients with antisynthetase syndrome, primarily anti–Jo-1, and also in anti–Mi-2 autoantibody–positive subjects in a post hoc analysis of a randomized controlled trial of rituximab in refractory dermatomyositis and polymyositis.  Rituximab has also been shown to be effective in treating patients with anti-SRP antibody immune-mediated necrotizing myopathy who were refractory to conventional immunotherapies.  

Several biologic agents are under investigation for the treatment of refractory cases of autoimmune inflammatory myopathies.  Studies evaluating the use of anti–tumor necrosis factor agents (etanercept and infliximab) have shown conflicting results and, in some cases, concern for inducing or worsening of the myositis.  However, abatacept, a T-cell inhibitor, which inhibits the binding of the costimulatory protein CD28 expressed on effector T cells, was shown to be effective in a randomized phase 2b trial by lowering disease activity at 6 months in patients with refractory dermatomyositis and polymyositis and showed beneficial effects on muscle tissue with an increase in regulatory T cells.   Larger studies evaluating the efficacy of abatacept in inflammatory myopathies are underway.  Other novel investigational agents are being explored as therapeutic options.  Some case reports of efficacy in immune-mediated myopathies include tocilizumab (a monoclonal antibody that blocks interleukin 6), sifalimumab (an anti–interferon-alpha monoclonal antibody), basiliximab (a monoclonal antibody blocking interleukin 2 receptor α-chain, CD25 antigen, present on the surface of activated T lymphocytes),  IMO-8400 (a novel synthetic phosphorothioate oligonucleotide antagonist to Toll-like receptors, which are expressed on muscle cells and keratinocytes that, when activated, are postulated to amplify the inflammatory response), belimumab (to explore whether the B cell–activating factor overexpression plays a role in immune-mediated myopathies), eculizumab (a monoclonal antibody directed against the complement component C5 to prevent cleavage into C5a and C5b-9), and ruxolitinib (Janus kinase inhibitors).

Although treatment for inflammatory myopathies remains challenging because several therapeutic options are available without consensus guidelines, patients with myositis tend to respond favorably to conventional immunotherapy when started early in the course of the disease.  Patients with severe or multisystemic involvement may be better served in multidisciplinary clinics with experienced clinicians familiar with second-line or third-line agents to treat refractory myositis. 

Supplements, such as vitamin D with calcium and a proton pump inhibitor (for gastric ulcer prophylaxis) when taken with prednisone, and folic acid (1 mg/d), when taken with methotrexate, aid in the overall outcome and well-being of the patient.  Physical exercise under the guidance of a physical therapist is an important complementary treatment that improves strength and reduces disability and is safe within 4 weeks of starting medical treatment.

Cancer Screening:  Because the majority of malignancies are identified in the first 3 years of myositis onset, a comprehensive evaluation in search of an underlying malignancy with chest, abdomen, and pelvis CT, as well as age-appropriate cancer screening (eg, mammogram, colonoscopy, gynecologic examination) should be performed, especially in myositis subtypes (based on autoantibody) with an increased risk of malignancy.  If negative, the screening should be repeated in those at high risk within the first 3 years of symptom onset.  One study demonstrated that a single positron emission tomography (PET) scan may be as sensitive as the combination of all other screening tests in detecting an underlying malignancy in patients with myositis.

Muscle biopsy vs antibodies based diagnosis

The need to do muscle biopsy despite autantibodies being positive in myopathies is a question that is often reflected upon.  The importance of myopathological correlation with autoantibodies is often cited as the need for muscle biopsy.

• The sensitivity/specificity is highly variable between one antibody and the other.  

• Most of antibodies are supportive of a diagnosis rather than diagnostic by themselves.  

• A few things to keep in mind:

  • Weakness in patients with a connective tissue disease can be multifactorial: toxic (steroid, colchicine, HCQ etc), related to deconditioning, or due to alternative etiology such as inherited myopathy etc.

  • Having a positive antibody does not necessarily mean the muscle is involved (e.g amyopathic dermatomyositis).

  • Patient-reported weakness does not mean they have a myopathy.

  • Lack of fibs on EMG does not imply the myopathy is not inflammatory especially when the inflammation is endomysial. Patients can have a normal CK and still have an inflammatory myopathy (especially dermatomyositis). The opposite is not true.

  • The presence of fibs does not mean the myopathy is inflammatory, many of the toxic myopathies (and others) have fibs as well.

  • Myositis treatment is a big commitment and is not without long term side effects and potential complications. So you want to know from early on what you are treating.

  • You want to make sure the patient does not have IBM in the right patient population.

  • It is very common to see patients treated for myositis for years and exposed to unnecessary immunotherapy while the diagnosis was wrong.

  • As with all tests, the significance of a positive myositis-specific autoantibody test depends on the pretest probability that the patient has an autoimmune myopathy.  For example:

    • In a patient with statin exposure, CK>1000, and proximal muscle weakness, the presence of an anti-HMGCR autoantibody should be sufficient to diagnose and treat the patient for anti-HMGCR myopathy. Is there any circumstance where a muscle biopsy would be indicated? Perhaps if you thought they had some additional muscle disease. For example, I've seen patients with both anti-HMGCR myopathy and IBM. This was suspected based on the additional presence of finger flexor and knee extensor weakness (atypical for anti-HMGCR myopathy) and the biopsy showed rimmed vacuoles. When treated, the proximal muscle weakness resolved, leaving the patient with just IBM features. But this kind of thing is very rare encounter.

    • A statin-treated patient with muscle pain, normal CK, and no weakness who tests positive for anti-HMGCR autoantibodies is a different story. This patient should really never have been tested for the autoantibodies in the first place because the pretest probability is so low. There is a 0.5% false-positive rate for the test, so I wouldn't do anything unless the CK started to rise. But they don't need a muscle biopsy either.

    • In a patient with classic dermatomyositis rash and proximal muscle weakness, I'm really not sure what the biopsy would add.  Regardless of whether the biopsy is normal (because an affected area was not sampled) or grossly abnormal, the patient still has dermatomyositis and needs to be treated.  If they are one of the 70% of DM patients who have a dermatomyositis-specific autoantibody, that can tell you a lot about their disease.  Anti-MDA5+ patients are likely to develop severe ILD and need to see a pulmonary specialist ASAP.  Anti-NXP2 and anti-TIF1 gamma patients have a high risk of cancer and need thorough malignancy screening.  

    • Myositis-associated autoantibodies are a different story.  For example, a lupus patient with antii-Ku autoantibodies on hydroxychloroquine who develops high CK and proximal muscle weakness doesn't necessarily have overlap myositis. They could have toxic myopathy from hydroxychloroquine.  I would probably get a muscle biopsy for this patient.  

    • All that being said, I do like to get muscle biopsies for research purposes.  And who knows, in the future, we may discover muscle biopsy features (or muscle gene expression profiles) that could help guide prognosis or therapy.

    • The ENMC 2011 criteria for IBM require a muscle biopsy. The cN1A Ab in IBM can be positive for years before weakness develops. It also be false positive in other mysitis. Another reason to do a muscle bx.

    • Allenback 2018 report of the ENMC 224th meeting for INM.  I do biopsy our suspected SANAM patients and SRP cases.  In SANAM, the issue often toxic vs autoimmune myopathy in a patient hospitalized in the context of acute weakness and statin exposure. The muscle pathology is helpful to separate those 2 entities with different treatments particularly MHC 1 expression on intact myofibers.  When present this facilitates early therapy in SANAM.

    • As a matter of clinical practice, the insight provided from a muscle biopsy is such that we do offer muscle biopsy for practically all patients suspected of myositis.

• We have a multidisciplinary (neurology, rheumatology, pathology, radiology) approach to IIM at our institution and I work closely with the neuropathology department and meticulously review the patient’s chart who undergo muscle biopsy.  Most of our patients get muscle MRI and almost all get extended myositis antibody panels plus HMGCR and Nt5C1A (when appropriate) (These two not included in the panels).

• We have a two-tier approach for muscle biopsy in IIMs based on ENMC guidelines on IMNM (Allenback et al PMID: 29221629) and DM (Mammen et al PMID: 31791867)

• Unless in very unusual and rare situation, we do not encourage muscle biopsy BEFORE having the results of MSA/MAAs available. We don’t encourage muscle biopsy in patients who have MSAs for COMMON Abs (such as Jo-1, NXP-2, , HMGCR, SRP. etc) with classic presentations and order biopsy when Ab is negative OR clinically does not fit OR rare antibodies that there is not enough clinical data about (anti-KS etc). Please see our guidelines and I appreciate feedback from all.

The caveat is what about turnaround time for Abs vs biopsy?

1. In many labs, FINAL pathology reports take longer than Abs (which is about 2 weeks, except OMRF) and preliminary report is often non-specific/not adding much to what we already know.

2. If clinicians feel that immunosuppressive treatment is necessary BEFORE the biopsy or ab results, we don’t disagree, since 1) these cases are rare, 2) short term Tx is unlikely change the final interpretation of the biopsy. 

There is a paradigm shift in IIM from clinicopathology to clinic-SERO-pathology (Nishino et al PMID: 31369423), I guess for the same reason that we don’t do muscle biopsy anymore in some hereditary conditions such as DMD, myotonic dystrophy, FSHD etc, we won’t likely perform muscle biopsy for some classic cases of IIM (HMGCR, Jo-1 etc).

In general, I think THE MORE you know about:

a) IIMs subtypes and in general myopathies (hereditary included)

b) Your specific patient (history and exam being the most important in addition to other extra muscular involvement and paraclinical data)

THE LESS you need muscle biopsy to tell you what is going on with the patient. and If you don't know what is going on, most likely muscle biopsy will not help you.

“If it looks like a duck, swims like a duck, and quacks like a duck, then it probably is a duck.”  However, it is important to recognize that 1) there are lots of duck species and need to be familiar with them 2) need to know your duck.

• One important factor to keep in mind is that unless your pathologist is familiar with the subtle findings and differences in muscle biopsy in each IIM, do all necessary stainings, knows how to differentiate between IIM subtypes using MORPHOLOGICAL biopsy findings (and not from Abs!) , your biopsy result may be reported as “inflammatory myopathy NOS” which will not add much to what you already knew. MSAs in general are often more specific in defining your IIM subtype especially in DM and IMNM. For instance, unless your pathologist don’t do MxA stain, and don’t look at the subtle muscle biopsy findings, distinction between between DM and Anti-synthetase Syndrome (ASyS) may not be easy: Both may show somewhat similar findings : perifasicular pathology /atrophy -but in ASyS there there are often perifasicular necrosis/degeneration etc)… but these can be easily determined if you check MSA and we know that ASyS is distinct clinical entity than DM ( PMID: 30267437)… although there are still some who classify it under PM or  DM …

• It is also important to recognize that there is no universally accepted or practiced method for testing autoantibodies. To my knowledge, dot blot and line blot methods are easiest and fastest but least accurate and Immunoprecipitation is the gold standard, which is commercially available ONLY at Dr Ira Targoff’s lab at Oklahoma Medical Research Foundation and the other methods (ELISA, Western blot, EIA ets) are in between depending on lab in terms of reliability. To provide an example, the rate of OJ Positive Ab among ASyS patients in Japan is 26% (2nd most common ASyS after JO-1), but it is 0.5-4% in the US. The difference could obviously be due to genetics and environmental factors; BUT it could well be due to inaccurate testing in the US, especially since testing OJ ab is challenging.

