Inflammatory myopathies (primary and secondary)

Inflammatory myopathies
Classification of Inflammatory Myopathy
Dermatomyositis
Diagnostic Evaluation in Myositis
MRI of muscle in diagnostic work-up of myositis
Electrodiagnostic Studies in Myositis (DM).
Polymyositis
Bohan and Peter Criteria for Diagnosis of DM and PM
Autoantibodies associated with inflammatory myopathies:
Myositis-Specific Antibodies:
Myositis-Associated Antibodies
Antisynthetase autoantibodies:
Antisynthetase syndrome
Dermatomyositis specific Myositis-specific autoantibodies
IMNM (NAM)
IBM autoantibodies
Treatment Link:
Inclusion body myositis (IBM)
Diagnostic Criteria (Griggs et al.) for Inclusion Body Myositis
European Neuromuscular Centre diagnostic criteria for inclusion body myositis.
Lloyd and Greenberg criteria require all three of the following features:
IBM functional rating scale
Treatment regimens for Immune-Mediated Myopathies
Algorithim approach in treatment of Myositis
Treatment Strategy
Muscle biopsy vs antibodies based diagnosis
Muscle Biopsy Guidelines
Classification of muscular manifestations of systemic diseases
Infectious diseases
Endocrinopathy and muscle disease
Metabolic disorders and muscle disease
Immunological disorders association with immune-mediated myopathies
Vascular disorders and myopathies
Hematological disorders
Cancer associated myositis:
Eosinophilic Myopathy
Other Associations with Inflammatory myopathies
GVHD associated polymyositis
Overlap Syndromes
Isolated neck extensor myopathy (INEM)
Diabetes and muscle disease
Current Classification and Management of Inflammatory Myopathies - PMC (nih.gov)
Case Vignettes

Inflammatory myopathies

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

Classification of Inflammatory Myopathy

Polymyositis (PM), dermatomyositis (DM), (immune-mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis, OM) including anti-synthetase syndrome , and inclusion body myositis (IBM) 

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. 

Muscle biopsy is the definitive diagnostic test for DM. 

Diagnostic Evaluation in Myositis

Several diagnostic tools are now available for evaluating patients suspected of having a myositis.  These include serum muscle enzymes, electrodiagnostic studies, myositis antibodies, muscle biopsy, and muscle MRI

Serum creatine kinase (CK) levels are often elevated as a result of muscle membrane damage and necrosis in patients with myositis.  In dermatomyositis, CK levels are often increased; however, they may range from normal to up to thousands of international units per liter.  Since CK values in dermatomyositis can be normal, the CK level may not necessarily reflect disease severity or may not always be useful in monitoring disease progression/activity.

Other enzymatic markers that may be elevated when released from damaged skeletal muscle include aldolase, lactate dehydrogenase, as well as the transaminases, aspartate transaminase (AST) and alanine transaminase (ALT) (which are present both in liver and skeletal muscle).  In patients with myositis, elevated levels of AST and ALT may cause confusion, raising a question of liver damage; thus, checking the γ-glutamyltransferase level, which is liver-specific (and normal in patients with myositis when the liver is unaffected), can be useful to distinguish liver damage from skeletal muscle inflammation.

MRI of muscle in diagnostic work-up of myositis

Muscle MRI is a useful noninvasive tool more recently used to aid in the diagnosis and management of inflammatory myopathies.  MRI scans may demonstrate distribution and severity of muscle involvement (reflecting disease burden), provide guidance to select