• It is also important to recognize that muscle biopsy may provide some misleading information if ordering MD or pathologists do not make clinical correlation, otherwise it may result in unintended consequences and studies. For instance, we had a classic TIF1g DM patient who underwent muscle biopsy, which showed no inflammation, but rather “neurogenic finings”.

• In our experience, although there have been false positive Ab results; however, most of these were clinically so obvious. The rate of having a meaningful muscle pathology finding (ie adding NEW or additional perspective to what we already knew about the patient WHICH changed the management and prognosis) were minimal in most MSA positive IIM cases with typical presentations.

Therefore, it is important to know:

1. Pre-test probability

2. limitations of Abs testing and

3. Limitation of the pathology and pathology lab

• Determine what is the goal of the biopsy?  I personally don’t prefer ordering biopsy to “confirm” the diagnosis of clinically obvious IIM subtype (eg classic HMGCR positive IMNM). Same rational as why we don’t do brain biopsy on an every MS patient to confirm it whether it is MS or rule out sarcoidosis! or not doing a chromosomal testing for a duck to prove it is a duck.  However, IF the goal is to RULE OUT a reasoanble alternative diagnosis, It is also important to determine whether there is a pathological features that differentiate the two. For instance, in many cases/ pathology labs, it may be impossible to differentiate between HMGCR Pos, SRP pos, or seronegative necrotizing myopathies, same for DM subtypes. There is very interesting emerging literature on the sero-pathological correlation in IIM ((Nishino et al PMID: 31369423), but I have seen only very few experts who are familiar with the subject and apply in in their interpretation (Stenzel Werner; from Germany, Ichizo Nishino from Japan and Alan Pestronk, Wash U, etc).

• What I mentioned is obviously from a clinician’s perspective not a researcher ‘s one.  We have a lot to learn especially about sero-pathological correlation. It is I think important to notice that how much of the reasoning in favor of biopsy is because of research vs. clinical care of that individual person and be clear about it with the patient.

• This is the only paper that I know of which has a table comparing sensitivity/specificity of MSAs from Dr Mammen’s group (PMID: 26668818)

• I am actually puzzled and intrigued by the fact that enrolment in current research trials in IIM is relying on an ancient criteria by Bohan and Peter published in 1976,  which used the binary of DM vs PM, when there was no MRI or any antibodies discovered and many different disease entities (such as IBM, IMNM, most of ASyS) are classified under a heterogenous entity called PM!  Dr Amato used the term “unicorn” on his paper (PMID: 12913184). When did not have any new PM pathology diagnosis in more than 200 muscle biopsies.

Muscle Biopsy Guidelines 

Idiopathic inflammatory myopathy (IIM)

• Please consider AVOID  muscle biopsy if the myositis Ab panel is positive for the following Abs AND patient has classic clinical and paraclinical findings for that specific Ab-pos IIM (CK, muscle MRI, extra muscular involvements): 

  • Dermatomyositis: Mi-2, MDA-5, Tif1-g   (REFERENCE 1) 

  • Anti-Synthetase Syndrome (ASyS): Jo-1

  • Immune Mediated Necrotizing Myopathy (IMNM): (HMGCR, SRP) (ENMC Guidelines: REFERENCE 2)

• Classic presentation for Mi-2 Pos DM: moderate-severe proximal weakness with typical/classic DM skin rash and highly elevated CK (>1500-2000), no lung or systemic involvement, more common in Hispanics.

• Classic presentation for MDA-5 Pos DM:  May present in 3 distinict phenotypes (REFERENCE 3):  pure DM, rapidly progressive ILD with very high mortality and myositis with severe skin ulcers (most typically in palmar papules). Ferritin is high in classic cases. Muscle biopsy maybe normal. 

• Classic presentation for Tif1g Pos DM: Age> 60, highest association with cancers (50-80%). 

• Classic presentation for Jo-1 Pos ASyS: ILD, mechanic hand, non-erosive arthritis, Raynaud’s phenomenon and fever.

• Classic cases for Immune SRP-positive IMNM:  

  • Moderate-severe and maybe very severe symmetric proximal weakness, highly elevated CK, no lung or systemic involvement, except possible cardiac involvement (elevated troponin, diastolic CHF). May be intractable to treatment, typically require aggressive Tx with multiple disease modifying treatments (i.e “triple therapy”).

•  Classic cases for HMGCR-positive IMNM: 

  • Moderate -severe weakness with or w/o past exposure to statins and highly elevated CK.

 Note: Skin rash may be seen in DM, ASyS and IMNM (HMGCR and SRP). Rash plus myositis does not equal DM 

 Please consider AVOIDING muscle biopsy in classic cases for IBM: 

• Slowly (over years, NOT months), gradually progressive, asymmetric weakness with preferential involvement of knee extensors and finger/wrist flexors in individuals more than 50 yo with mild-moderately elevated CK, with or w/o positive Nt5C1A Ab and/or confirming muscle MRI: atrophy in vasti muscle with relative sparing of the rectus femoris. 

REFERENCES:

1.      Mammen AL, et al; ENMC 239th Workshop Study Group. 239th ENMC International Workshop: Classification of dermatomyositis, Amsterdam, the Netherlands, 14-16 December 2018. Neuromuscul Disord. 2020 Jan;30(1):70-92. PMID:31791867

2.      Allenbach Y, et al ; Immune-Mediated Necrotizing Myopathies Working Group. 224th ENMC International Workshop:: Clinico-sero-pathological classification of Immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016. Neuromuscul Disord. 2018 Jan;28(1):87-99. PMID: 29221629

3.      Allenbach Y, Different phenotypes in their matoma site is associated with anti MDA 5 antibody ; Study of 121 cases. Neurology. 2020, Jun Nov;39(11):1971-1981. PMID: 32487712

Classification of muscular manifestations of systemic diseases

Muscular manifestations in systemic diseases maybe classified as acute, subacute, or chronic.  Acute muscle manifestations include pathogen-caused myositis, muscle infarction, or rhabdomyolysis.  Subacute or chronic muscular manifestations of systemic diseases include secondary endocrine or secondary metabolic myopathy, myasthenia, immune-mediated myositis, muscle abscess, or vasculitis with secondary myopathy.  They may be further classified as transient or permanent, as mild or severe, as dominating or not dominating the clinical presentation, or as affecting a single muscle, a group of muscles, or the entire musculature.

Infectious diseases

Viral infections – Systemic viral infections may manifest in the muscle as myositis, rhabdomyolysis, or myasthenia.  The most frequent among the muscle manifestations is myositis with a self-limiting course.  More rarely, viral infections may manifest with rhabdomyolysis. Myasthenia due to viral infections is only reported in single cases.  Only few data about the clinical manifestations, frequency of muscle manifestations, and causative agents are available.  

• Myositis – In a retrospective study of 35 patients with viral myositis, muscle manifestations included localized pain of the calves (80%), lower limb weakness (71%), impaired ambulation (57%), and gait disturbance (40%) lasting on the average 3.6 days.  Symptoms were associated with elevated muscle enzymes.  Myositis may affect all muscles, a group of muscles, or a single muscle.  In a study of 355 pediatric patients with laboratory-confirmed influenza-B, 17.9% developed myositis.  During the influenza pandemic in 2009, children developed more frequently myositis as compared to adults.  Infections with human T-cell lymphotropic virus (HTLV-1) may manifest as axial myositis . Some of the viral infections may also cause orbital myositis, such as infections with the chickenpox virus.  Rarely, a single muscle like the serratus anterior may be affected during flu.  Concerning the causative agents, viral myositis has been reported following infections with influenza-B, influenza-A, parainfluenza-1, parvoviruses, HTLV-1, Epstein-Barr virus, arboviruses (e.g., dengue myositis), adenovirus , coxsackie, herpes, human immunodeficiency virus-1 (HIV-1), or chickenpox.  Most frequently myositis is due to infection with the influenza or parainfluenza virus. These patients may present with acute onset calf pain, tenderness, or gait disturbance.  Myositis in dengue infection can be fulminant and affect the respiratory muscles requiring artificial ventilation.  Only rarely is myositis due to infection with parvovirus-B19, HCV (19), or the West Nile virus.  Chronic HCV infection may be also associated with dermatomyositis or inclusion body myositis.  Infection with the New Jersey polyomavirus NJPyV-2013 may cause vasculitic myopathy.  Muscle-tropic viruses often spread to the CNS, which may dramatically increase morbidity and mortality.  Whether patients with an underlying subclinical primary or secondary myopathy or those taking muscle-toxic drugs are particularly prone to develop viral myositis is unknown.  Infection with HIV-1 may be associated with polymyositis, dermatomyositis, or inclusion body myositis. Polymyositis from HIV-1 may be complicated by the development of muscle abscesses. HIV-myositis may be even the initial manifestation of acquired immunodeficiency syndrome (AIDS).  

• Rhabdomyolysis – Viral infections, particularly dengue and influenza-A, have been recognized as cause of rhabdomyolysis with considerable morbidity and mortality.  Rhabdomyolysis as a complication of a viral infection occurs particularly in children and usually has a benign course.  The main complication of rhabdomyolysis is acute renal failure, often requiring hemofiltration or hemodialysis.  Rhabdomyolysis occurs in 1% of the patients with dengue infections.  Risk factors for developing rhabdomyolysis include myalgia, arterial hypertension, and acute renal failure.  More rarely rhabdomyolysis may be triggered by infections with influenza-A, influenza-B, parainfluenza, herpes-6, varicella zoster, cytomegaly virus (CMV), coronavirus-NL63, chikungunya, Alkhurma hemorrhagic fever virus, or HIV-1.  Rhabdomyolysis in dengue fever infections can be life-threatening in some cases.

• Myasthenia – Whether viral infections cause myasthenia is under debate.  Well-known, however, is that infections may deteriorate myasthenia.  There are, however, some reports indicating that a causal relation between a viral infection and the development of myasthenia may exist.  In six Chinese patients with a West Nile virus infection, myasthenia developed 3–7 months after the infection. Further evidence for an association between viral infections and myasthenia are results of single-fiber EMG investigations in patients with influenza or echovirus infection showing a neuromuscular transmission defect.

Bacterial infections – Systemic bacterial infections manifest in the muscle as myositis or rhabdomyolysis.

• Myositis – Bacterial infections associated with myositis usually manifest as bacterial polymyositis.  Commonly, bacterial polymyositis is a purulent infection accompanied by muscle abscesses (pyomyositis).  The main etiologic agent of bacterial polymyositis is Staphylococcus aureus.  Staphylococcal pyomyositis is a severe infection with high mortality being increasingly recognized in temperate climates.  Pyomyositis may originate from a focal infection such as arthritis, sacroiliitis, a spinal abscess, or from bacteremia or sepsis.  Pyomyositis may develop after trauma, may remain focal, and may resolve upon a nonsurgical approach.  Pyomyositis may affect a single muscle, such as the rectus femoris muscle, or may affect all muscles resulting in quadriparesis, as described in a patient after induction of chemotherapy for lymphoblastic leukemia.  Pyomyositis may be diagnosed with ultrasound and culture of the aspirate.  Pyomyositis of the iliopsoas muscle may be complicated by septic pulmonary embolism.  These patients may require abscess drainage under CT-guidance.  Presence of intramuscular hemangiomas seems to predispose for pyomyositis, as reported in a 4-year-old child with fatal meningitis.  Sepsis from streptococcus group-G originating from arthritis may cause diffuse polymyositis without skin lesions or toxic shock syndrome.  A severe form of bacterial myositis is streptococcal necrotizing myositis, which is often fatal.  Muscle abscesses may also result from infection with Klebsiella pneumoniae or Mycobacterium tuberculosis.  A rare cause of systemic myositis may be infection with Campylobacter jejuni.  Predisposing factors include skin penetration or impaired host immunocompetence (HIV-1, transplant recipient).

• Rhabdomyolysis – Occasionally, rhabdomyolysis may be a manifestation of a bacterial infection.  Rhabdomyolysis has been particularly reported during infections with Staphylococcus aureus, Salmonella, brucella, Mycoplasma pneumoniae, tuberculosis, tetanus, Legionella, or Bacillus cereus.  In a 6-year-old girl, life-threatening rhabdomyolysis was triggered by Streptococcus bovis sepsis.

Protozoal infections – Muscle manifestations of protozoal infections include myositis or rhabdomyolysis.

• Myositis – Protozoal infections are a frequent cause of myositis.  In some of these cases, myositis may be the dominant feature of the infection, such as in muscular sarcocystis.  Causative agents include sarcocystis, plasmodium falciparum, toxoplasma gondi, neospora, microspora, borrelia, pleistophora, babesia, ehrlichia, or trypanosoma.  Muscular sarcocystis is clinically characterized by myalgia with or without fever, and delayed onset of hyper-CKemia and eosinophilia with the possibility of relapses.  Muscular sarcocystis is particularly prevalent in Malaysia.  Other frequent protozoal infections with muscular involvement include toxoplasmosis and malaria. In toxoplasmosis, severe polymyositis may be even the presenting manifestation.  In a patient with AIDS, myositis due to toxoplasmosis developed despite adequate antimicrobial treatment.  Rarely, toxoplasmosis may be associated with dermatomyositis.  Occasionally, falciparum malaria may manifest with myositis.  A rare protozoic infection with muscle involvement is neosporosis.  In immune-compromised patients, microsporidia, obligate intracellular parasites, may manifest as focal or generalized myositis.  Focal myositis may be also a rare manifestation of Lyme disease (Lyme myositis).  Lyme myositis may even mimic dermatomyositis.  Infection with Borrelia burgdorferi may also cause idiopathic inflammatory myopathy.  In immune-compromised patients, myositis may be rarely caused by pleistophora.  Ocular myositis may be caused by ehrlichiosis, babesiosis, or Lyme disease.  In immune-compromised patients, ocular myositis may be also due to Trypanosoma cruzi infection.

• Rhabdomyolysis – Rhabdomyolysis due to protozoal infections has been particularly reported in malaria.  Another rare cause of rhabdomyolysis due to protozoal infection is babesiosis or ehrlichiosis.  Rhabdomyolysis due to Borrelia burgdorferi infection has been reported only once.

Helminthic infections – Helminthic infestations are frequently associated with muscle disease.  Helminthic infestations manifest in the muscle predominantly as myositis.  Helminthes potentially affecting the muscle include Toxocara (toxocarosis),  Echinococcus granulosus (hydatidosis), Cysticercus (cysticercosis), Trichinella (trichinosis), Strongyloides (strongyloidiasis), Haycocknema perplexum, Spirometra (sparganosis), Fasciola (fasciolosis), or Filaria (filariasis).  Toxocara infection may go along with lumbar myositis.  In the tropics, visceral larva migrans (toxocarosis) may manifest as tropical pyomyositis requiring repeated debridement.  Hydatid cysts from infestation with Echinococcus may rarely occur in a single muscle as the initial manifestation.  Most commonly, liver and lung are affected.  Hydatid cysts of the muscle have been occasionally observed in patients with primary muscle disease.  Cysticercosis may initially manifest as ptosis if the lid elevator is affected.  Cysticercosis may also manifest as ocular myositis.  Focal cysticercal myositis may be diagnosed with muscle ultrasound or MRI.  Trichinosis manifests clinically in the muscle as myalgias due to dermato-polymyositis.  Trichinella has a unique relation to the muscle as it is located intracellularly.  Patients may present with myalgia, fever, and elevated muscle enzymes.  Rarely, trichinosis may go along with muscle weakness.  In case of focal necrosis due to trichinosis, EMG may show profuse fibrillations.  Later in the course, fibrosis and contractures may develop.  Strongyloides rarely affects the musculature.  Occasionally, patients taking steroids or immuno-suppressants may develop polymyositis from strongyloides infestation.  In Australia, myositis may be due to infestation with the nematode Haycocknema perplexum.  In single cases, sparganosis may manifest as ocular myositis.  Rarely, cutaneous fascioliasis may cause myositis of the intercostal muscles.  Filariasis rarely manifests as myositis with muscle swelling.

Endocrinopathy and muscle disease

Thyroid dysfunction

• Hypothyroidism is a well-known cause of muscle disease (hypothyroid myopathy).  In contrast to hyperthyroid myopathy, CK is usually elevated.  Pain is frequent, and muscles can be swollen.  Additionally, hypothyroidism due to autoimmune disease may be associated with dermatomyositis or polymyositis.  Rarely, hypothyroidism may also go along with rhabdomyolysis.  In infancy or childhood, hypothyroidism may manifest as Kocher–Debre Semelaigne syndrome, characterized by lower limb or generalized muscle hypertrophy, myxedema, short stature, and cretinism.  In adults, hypothyroidism may manifest as Hoffmann’s syndrome, characterized by muscle stiffness and muscle pseudo-hypertrophy.  Muscle enzymes are generally elevated in hypothyroid myopathy.  The EMG may show a myopathic, neuropathic, or a mixed pattern.  Clinical manifestations of hypothyroid myopathy return to normal with hormone replacement therapy.  

• Hyperthyroidism – Graves’ disease may manifest in the skeletal muscle as mild and usually painless proximal weakness or as idiopathic ocular myositis. Myositis may respond favorable to thiamazole without adding steroids.  Thyrotoxicosis may go along with episodic muscle weakness due to polymyositis. Thyrotoxicosis may also manifest as acute or chronic bulbar muscle dysfunction (bulbar myopathy).  If thyrotoxicosis leads to hypokalemia, generalized muscle weakness may ensue (thyrotoxic periodic paralysis).  A rare manifestation of hyperthyroidism or thyrotoxicosis may be myokymia.

Parathyroid dysfunction

• Hyperparathyroidism may cause muscle weakness (dropped head syndrome), muscle pain, or ischemic, calcifying myopathy.  Hyperparathyroidism may also go along with spontaneous rupture of the Achilles tendons.  Rarely, the initial manifestation of hyperparathyroidism may be dysphagia.  FDG-PET in hyperthyroidism may show tumors mimicking muscular metastases.  Affection of the muscle in hypoparathyroidism may present as myopathy, neuromyotonia, or rhabdomyolysis.

Other endocrinopathies

• Hypoadrenalism as well as hyperadrenalism may be complicated by generalized muscle weakness.  In case of acromegaly, the muscles may be hypertrophic and stronger than normal, but later in the course proximal weakness may become evident.

Metabolic disorders and muscle disease

Various metabolic disorders secondarily affect the muscle.  The most well-known are hemochromatosis, amyloidosis, and porphyria.

• Hemochromatosis – Hereditary hemochromatosis and other iron-metabolism disorders resulting in iron overload may involve the skeletal muscle (iron-overload myopathy) which usually manifests as myalgias and fatigue.  Figures about the prevalence of iron-overload myopathy are highly variable.  In a study of 46 patients with hereditary hemochromatosis, myopathy was diagnosed in none of them.  In a study of 395 patients with hereditary hemochromatosis on the contrary, 43% were diagnosed with fibromyalgia.  In a study of 88 patients with chronic fatigue syndrome, 2.6% had hereditary hemochromatosis.  Among 10 patients under hemodialysis, muscle biopsy disclosed iron deposition in muscle fibers or macrophages in 70% of them.  Clinically, these patients presented with proximal muscle weakness.

• Amyloidosis – Muscle involvement is frequent in amyloidosis and manifests as amyloid myopathy, clinically characterized by muscle hypertrophy (muscle overgrowth), or weakness.  Depending on the cause of amyloidosis, different types of amyloid (AA, AL) may be produced.  Amyloidosis usually manifests systemically in all muscles but occasionally only a single muscle or a few muscles is/are affected.  Amyloidosis is characterized by extracellular and perivascular deposition of AA or AL amyloid.  Rarely, amyloid myopathy occurs in patients with hereditary transthyretin amyloidosis (ATTR).  Occasionally, systemic amyloidosis due to multiple myeloma may be exclusively detectable in the skeletal muscle as ring-fiber-like muscle fibers, staining positive for Congo-red.  Rarely, amyloidosis due to IgD multiple myeloma may manifest as myositis.  In systemic AL, amyloidosis amyloid myopathy may manifest with joint contractures.  Amyloidosis of the muscle may also occur in monoclonal gammopathy.  Histologically, amyloid myopathy can mimic inclusion body myopathy.  In such cases, noncongophilic deposition of kappa-light chains can be seen as subsarcolemmal rings.  Focal accumulations of amyloid may present as amyloidoma (tumoral amyloidosis).  Interstitial amyloid deposition in the muscle may rarely occur in patients with myopathy due to mutations in the anoctamin-5 gene.

• Porphyrias – Porphyrias are diseases in which porphyrins, necessary to produce heme, accumulate.  Most frequently, they manifest in the skin, brain, or peripheral nerves.  More rarely, they manifest in the skeletal muscle.  

Immunological disorders association with immune-mediated myopathies

A number of immunological disorders may involve the skeletal muscle presenting as polymyositis, dermatomyositis, rarely as inclusion body myositis, or as ocular myositis.  The most important among these disorders are systemic lupus erythematosus (SLE), Sjogren syndrome, rheumatoid arthritis, systemic sclerosis, psoriasis,and the antisynthetase syndrome (ASS).

• Systemic lupus erythematosus (SLE) – SLE is a chronic inflammatory, multisystem disease with a broad spectrum of clinical and serological abnormalities.  SLE has been repeatedly reported to manifest with muscle disease.  Muscle manifestations of SLE include polymyositis or rhabdomyolysis.  Some patients with SLE may even develop myositis together with rhabdomyolysis.  Myositis is much more frequent than rhabdomyolysis.  In a study of 15 SLE patients, 9% had developed clinical myositis.  However, histopathological evidence of myositis was seen in 47% of these patients.  Type-2 atrophy was the predominant histopathological finding.  Occasionally, myositis may be the initial manifestation of SLE.  Rarely, SLE may manifest as ocular myositis.  Muscle involvement in SLE may also manifest as necrotizing autoimmune myopathy with muscle weakness and rhabdomyolysis.  Polymyositis is also a feature of mixed connective tissue disease, including clinical and laboratory manifestations of SLE, scleroderma, and polymyositis along with high titers of anti-U1 and anti-U2-nRNP antibodies.  Myositis may also occur in patients with SLE/polymyositis or SLE/dermatomyositis overlap syndrome.  Rhabdomyolysis in SLE may be fatal in some cases.

• Sjogren syndrome – The skeletal muscle is frequently affected in Sjogren syndrome usually manifesting as myalgia or weakness.  In 3% of the patients, myositis has been described.  In a study of 573 patients with Sjogren syndrome, myositis was found in 4.9% of them.  Occasionally, muscle affection manifests as ocular myositis.  Rarely, dermatomyositis may occur.  Occasionally, Sjogren syndrome may be also associated with polymyositis.  In some patients, Sjogren syndrome was even associated with inclusion body myositis.  The latter patients usually carried the HLA-DRB1 allele or its equivalent HLA-DR3 or the MHC ancestral haplotype. This is why the association of Sjogren syndrome and sporadic inclusion body myositis was assumed due to a genetic predisposition linked to MHC .

• Rheumatoid arthritis – Affection of the skeletal muscles in rheumatoid arthritis manifests as rheumatoid myositis.  Causes of rheumatoid arthritis are variable and include inflammation, drugs, impaired joint flexibility, or sedentarism.  Muscle enzymes are usually highly elevated.  Electromyography (EMG) may show short-duration, low-amplitude, polyphasic motor unit action potentials.  Active inflammation can be found on both muscle ultrasound and MRI.  Muscle biopsy may show nonspecific findings, such as changes in fiber size or internal structure, pleomorphic mitochondria, dilated sarcotubular system, multiple internal or subsarcolemmal nuclei, a trend toward type-II-fibers, fiber atrophy, degenerative/regenerative modifications, and inflammatory features such as patchy B- or T-cell infiltrates, mainly perivascularly or endomysial, but also in the perimysial compartment.  In rare cases, rheumatoid myositis may be complicated by compartment syndrome or may affect the extraocular muscles (ocular myositis).  Adalimumab has been reported to induce myositis in rheumatoid arthritis.

• Eosinophilic myositis has been reported in a patient with myotonic dystrophy-1 and rheumatoid arthritis.

• Systemic sclerosis – Systemic sclerosis is characterized by arthralgia, synovitis, contractures, tendon friction rubs, tenosynovitis, and muscle disease.  Muscle involvement in systemic sclerosis is frequent.  Muscular manifestations of systemic sclerosis include myositis with myalgia and weakness.  Rarely, patients with systemic sclerosis may develop inclusion body myositis.  In a study of 1145 patients with systemic sclerosis, 5.6% had elevated CK.  This subset of patients had a poor prognosis impacting survival, particularly in male with early onset, topo1 and RNP autoantibodies, and interstitial lung disease.  If muscle weakness includes the head extensor muscles, dropped head syndrome may ensue.  Muscle MRI is an appropriate tool to support the diagnosis of muscle involvement in systemic sclerosis.  In some patients, myositis responded favorably to immunoglobulin.

• Psoriasis – Psoriasis is a noninfectious, inflammatory dermatological disorder, which presents as systemic disease if joints, bands, eyes, arteries, or the heart are additionally involved.  Psoriasis is associated with an increased risk of diabetes and ischemic stroke.  Only rarely muscle involvement has been reported. In a study of 11370 patients with psoriasis, 13 had a pathologically confirmed myopathy (0.11%).  Eleven had generalized inflammatory myopathy and 2 had focal muscular inflammation.  In two-thirds of these patients, onset of psoriasis preceded that of myopathy.  Patients receiving a TNF-alpha blocker had an increased risk of developing myositis.  Rarely, orbital myositis has been reported.  FDG-PET may show an increased tracer-uptake in affected muscles.  In a single case, psoriasis was associated with dermatomyositis and antibodies against the glomerular basement membrane.

• Sarcoidosis.  Sarcoid myositis is a systemic disorder of unknown cause.  It is characterized by non-caseating granulomas.  It can be classified into three types: chronic myopathy, palpable nodules, and acute myositis.  Chronic myopathy is a condition wherein the disease has a steady and slow progress.  In this condition, the patient has proximal myopathy bilaterally and symmetrically, and the creatine kinase levels are normal.  The second type is palpable nodules, where the patient presents with painful nodules on the muscles of the extremities, and muscle biopsy specimens reveal non-caseating granulomas.  This type of sarcoid myositis is not associated with muscle weakness.  The third type is the rarest manifestation that this patient presented with – acute sarcoid myositis.   It usually presents in females aged 40–55 years.  Most patients report acute or insidious respiratory problems, as well as proximal muscle weakness.  It mimics polymyositis.  It usually involves chronic self-limited episodes of relapse and remission of symptoms.  Investigations reveal a creatine kinase of around 2000, and the condition itself is diagnosed via MRI and muscle biopsy. The treatment of choice is steroids.

Vascular disorders and myopathies

Muscle function not only depends on appropriate innervation and energy production, but also on sufficient blood perfusion.  Muscle perfusion may depend not only on cardiac function but also on muscle artery contractility.  Physiologically, endothelial cells produce basal and stimulated nitric oxide (NO).  During exercise, NO production is stimulated, which contributes to exercise-induced muscle hyperemia.  In patients with reduced NO production due to reduced activity of NO-synthetase (NOS), reduced microcirculation contributes to exercise-induced muscle fatigue.  NO deficiency results in muscle hypoperfusion with decreased provision of nutrients and thus decreased protein production.  Microvascular perfusion is particularly compromised in systemic vasculitis, which includes Behcet disease, Wegener’s granulomatosis, and Churg–Strauss syndrome.

• Behcet disease – Behcet disease is a form of systemic vasculitis with the classical triad of oral ulcers, genital ulcers, and uveitis.  Involvement of the skeletal muscle is rare.  The most common muscle manifestation is myositis.  Myositis usually shows a focal distribution.  In single cases, orbital myositis has been reported.  Only a single extra-ocular muscle may be affected.  Only rarely may myositis dominate the clinical presentation.  Development of myositis in Behcet disease may be triggered by stress such as surgery.  Occasionally, myositis may be of the necrotizing type.  Generalized myositis may be diagnosed by muscle ultrasound, CT, or MRI.  Generalized myositis in Behcet disease may occasionally respond favorably to cyclosporine.

• Wegener’s granulomatosis – Wegener’s granulomatosis (granulomatosis with polyangiitis) is a systemic necrotizing vasculitis which is associated with granulomatous infection of the nasopharynx, the sinuses, the oropharynx, and the lower bronchial airways.  Muscle involvement is infrequent and usually manifests as myositis.  The most common type of myositis in Wegener’s granulomatosis is ocular myositis.  If myositis predominantly affects the lower limb muscles, it may go along with muscle weakness and gait disturbance.

• Churg–Strauss syndrome – Churg–Strauss syndrome, also known as eosinophilic granulomatosis with polyangiitis, is a granulomatous vasculitis of the small arteries accompanied by infiltrates of eosinophils.  It manifests clinically in three stages, initially as allergic cold and asthma, followed by eosinophilic infiltration of the lung and intestines and systemic vasculitis.  Myositis is a rare muscle manifestation of the disease and presents with myalgia, fever, and muscle weakness .  Myositis in Churg–Strauss syndrome may not only concern all muscles resulting in polymyositis but may occur focally as orbital myositis.

Hematological disorders

Hematological disorders are rarely associated with muscle disease. Muscle involvement has been particularly reported in sickle cell anemia.  Muscle affection in sickle cell anemia includes myalgia, focal myopathy, focal myositis, pyomyositis, myonecrosis, fibrosis, fasciitis, or rhabdomyolysis. Muscle involvement is more frequent in hematological neoplasms, but they are described in more detail below.

Muscle disease in neoplasms is a paraneoplastic phenomenon and includes focal or generalized myositis, polymyositis, dermatomyositis, or necrotizing myopathy. Neoplasms associated with muscle disease include leukemia, lymphomas, or other solid tumors.

Leukemia:  Polymyositis/dermatomyositis are symmetric, proximal, paraneoplastic, inflammatory myopathies with or without distinct cutaneous eruptions. They have been long recognized in association with cancer.  Only rarely may polymyositis/dermatomyositis be associated with acute myelocytic leukemia. In single cases, chronic lymphatic leukemia may go along with inclusion body myositis  Pyomyositis may be the initial presentation not only of chronic myeloid leukemia but also of acute lymphocytic leukemia.  In a girl with secondary acute myelogenous leukemia following chemotherapy, tuberculous myositis developed. Chemotherapy for leukemia may occasionally induce pyomyositis.

Lymphoma:  Lymphoma is frequently associated with muscle disease, particularly with polymyositis or dermatomyositis. B-cell lymphoma, T-cell-lymphoma, and Hodgkin’s lymphoma have been reported in association with dermatomyositis or polymyositis. In a study of 32 patients with polymyositis/dermatomyositis, 20 had B-cell lymphoma, four had T-cell lymphoma, and two had Hodgkin’s lymphoma. In single cases, B-cell lymphoma manifested with isolated myositis of a single extra-ocular muscle. Non-Hodgkin lymphoma may directly develop inside the muscle.

Other malignancies:  Paraneoplastic myopathy has been reported also in a number of other neoplasms. Lung, gastrointestinal, and breast carcinomas are frequently associated with necrotizing myopathy. The bladder transitional cell tumor may cause necrotizing myopathy with pipestem capillaries. Waldenstrom’s macroglobulinemia may go along with antidecorin (BJ) myopathy.  Patients with thymoma may develop rippling muscle syndrome. Patients with paraproteinemia (M-protein, lambda > kappa light chains, IgG) or carcinoids may present with scleromyxedema.

Diagnosis:

Methods to diagnose muscle manifestations of systemic disease are the same as those applied for diagnosing primary muscle disease. The basis is a thorough individual and family history and a thorough clinical exam. Determination of muscle enzymes, EMG, muscle imaging, and a muscle biopsy may be of additional help.

FDG-PET may show increased muscular tracer uptake in myositis or tumors. Viral infections causing myositis may be diagnosed by detection of serum antibodies against viruses or by PCR. CK values may be higher during the acute stage of an influenza infection than during the convalescence stage. Determination of various muscle-specific antibodies or auto-antibodies, such as anti-Jo1, anti-PL7, anti-PL12 (ASS), anti-EJ, anti-OJ, anti-SRP, anti-Mi-2, anti-PM-Scl75, anti-PM-Scl100, and anti-Ku (overlap syndromes) may be necessary to establish the diagnosis of muscle disease in immunological disorders. U1-nRNP antibodies may be determined when suspecting SLE, scleroderma, or polymyositis overlap syndrome.Topo1 and RNP antibodies may be positive in myopathy from systemic sclerosis. Antidecorin antibodies (BJ antigen) may indicate Waldenstrom’s macroglobulinemia. Determination of ryanodine-receptor antibodies may be helpful for diagnosing myasthenia gravis or myositis, and determination of monoclonal antibodies (M-proteins) may suggest scleromyxedema.

Single-fiber EMG may show a disturbed neuromuscular transmission during the acute stage of influenza or echovirus infections. Disturbed neuromuscular transmission may explain muscle weakness and fatigue during a viral infection. If muscle imaging reveals an enhancing lesion with a fluid density and needle aspiration shows pus, Staphylococcus aureus is growing in 85% of the cases. Before diagnosing a secondary myopathy, a primary myopathy needs to be excluded.

Cancer associated myositis: 

• Occurs in patients with >50 years

• B-cell lymphoma is the most common hematologic malignancy associated with PM/DM.

• In half the myositis is diagnosed before lymphoma.

• DM is more frequent than PM.

• anti-Jo1 ab is negative.

Eosinophilic Myopathy

Part of hypereosinophilic syndrome (HES):  HES Dx criteria:

1. Persistent eosinophilia of 1500 eosinophlis/mm3 for at least 6 months

2. No evidence of parasitic or other recognized causes of eosinophilia

3. Signs and sx of organ system involvement related to infiltration of eosinophils.

Other systemic manifestations of HES: encephalopathy, peripheral neuropathy, myocarditis/pericarditis (fibrosis, CHF, arrhythmia, and conduction block), pulmonary (fibrosis, pleuritis, and asthma), renal and GI involvement, and skin changes (petechial rash, splinter H'ges of nail beds, livedo reticularis, and Raynaud's phenomena). Eosinophilic PM, HES, CSS fall into the spectrum of the same disease process.

The etiologies of eosinophilic fasciitis, perimyositis, or myositis are not established, but are usually considered as idiopathic, or related to systemic dysimmune diseases or hematological malignancies such as myelodysplastic syndromes.

Subclasses:

• focal eosinophilic myositis

• eosinophilic PM

  • Pts with focal eosinophilic myositis and eosinophilic PM present with focal or generalized muscle weakness +/- myalgias and skin changes

• eosinophilic perimyositis

  • Pts with eosinophilic perimyositis typically have myaglia without significant weakness.  

Laboratory features: CK is usually elevated in focal EM, and eosinophilic PM but is often normal in eosinophilic perimyositis.  Hypereosinophilia, hypergammaglobulinemia, anemia, RF.  ESR is elevated in <50%.  Serum ANA is usually negative.  ECG may show cardiac arrhythmia.  CXR may show pulmonary infiltrates.  EMG shows increased insertional and spontaneous activity (PWs, fibs) with early recruitment of small short amplitudes, polyphasic MUAPs.  In addition, there may be evidence of superimposed multiple mononeuropathies on EMG/NCS.

Histopathology:  muscle bx in focal EM and eosinophilic PM reveal an endomysial inflammatory cell infiltrate, often but not always eosinophilic infiltrates.  Inflammatory cells may appear to surround and invade muscle fibers.  Nodular granulomas may also be seen.  In eosinophilic perimyositis, muscle biopsies reveal an inflammatory cell infiltrate (eosinophils not a constant feature) restricted to the fascia and superficial perimysium.

Pathogenesis: Unknown etiology.  Eosinophilia may be the result of effect of T-cell clones.  Oligoclonal expansion of T cells within the muscle in PM is noted.  T-lymphocytes secrete IL5 and IL3 cytokines which are needed for growth and differentiation of eosinophils.  Eosinophils, in turn, damage muscle fibers by their release of the eosinophilic major basic protein, which causes lysis of cell membranes. 

DDx:  LGMD2A (calpainopathy), parasitic infestations (trichinosis), vasculitis (CSS), T-cell lymphoma and aplastic anemia, toxic oil and L-tryptophan-induced eosinophilic-myalgia syndrome, idiopathic eosinophilic fascitis (Shulman syndrome), HES, and eosinophilic myopathy.  In all these conditions, the peripheral blood eosinophil count is elevated. 

Treatment and Prognosis:  Fewer than 20% of patients survive beyond 3 years.  Response to corticosteroids is variable, but some do respond. Most require a 2nd line cytotoxic agent.  BMT for refractory cases. Mutations in the calpain-3 gene must be checked to see if LGMD2A is not missed.  

Other Associations with Inflammatory myopathies

Inflammatory myopathies are associated with multiple disease processes including Sjögren’s syndrome and systemic lupus erythematosus. They are also associated with infections including human immunodeficiency virus, human T cell leukemia virus type 1, and influenza virus.  Myopathies can occur with cancer in cases such as polymyositis, impaired nutrition, tumor invasion, and paraneoplastic syndrome.  Inflammatory myopathies are described in eosinophilic polymyositis, diffuse fasciitis with eosinophilia, as well granulomatous and giant cell myositis, but they are not described with plasma cell dyscrasia, renal failure, Campylobacter infection or pancreatitis.

Eosinophilic polymyositis, can be sometimes the initial manifestation of a monoclonal T-cell expansion.

GVHD associated polymyositis

• GVHD is a major complication of bone marrow transplantation, and it can mimic autoimmune diseases like scleroderma, dermatomyositis, polymyositis, medication-induced myositis, and sicca syndrome. It develops in 33%–64% of allogenic stem cell transplantation (SCT) and is more common with advancing age and in patients with a history of acute GVHD.

• It is a multiorgan disease that can develop months to years after the graft. A study has shown that GVHD-induced myositis developed anywhere between 7 and 55 months after transplantation.

• Involvement of skeletal muscles is rare (less than 1% of patients who undergo bone marrow transplantation) and even more rare when skeletal muscles are the main target. The incidence of myositis is not related to the underlying disease that was treated with bone marrow transplantation.

• CK ranged between 454 and 8,400 U/L.

• EMG shows irritative myopathy.

• Muscle biopsy shows inflammatory myopathy in 80% of cases.

• All patients have involvement of other organs, mostly the skin and liver. The skin lesions are different from those of dermatomyositis. The skin is diffusely indurated and firm, with mild erythema.

• Patients respond well to steroids and azathioprine or cyclosporine.

• Tacrolimus is reported to cause polymyositis, but no skin lesions are reported. Yet, it may be better to replace it with another immunosuppressive agent in this case.

• Pathological identification of the type of cells in the muscle lesions can determine if the cells are donor related, thus confirming GVHD

Overlap Syndromes

When autoimmune myopathy occurs in the context of another connective tissue disease, such as systemic sclerosis, lupus erythematosus, or rheumatoid arthritis, the patient is said to have a myositis overlap syndrome.  While little is known about these overlap syndromes, one 2015 study showed that more than one-third of muscle biopsies from patients with scleroderma-myositis overlap include endomysial inflammation without evidence of non-necrotic muscle cells surrounded and invaded by lymphocytes ; patients with these biopsy findings would be categorized as having nonspecific myositis based on the 2004 European Neuromuscular Centre (ENMC) diagnostic criteria.  Interestingly, approximately one-fifth of patients with sclerodermamyositis had a necrotizing myopathy.  Very few patients had muscle biopsy features consistent with dermatomyositis.  Rarely, patients may present with more than one autoimmune neuromuscular condition.  For example, a handful of patients with both autoimmune myopathy and myasthenia gravis were recently described in the context of an improving dermatomyositis rash.  Since the majority of patients with myastheniamyositis overlap had positive anti- acetylcholine receptor (AChR) antibodies, it is now recommended to routinely checking for these in patients with autoimmune myopathy. 

Dropped Head Syndrome

Isolated neck extensor myopathy (INEM)

DHS is relatively rare condition that may occur as a result of several neurological, neuromuscular, muscular, and other causes.

Neurological causes includes amyotrophic lateral sclerosis (ALS),  Parkinson disease, multiple system atrophy, cervical dystonia, postpolio syndrome, cervical myelopathy, chronic inflammatory polyneuropathy (CIDP).  Neuromuscular causes include myasthenia gravis (MG), Lambert-Eaton myasthenia syndrome (LEMS). Muscular causes includes primary inflammatory such as polymyositis, scleromyositis, isolated inflammatory axial myopathy, primary non-inflammatory such as nemaline myopathy, mitochondrial myopathy, congenital myopathy, FSHD, and isolated neck extensor myopathy (INEM). 

INEM presents with chin-on-neck deformity (dropped head syndrome(DHS)), neck pain, kyphosis, dysphagia, and horizontal gaze difficulties. INEM is due to the nonprogressive weakness of neck extensors which may involve shoulder girdle muscles. INEM is more prevalent in elderly females with no specific risk factors identified. Etiology remains idiopathic, however, self-limiting inflammation in neck extensors and loss of elasticity due to mechanical stretching have been suggested.  Creatine kinase level is usually normal.  Electromyography of the paraspinal muscles shows fibrillations with short duration motor unit potentials.  Muscle biopsy usually reveals myogenic atrophic changes.  Conservative treatment with bracing and physical therapy results in no or minimal improvement.   Empiric treatment with immunosuppressive (steroid +/- azathioprine) can be effective; surgery reserved for refractory cases. INEM is a relatively benign condition compared to other serious neuromuscular disorders causing DHS. 

Dropped head syndrome: diagnosis and management - PMC 

Isolated neck extensor myopathy | Neurology 

Dropped head syndrome due to neuromuscular disorders: Clinical manifestation and evaluation - PMC 

Diabetes and muscle disease

Diabetes is a catabolic condition which manifests in the muscle as diabetic myopathy.  Diabetic myopathy encompasses a spectrum of abnormalities, including muscle wasting, muscle inflammation, ischemia, infarction, hemorrhage, necrosis, fibrosis, or fatty atrophy. Clinical manifestations vary depending on the underlying abnormality.  

• The most frequent muscle manifestation in diabetes is painless muscle wasting (diabetic amyotrophy), which is either due to a diabetic plexus lesion or due to affection of satellite cells by the diabetes.  

• A further frequent manifestation of diabetic myopathy is diabetic myonecrosis presenting as self-limiting condition with acute onset of swelling and severe muscle pain.  Typically, patients have no fever, normal white blood cell count, normal blood sedimentation rate, but elevated C-reactive protein.  Usually, myonecrosis occurs in poorly controlled diabetes .  The diagnosis is established by muscle MRI, and the treatment of choice is bed rest and analgesics.  

• An increasingly recognized manifestation of diabetic myopathy is diabetic muscle infarction, which is regarded as rare and occurs in long-standing diabetic patients.  Clinical manifestations of muscle infarction include acute onset local pain, together with a focal, palpable mass lesion.  The diagnosis is established by muscle MRI.  Additionally, the expression level of Pax7, MyoD, myogenin, and fatal myosin-heavy-chain (MHC) is significantly decreased in diabetic myopathy

Current Classification and Management of Inflammatory Myopathies - PMC (nih.gov) 

Case Vignettes

Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin - PMC (nih.gov) 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107255/

https://hal.sorbonne-universite.fr/hal-03523499/document

Cutaneous dermatomyositis in adults: Overview and initial management

AUTHOR:Ruth Ann Vleugels, MD, MPH, MBASECTION EDITOR:Jeffrey Callen, MD, FACP, FAADDEPUTY EDITOR:Abena O Ofori, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2024.

This topic last updated: Oct 12, 2022.

INTRODUCTION

Classic dermatomyositis (DM) is an idiopathic inflammatory myopathy that most commonly presents with progressive, symmetric, proximal muscle weakness and a group of characteristic cutaneous findings. The cutaneous manifestations may also develop in the absence of detectable muscle disease and can persist after the successful treatment of DM-associated myositis.

In addition to pathognomonic findings, such as Gottron's papules and the heliotrope eruption, DM often presents with intensely pruritic areas of confluent, violaceous erythema on the scalp, face, upper trunk, and upper extremities (picture 1A-D). The pruritus can be disabling.

Skin lesions of DM are often resistant to photoprotection and topical therapies alone, necessitating the initiation of antimalarial drugs and/or methotrexate. Patients who fail to respond to these interventions may require more aggressive immunosuppressive or immunomodulatory therapies.

The initial management of the cutaneous manifestations of DM will be discussed here (algorithm 1). The treatment of refractory cutaneous DM, as well as the clinical manifestations, diagnosis, and management of the noncutaneous manifestations of DM and juvenile DM, are reviewed elsewhere.

●(See "Management of refractory cutaneous dermatomyositis in adults".)

●(See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●(See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis".)

●(See "Initial treatment of dermatomyositis and polymyositis in adults".)

●(See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

●(See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

●(See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations".)

●(See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis".)

●(See "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis".)

OVERVIEW OF CLINICAL FEATURES

Cutaneous findings — Skin changes associated with dermatomyositis (DM) include pathognomonic findings, such as Gottron's papules (pink-violaceous papules overlying interphalangeal and metacarpophalangeal joints), Gottron's sign (macular, pink-violaceous erythema overlying other joints, such as the elbows or knees), and the heliotrope eruption (pink-violaceous erythema, with or without edema, involving the periorbital skin) (picture 2A-D). Pink-violaceous erythema of the scalp, V of the neck, shoulders, extensor surfaces of the upper extremities, upper chest, and upper back are additional characteristic findings (picture 1A-D). Scale may or may not be present but is typically prominent on the scalp, where it may be accompanied by diffuse alopecia (picture 1E).

In patients with darker skin types, cutaneous lesions often exhibit a more violaceous hue and may also exhibit prominent hyperpigmentation (picture 3). In patients with lighter skin types, cutaneous lesions tend to appear pink to red, although some will also demonstrate the characteristic violaceous hue. Additional examples of cutaneous manifestations of DM include poikiloderma, calcinosis cutis, prominent periungual telangiectasias, and cuticular hypertrophy. Panniculitis presenting as erythematous, tender, subcutaneous nodules on the lower or upper extremities is a rare manifestation [1]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Skin findings in dermatomyositis' and "Calcinosis cutis: Etiology and patient evaluation".)

The distribution of cutaneous lesions in DM suggests that photosensitivity may contribute to the development of skin lesions. Similar to findings in lupus erythematosus, significantly reduced minimal erythema doses (MEDs; the minimal irradiation dose required to elicit cutaneous erythema) to ultraviolet B (UVB) light have been detected in patients with DM [2]. In one study in which 19 patients with DM were irradiated with UVB light, 9 (47 percent) exhibited reduced MEDs [2]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.)

Impact on quality of life — Quality-of-life impairment related to skin disease is significant in DM and has been shown to be greater in patients with DM than in patients with psoriasis or atopic dermatitis [3]. Patients frequently experience debilitating symptoms of severe pruritus or burning in affected areas, which can result in emotional distress and loss of sleep. Scalp pruritus may be particularly intense and is the initial presenting symptom in DM in some patients.

Disease course — Cutaneous disease may persist for years. In one systematic review of primarily adult patients with cutaneous DM without myositis, the mean duration of skin disease was 4.5 years [4]. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Prognosis'.)

CLASSIFICATION OF CUTANEOUS DERMATOMYOSITIS

Most patients with dermatomyositis (DM) exhibit both cutaneous disease and muscle weakness (classic DM). However, a subset of patients develops characteristic skin findings of DM in the absence of muscle symptoms. This group is often referred to as clinically amyopathic dermatomyositis (CADM) and consists of both patients who lack clinical findings of myositis, but have evidence for myositis on laboratory, radiologic, or electrophysiologic studies (hypomyopathic DM), and patients in whom all signs of muscle involvement are absent (amyopathic DM) [5]. It is estimated that 9 to 13 percent of patients with CADM for more than six months eventually develop classic disease [4,5]. Descriptions of the various presentations of cutaneous DM are reviewed below.

Classic dermatomyositis — Most patients with DM present with simultaneous cutaneous and muscle involvement, evidenced by proximal muscle weakness and diagnostic testing that reveals the presence of myositis. However, the onset of cutaneous disease can precede the appearance of myositis by up to several months in 30 percent of patients with classic DM and follows shortly after muscle involvement in 10 percent [4]. The term "premyopathic dermatomyositis" is used to describe patients who have no clinical evidence for muscle disease but have had cutaneous manifestations of DM for less than six months.

Amyopathic dermatomyositis — Historically, amyopathic DM was known as "dermatomyositis sine myositis." This variant is considered a distinct form of DM, rather than classic DM in which the onset of muscle involvement is delayed for a prolonged period. Amyopathic DM is diagnosed in patients who lack muscle weakness and have no laboratory or radiologic signs of myositis despite the presence of cutaneous findings consistent with DM for at least six months [5]. Of note, the use of immunosuppressive drugs for cutaneous DM for two consecutive months or longer within the first six months of skin disease may prevent the development of clinically significant myositis [5]. In addition, the presence of drug-induced, DM-like cutaneous changes, such as can occur with hydroxyurea, must be excluded.

Approximately 10 to 20 percent of patients with DM seen in academic health centers have amyopathic disease [6]. The proportion may be higher among patients referred to dermatologists; in one dermatology referral center, approximately 40 percent of patients with DM had the amyopathic variant [7].

Hypomyopathic dermatomyositis — Similar to amyopathic DM, hypomyopathic DM presents with cutaneous findings consistent with DM and the absence of clinically appreciable muscle weakness for at least six months after the appearance of skin lesions [5]. In contrast to amyopathic disease, subclinical evidence for myositis is evident through serologic testing for muscle enzymes, electromyography (EMG), muscle biopsy, or magnetic resonance imaging (MRI).

Hypomyopathic DM is less common than amyopathic DM; among 281 patients with CADM in a systematic review, 37 (13 percent) had hypomyopathic disease and 197 (70 percent) had amyopathic DM.

Postmyopathic dermatomyositis — In classic DM, cutaneous and muscle disease often have a discordant response to therapy. Postmyopathic DM describes the persistence of cutaneous symptoms following the resolution of muscle disease with immunosuppressive therapy [4,5].

PATIENT EVALUATION

Indications for biopsy — A diagnosis of cutaneous dermatomyositis (DM) is suggested by the constellation of characteristic cutaneous findings, muscle weakness, and laboratory evidence of myositis. However, in patients who present with ambiguous cutaneous findings or cutaneous findings that are suggestive of DM in the absence of clinical signs of muscle disease, a skin biopsy should be performed.

The histopathologic findings in DM are variable but typically include an interface dermatitis characterized by vacuolization of basal keratinocytes, a lymphocytic infiltrate in the superficial dermis, and dermal mucin. The biopsy is useful for ruling out other disorders that may resemble DM, including seborrheic dermatitis, contact dermatitis, atopic dermatitis, polymorphous light eruption, and papulosquamous disorders (such as lichen planus or psoriasis). (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Muscle biopsy'.)

The greatest challenge in the diagnosis of DM involves the distinction between amyopathic DM and acute cutaneous lupus erythematosus (ACLE) or subacute cutaneous lupus erythematosus (SCLE), which, like DM, can present with photodistributed erythema and elevated antinuclear antibodies. The histopathologic findings of DM are indistinguishable from those of ACLE and SCLE. Of note, the intense pruritus often associated with DM usually does not occur in patients with ACLE or SCLE. In addition, the malar rash of ACLE traditionally spares the nasolabial folds, while the midfacial erythema of DM often involves these areas. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Muscle biopsy'.)

Additional tests — In the patient who presents with cutaneous features that are consistent with DM, investigation for concomitant muscle disease should be performed. Due to the possibility of subsequent development of muscle disease, patients without myositis should be evaluated with a muscle examination and serum creatinine kinase and aldolase levels every two to three months [8]. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Testing for myopathy'.)

As in classic DM, adults with clinically amyopathic dermatomyositis (CADM) have an increased risk for pulmonary disease and internal malignancy. Thus, patients should be evaluated and followed for the presence of these disorders. In a systematic review that analyzed 291 adult patients with CADM, 36 (13 percent) developed interstitial lung disease, and 41 cases (14 percent) were found to be associated with internal malignancy [5]. Juvenile DM is not associated with pulmonary disease or an increased risk for malignancy. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Evaluation' and "Malignancy in dermatomyositis and polymyositis", section on 'Approach to screening' and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Risk of malignancy'.)

TREATMENT

Therapy for cutaneous disease is usually indicated due to the presence of severe pruritus and patient distress over the appearance of skin lesions.

Challenges — The management of cutaneous manifestations of dermatomyositis (DM) can be challenging. Cutaneous manifestations are often more resistant to therapy than concomitant muscle involvement.

In addition, the best therapeutic approach for the cutaneous manifestations of DM remains unclear. Data on therapies are limited and primarily restricted to case reports and retrospective studies, although randomized clinical trials are emerging in DM [9-11]. Interpretation of the available literature is difficult because many studies have included patients with different variants of DM (eg, DM, polymyositis, and antisynthetase syndrome; both adult and juvenile DM; or both classic and amyopathic DM) or patients who are also receiving systemic glucocorticoids or other immunosuppressive therapies for muscle disease.

Moreover, the historical lack of standardized measures to assess responses to therapy has compromised the systematic interpretation of published literature. The consistent use of validated, objective measures of response to therapy, such as the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), will be useful for interpreting the results of future studies [12,13].

Treatment overview — A multipronged approach to treatment is often necessary to achieve a satisfactory response in patients with cutaneous DM (algorithm 1).

Our initial approach to patients with cutaneous DM typically consists of four elements:

●Aggressive photoprotection to reduce the exacerbating effects of ultraviolet light

●Antipruritic agents to manage the associated (and often severe) pruritus

●Topical corticosteroids or topical calcineurin inhibitors for local treatment of skin manifestations

●Systemic medications aimed at attaining sustained control of the disease

A small subset of patients with very mild cutaneous DM can achieve satisfactory improvement with the first three interventions. However, most patients with cutaneous manifestations of DM also require systemic treatment with antimalarial drugs, methotrexate, or other medications. (See 'Selection of systemic therapy' below and "Management of refractory cutaneous dermatomyositis in adults".)

Interventions for all patients — Implementation of photoprotection, antipruritic therapies, and topical corticosteroid or topical calcineurin inhibitor therapy is suggested for all patients (algorithm 1).

Photoprotection — Strict photoprotection is considered an integral part of the treatment of cutaneous DM because ultraviolet light exposure may exacerbate cutaneous disease [2,14,15]. Even limited sun exposure can be detrimental [15]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection".)

Year-round daily photoprotection with a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30 is recommended, and reapplication should occur every three to four hours [16]. Wide-brimmed hats, sun-protective clothing, and avoidance of sun exposure should also be encouraged. Given the degree of photoprotection mandated in this patient population, consideration should be given to vitamin D status and vitamin D supplementation. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection' and "Selection of sunscreen and sun-protective measures" and "Vitamin intake and disease prevention", section on 'Vitamin D'.)

Interventions for pruritus — Pruritus is a prominent feature of DM and can have significant adverse effects on quality of life [3,17]. Pruritus can interfere with sleep patterns and activities of daily living and should be treated aggressively with topical or oral antipruritic agents.

●Topical antipruritic therapies – Topical agents containing pramoxine, menthol, or camphor may provide temporary symptomatic relief. Topical corticosteroid therapy, as described below, may also improve pruritus. (See 'Topical corticosteroids' below.)

●Oral antipruritic therapies – Use of oral sedating antihistamines (eg, hydroxyzine, cyproheptadine, or doxepin) or other agents, such as amitriptyline or gabapentin, is often necessary to improve pruritus. Nonsedating antihistamines are not beneficial. (See "Pruritus: Therapies for generalized pruritus", section on 'General approach'.)

Skin-directed therapy — The relative safety of topical anti-inflammatory agents, including topical corticosteroids and topical calcineurin inhibitors, favors the use of these drugs in DM. However, most patients require combination therapy with a systemic agent. (See 'Selection of systemic therapy' below.)

Topical corticosteroids are generally the preferred initial topical therapies for involvement on the scalp, trunk, and extremities. Topical calcineurin inhibitors are more expensive than most topical corticosteroids and are typically reserved for patients who do not improve with topical corticosteroids or for long-term topical therapy in areas prone to corticosteroid-induced cutaneous atrophy, such as the face. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Topical corticosteroids — Clinical experience supports the use of topical corticosteroids for reducing the erythema and pruritus associated with DM [18]. In general, topical corticosteroids are considered adjunctive as most patients will require systemic therapy to adequately treat their DM skin disease. High-potency (eg, group 1) topical corticosteroids are often used to treat the hands, extensor surfaces, and scalp, where the risk of corticosteroid-induced cutaneous atrophy is low, while lower-potency agents (eg, groups 6 to 7) are used for disease in areas that are more prone to atrophy, such as facial erythema and the heliotrope eruption (table 1).

Application with occlusion (ie, coverage of the site of application by a bandage, gloves, or other dressing) increases the penetration and potency of topical corticosteroids, and the use of high-potency topical corticosteroids under occlusion may be beneficial for refractory, hyperkeratotic lesions, particularly those on the dorsal hands [4]. Topical corticosteroids are generally applied once daily when occlusion is used and twice daily in the absence of occlusion. Foam, spray, gel, oil, shampoo, or solution formulations may facilitate application on hairy areas, such as the scalp. Some experts have found topical clobetasol foam particularly helpful for scalp involvement [4].

Improvement in erythema and pruritus from topical corticosteroid therapy is usually evident within two weeks, but continued treatment is often necessary to maintain the response. Upon achievement of a satisfactory response, the application frequency and potency of the topical corticosteroid can be gradually reduced, as tolerated. The inclusion of treatment-free periods (eg, two weeks on, two weeks off therapy) is suggested to reduce the risk of local and systemic adverse effects. When long-term, continuous use of a topical corticosteroid appears necessary, a topical calcineurin inhibitor can be initiated as a corticosteroid-sparing therapy. (See 'Topical calcineurin inhibitors' below.)

Intralesional corticosteroid therapy is occasionally used for refractory lesions or for scalp disease; however, intralesional therapy is often impractical given the extent of cutaneous disease [18]. (See "Intralesional corticosteroid injection".)

Topical corticosteroids can induce local cutaneous atrophy, particularly in the setting of long-term use of high-potency agents. In addition, systemic absorption can lead to suppression of the hypothalamic-pituitary axis, particularly when used in patients with widespread disease. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Topical calcineurin inhibitors — Topical calcineurin inhibitors (most often tacrolimus 0.1% ointment) are typically utilized for patients who do not improve with topical corticosteroids or for long-term topical therapy in areas that are prone to cutaneous atrophy. Topical calcineurin inhibitors are applied to affected skin twice daily. Improvement in erythema and symptoms may be evident within the first month of treatment [19,20].

Several case reports and a small, uncontrolled study have documented successful treatment of cutaneous disease in DM with topical tacrolimus [6,19-22]. All patients were on additional therapeutic agents at the time of treatment. In the uncontrolled study, six patients (five adults and one child) were treated with tacrolimus 0.1% ointment for six to eight weeks [22]. Dramatic (>90 percent) improvement was noted in two patients, and moderate (40 to 90 percent) or minimal (20 to 40 percent) improvement was noted in one and three patients, respectively [22].

In contrast, a prospective study of five patients with cutaneous DM found a lack of benefit with topical tacrolimus [23]. No difference in disease severity was detected between skin treated with tacrolimus 0.1% ointment (twice daily for two months) and contralateral skin that was not treated with tacrolimus.

Additional studies are necessary to determine the efficacy of topical calcineurin inhibitors for cutaneous manifestations of DM. Documentation of a beneficial effect of pimecrolimus for cutaneous DM is limited to case reports documenting improvement after several months of treatment [24]. We personally have noted modest success with this drug.

Pruritus or burning sensations at sites of application are potential adverse effects of topical calcineurin inhibitors. In addition, rare reports of the development of internal malignancies in patients treated with these agents led the US Food and Drug Administration to place a boxed warning on topical tacrolimus and pimecrolimus drug labels. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)

Selection of systemic therapy — Most patients require systemic therapy to achieve satisfactory suppression of cutaneous disease. The goals of systemic treatment are to achieve resolution of pruritus and skin changes or to achieve a level of improvement in which mild, residual disease can be successfully managed with topical therapy. The clinical presentation influences the approach to treatment (algorithm 1).

Patients with extracutaneous involvement — Improvement in skin disease may occur during treatment for extracutaneous manifestations of DM, such as during treatment with systemic glucocorticoids or methotrexate, common initial treatments for muscle disease. Thus, in this population, the need for systemic therapy specifically for skin disease usually occurs when there is persistent activity of cutaneous DM despite adequate control of extracutaneous DM (eg, postmyopathic DM) and appropriate use of photoprotection and skin-directed therapies. The approach to the treatment of cutaneous manifestations in this population is similar to the approach for patients without extracutaneous DM. (See "Initial treatment of dermatomyositis and polymyositis in adults" and 'Mild cutaneous dermatomyositis' below and 'Severe cutaneous dermatomyositis' below.)

The type of extracutaneous involvement present may also influence treatment selection. For example, methotrexate is associated with risk for pulmonary toxicity and would be a less favorable choice for skin disease in patients with DM-associated interstitial lung disease. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

Of note, continuation of systemic glucocorticoid therapy is not advised for the treatment of cutaneous DM when systemic glucocorticoids are no longer required for other manifestations of DM. The potential for serious adverse effects from long-term glucocorticoid treatment and the limited evidence for efficacy of systemic glucocorticoid therapy for cutaneous disease preclude routine use of systemic glucocorticoid therapy [4]. (See "Major adverse effects of systemic glucocorticoids".)

Mild cutaneous dermatomyositis — Mild cutaneous DM is generally considered skin disease that involves a limited body surface area and/or causes minimal pruritus. With the exception of patients with very mild cutaneous DM, photoprotection, antipruritic agents, topical corticosteroids, and topical calcineurin inhibitors alone are generally insufficient for achieving adequate improvement in cutaneous DM; therefore, we typically begin systemic therapy immediately (algorithm 1). The primary systemic agents used for initial management are antimalarial drugs (eg, hydroxychloroquine, quinacrine, chloroquine) and methotrexate.

Preferred initial therapy — Hydroxychloroquine is often used as a first-line therapy for mild cutaneous DM based upon the long history of its use for this indication, the overall well-tolerated nature of this drug, and small, uncontrolled studies that have supported its efficacy (algorithm 1). However, many patients may require additional systemic therapy [25]. (See 'Hydroxychloroquine' below and 'Patients with poor response to hydroxychloroquine' below.)

Of note, antimalarial drugs, such as hydroxychloroquine, do not appear to be useful for other common manifestations of DM, such as muscle or pulmonary disease [26]. This observation suggests that the beneficial effects of antimalarials on the skin may be a result of photoprotective properties of antimalarials rather than systemic immunomodulation. Alternatively, the difference in efficacy may be a result of divergent pathogenic mechanisms for skin and muscle disease [27,28]. (See "Initial treatment of dermatomyositis and polymyositis in adults".)

Hydroxychloroquine — Hydroxychloroquine may improve the cutaneous manifestations of DM.

●Administration and efficacy – The typical total daily dose for cutaneous DM in adults is 300 to 400 mg daily, divided over two doses daily. The total daily dose should be less than or equal to 5 mg/kg (based upon real body weight) to minimize risk for hydroxychloroquine-induced retinopathy [29]. Smoking may decrease the efficacy of antimalarial drugs [30,31], and smoking cessation should be encouraged in patients who receive antimalarial therapy. (See "Antimalarial drugs in the treatment of rheumatic disease".)

Responses to antimalarial medications may not be evident until 6 to 12 weeks after the initiation of therapy [4]. A three-month trial is an appropriate period for the assessment of treatment efficacy.

Evidence for the efficacy of hydroxychloroquine is limited to small, uncontrolled studies. An open study of seven patients in whom cutaneous DM persisted during systemic glucocorticoid therapy or worsened during glucocorticoid tapering found that the addition of hydroxychloroquine to the therapeutic regimen led to complete resolution of skin disease in three patients and partial improvement in the other four [32]. Additional small, retrospective studies also demonstrate favorable results with hydroxychloroquine for cutaneous DM [33-36].

An analysis of a series of 115 patients with amyopathic or hypomyopathic DM managed at tertiary care centers suggests that systemic therapy with hydroxychloroquine alone may not be sufficient for many patients with cutaneous DM; only 10 of 88 patients (11 percent) treated with antimalarial therapy achieved control of skin disease [25]. The severity of disease in patients included in the study was not assessed.

●Adverse effects – Ocular, gastrointestinal, hematologic, and neurologic adverse effects may occur secondary to antimalarial therapy. The risk of irreversible retinopathy is restricted to hydroxychloroquine and chloroquine. Thus, patients treated with either of these drugs should have a baseline ophthalmologic examination prior to, or soon after, the initiation of therapy and require follow-up for the development of retinal abnormalities [29]. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity'.)

Cutaneous adverse effects related to hydroxychloroquine treatment have also been reported in patients with DM. Retrospective studies suggest cutaneous drug eruptions secondary to hydroxychloroquine occur in approximately 30 percent of patients with DM [25,37]. The eruption is most often a morbilliform eruption, but the development of bullae or drug reaction with eosinophilia and systemic symptoms (DRESS) is possible. In addition, worsening of cutaneous disease has been reported in two children with DM after the initiation of hydroxychloroquine [38]. The autoantibody phenotype may influence risk for cutaneous adverse reactions [39].

Patients with poor response to hydroxychloroquine — When the response to hydroxychloroquine is inadequate, we typically add quinacrine or methotrexate to hydroxychloroquine therapy in an attempt to augment the response (algorithm 1). Methotrexate may be used alone for patients who cannot tolerate antimalarial therapy.

The efficacy of hydroxychloroquine plus quinacrine versus hydroxychloroquine plus methotrexate for cutaneous DM has not been directly compared, leaving uncertainty regarding relative efficacy. Our selection of quinacrine versus methotrexate is often influenced by patient comorbidities and disease severity. Although quinacrine offers the advantage of a more benign adverse effect profile, in our experience, the combination of hydroxychloroquine and methotrexate often provides a more substantial response than the combination of hydroxychloroquine and quinacrine. Thus, for patients who are likely to tolerate either agent, we tend to favor the addition of methotrexate as disease severity increases. (See 'Severe cutaneous dermatomyositis' below.)

Substitution of hydroxychloroquine with chloroquine is an alternative for patients with insufficient responses to hydroxychloroquine that we use less frequently because of greater concern for ocular toxicity. (See 'Chloroquine' below.)

Therapeutic options for patients who fail to respond to antimalarials and methotrexate are reviewed separately. (See "Management of refractory cutaneous dermatomyositis in adults".)

Quinacrine — The addition of quinacrine (100 mg per day) to hydroxychloroquine or chloroquine therapy may improve the response to treatment. In the United States, quinacrine can only be obtained at compounding pharmacies. In addition, it is not approved for human use in the United States. Limited availability and increased cost has made obtaining quinacrine difficult in the United States.

●Administration and efficacy – Similar to hydroxychloroquine, responses to quinacrine may not be evident before six to eight weeks. At least three months of treatment is suggested prior to assessing the response to treatment.

In a retrospective case series in which 7 out of 17 patients (41 percent) with DM experienced at least near clearance of cutaneous disease with antimalarial therapy alone, 4 of the responders required the addition of quinacrine to hydroxychloroquine or chloroquine therapy to achieve this level of improvement [40]. This observation suggests that a subset of patients may benefit from combination antimalarial therapy after failure to respond sufficiently to monotherapy.

●Adverse effects – Reversible yellow discoloration of the skin is a common adverse effect of quinacrine. Quinacrine does not cause retinopathy, which enables use of the drug in patients taking hydroxychloroquine or chloroquine. In contrast, hydroxychloroquine and chloroquine, both of which can induce ocular damage, should not be taken simultaneously. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects'.)

Methotrexate — Methotrexate can be effective for cutaneous disease in DM; however, the drug has a broader side effect profile than hydroxychloroquine, supporting the use of hydroxychloroquine as the initial choice of therapy in patients with mild disease (algorithm 1).

●Administration and efficacy – Methotrexate is taken on a weekly basis and can be given orally, intramuscularly, or subcutaneously. Methotrexate is not given daily.

Treatment with methotrexate requires monitoring of complete blood counts, liver function, and renal function. Prior to administering methotrexate, we obtain baseline laboratory tests (complete blood count, renal function tests, and liver function tests). In addition, we assess patients for hepatitis B and C because chronic liver disease is a risk factor for methotrexate-induced hepatotoxicity.

We usually begin at a dose of 5 to 10 mg per week, depending upon the patient's age and health status (eg, healthy people under 65 years of age may begin at 7.5 or 10 mg weekly, whereas those with renal insufficiency or other comorbidities that may make tolerating methotrexate more challenging may be started at 5 mg/week).

Laboratory tests (complete blood count with differential, hepatic function panel, and renal function) are checked after two weeks, and if normal and the patient is not experiencing any clinical side effects, the weekly dose is increased. Various methods are utilized in terms of dose escalation. Some experts increase the weekly dose by 2 to 5 mg per week (depending on the patient's age and health status) every one to two weeks until the target dose is reached, checking laboratory tests every two weeks. Others choose to increase the dose directly to 25 mg after the first two-week laboratory check in healthy patients.

We typically titrate methotrexate up to a dose of 25 mg/week, although occasionally, doses of up to 30 mg weekly are used [41]. We hold at that dose for at least 12 weeks, as the onset of action of methotrexate is frequently not seen until two to three months of therapy at the "full" "target" dose. Because absorption of oral methotrexate may be reduced at higher doses [42], when doses exceed 15 mg/week, we split the total dose of methotrexate into a morning and an evening dose or instruct the patient to take the second half of the dose on the following day.

Once the dose of methotrexate is stable, laboratory tests are repeated every two to three months. Improvement in cutaneous manifestations usually occurs within eight to twelve weeks.

Administration of folic acid (1 mg per day) or leucovorin (5 mg per week, 8 to 12 hours after methotrexate administration in patients who do not respond sufficiently to folic acid) may decrease the incidence of some methotrexate-induced adverse effects.

The efficacy of methotrexate for the cutaneous manifestations of DM has not been studied in randomized trials, and evidence for the support of this therapy is primarily limited to retrospective analyses [43-46]. In one retrospective study of 13 patients with cutaneous DM who were treated with methotrexate (2.5 to 30 mg/week), eight achieved complete or almost complete clearance of skin lesions [45]. All patients who were simultaneously treated with systemic glucocorticoids were able to reduce or discontinue glucocorticoid therapy.

The presence of an abundant lymphocytic infiltrate on skin biopsy seemed to portend an increased likelihood for a response to methotrexate (7.5 to 20 mg/week) in a separate retrospective study in which 8 of 11 patients who failed to improve adequately with systemic glucocorticoids improved during methotrexate therapy [46]. However, further investigations are necessary to confirm this finding.

●Adverse effects – Gastrointestinal upset, stomatitis, and leukopenia can occur during treatment with methotrexate but may be minimized by folic acid or leucovorin supplementation. Hepatotoxicity and pulmonary fibrosis are additional adverse effects associated with this drug [43]. (See "Major adverse effects of low-dose methotrexate".)

Due to the risk of liver toxicity, pre-existing liver disease and alcohol abuse are relative contraindications for methotrexate. In addition, the risk of methotrexate toxicity is increased in patients with renal insufficiency; doses must be adjusted in this population.

Teratogenicity is another potential adverse effect of methotrexate; the drug should not be given to pregnant women. Methotrexate should also be avoided in women for one to three menstrual cycles prior to pregnancy and in men for one month prior to an attempt to conceive.

Chloroquine — An alternative intervention for patients who fail to respond adequately to hydroxychloroquine is to discontinue hydroxychloroquine and switch to chloroquine (250 mg per day). This concept is based upon the perception that some patients who do not respond to hydroxychloroquine can respond to chloroquine, although the response to a switch appears variable and data to confirm greater efficacy of chloroquine in cutaneous DM are lacking [40]. Similar to hydroxychloroquine, responses may not be evident until six to eight weeks after treatment initiation. A reasonable trial period for assessment of effect is three months.

The greater risk for drug-induced retinopathy from chloroquine compared with hydroxychloroquine contributes to our preference for hydroxychloroquine for first-line therapy [47]. To minimize the risk for retinopathy, the dose of chloroquine should not exceed more than 3 mg/kg per day based upon the patient's ideal body weight. (See "Antimalarial drugs in the treatment of rheumatic disease".)

Severe cutaneous dermatomyositis — Often, despite its broader side effect profile, we utilize methotrexate alone or in combination with hydroxychloroquine rather than hydroxychloroquine alone as the initial systemic treatment for severe cutaneous DM (algorithm 1). Severe cutaneous DM is generally considered disease that is associated with intolerable pruritus, impacts a substantial body surface area, or is otherwise disabling. The regimen for methotrexate is similar to the regimen used for milder disease.

The preference for methotrexate for severe disease is based upon clinical experience that suggests methotrexate may be more effective than hydroxychloroquine for cutaneous DM. In one series of 115 patients with amyopathic or hypomyopathic DM managed at four tertiary care centers, only 10 of 88 patients (11 percent) treated with antimalarial drugs achieved control of skin disease [25].

Clinicians vary on the approach to methotrexate therapy. While some clinicians, including the author, prefer to start methotrexate and hydroxychloroquine simultaneously, others assess the response to methotrexate and subsequently add hydroxychloroquine if there is an insufficient response to therapy.

Tapering of systemic therapy — Once a patient achieves satisfactory improvement with antimalarial and/or methotrexate therapy and maintains the response for several months, slow tapering of the treatment should be attempted to reach the lowest dose necessary to maintain the response. For patients who respond to combination therapy with hydroxychloroquine and quinacrine or hydroxychloroquine and methotrexate, we typically attempt to discontinue quinacrine or methotrexate prior to tapering hydroxychloroquine. Quinacrine can be stopped acutely without tapering. We generally taper the weekly dose of methotrexate by 2.5 to 5 mg every two to three months, provided relapse has not occurred.

Cutaneous DM is usually a chronic condition. In our experience, many patients require continuation of some level of systemic therapy for years. (See 'Disease course' above.)

Recurrent and resistant disease — Some patients with DM may relapse after an initial response to the above therapies or may fail to respond to these treatments [48]. The management of patients with recalcitrant or recurrent DM is reviewed separately (algorithm 1). (See "Management of refractory cutaneous dermatomyositis in adults".)

Other therapies — Treatment with topical brimonidine, an alpha-2 adrenergic agonist used to improve facial erythema in patients with rosacea, appeared effective for temporarily improving DM-associated facial erythema in a single patient with amyopathic DM [49]. Further study is necessary prior to a recommendation for the use of this therapy for cutaneous DM.

CALCINOSIS CUTIS

The treatment of calcinosis cutis in patients with dermatomyositis (DM) is reviewed elsewhere. (See "Management of refractory cutaneous dermatomyositis in adults", section on 'Calcinosis cutis' and "Calcinosis cutis: Etiology and patient evaluation" and "Calcinosis cutis: Management".).

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatomyositis and polymyositis".)

SUMMARY AND RECOMMENDATIONS

●General principles – Dermatomyositis (DM) is an idiopathic inflammatory disorder for which cutaneous findings are a prominent feature. Inflammatory myopathy also frequently occurs in DM but may precede, follow, or remain absent in patients with cutaneous manifestations of the disease. In some patients, cutaneous findings may persist after the successful treatment of myositis. (See 'Overview of clinical features' above and 'Classification of cutaneous dermatomyositis' above.)

●Clinical features – Patients with DM often present with a pruritic, pink-violaceous, macular, and papular eruption that primarily affects the upper body (picture 1D-E). Pruritus can be intense and may have significant effects on patient quality of life. (See 'Overview of clinical features' above.)

●Management – Data on treatment options for the cutaneous manifestations of DM are limited. Photoprotection, management of pruritus, and topical therapy are important components of management for all patients. Most patients also require systemic therapy to achieve control of cutaneous DM (algorithm 1). (See 'Treatment overview' above and 'Interventions for all patients' above.)

•Skin-directed therapy – For patients with cutaneous manifestations of DM, we suggest topical corticosteroids for initial topical therapy (Grade 2C). Topical calcineurin inhibitors are an additional option that may be useful for long-term treatment in skin areas at greatest risk for corticosteroid-induced skin atrophy. (See 'Skin-directed therapy' above.)

•Systemic therapy

-Associated extracutaneous involvement – Cutaneous DM may improve during treatment of other manifestations of DM, such as myositis. The need for systemic treatment specifically for cutaneous disease typically arises when active skin disease persists despite adequate control of other manifestations. (See 'Patients with extracutaneous involvement' above.)

-Mild cutaneous dermatomyositis – For patients with mild cutaneous DM (eg, less than 10 percent body surface area involvement, tolerable pruritus, and nondisabling), we suggest hydroxychloroquine rather than methotrexate as the initial systemic therapy (Grade 2C). For patients who do not improve sufficiently with hydroxychloroquine, we suggest the addition of quinacrine or methotrexate (Grade 2C). (See 'Mild cutaneous dermatomyositis' above.)

-Severe cutaneous dermatomyositis – For patients with severe cutaneous DM (eg, at least 10 percent body surface area involvement, intolerable pruritus, or otherwise disabling disease), we suggest methotrexate rather than hydroxychloroquine as the initial systemic therapy (Grade 2C). Methotrexate and hydroxychloroquine may be started simultaneously or hydroxychloroquine may subsequently be added if there is an insufficient response to methotrexate. (See 'Severe cutaneous dermatomyositis' above.)

•Role of systemic glucocorticoids – Systemic glucocorticoids are not indicated for the initial management of cutaneous DM. The response to systemic glucocorticoids is unpredictable, and the adverse effects associated with long-term therapy limit the use of these drugs for cutaneous DM. (See 'Patients with extracutaneous involvement' above.)

OCTAGAM® 10% [Immune Globulin Intravenous (Human)] liquid | Dosing & Infusion Rates (DM) (pfizerpro.com) 

DRESS

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718748/

anti-SRP54ab (normal: 11).  WUSTL  (Dr. Pestronk's lab).  Young tall, black man with rapid onset of muscle weakness, very high aldolase, think anti-SRP54-ab. 

https://pmc.ncbi.nlm.nih.gov/articles/PMC9612835/

Immune mediated myopathy due to anti-Ro-ab.  

TNF-α inhibitor-related autoimmune disorders

Tumor Necrosis Factor Inhibitor–Associated Dermatomyositis | Dermatology | JAMA Dermatology | JAMA Network 

https://assets.bmctoday.net/practicalneurology/pdfs/PN0721_CF4_IIM_2.pdf

https://www.mayoclinicproceedings.org/article/S0025-6196(12)01044-0/pdf

Overlap of Sjögren's Syndrome and Immune-Mediated Necrotizing Myopathy With Interstitial Lung Disease: A Case Report - PMC 

https://reumaped.es/images/site/pdf/cuestionarios/MDAAT_MyositisDiseaseActivityAssessmentTool.pdf

https://www.hopkinsmyositis.org/tag/scleroderma-associated-myopathy/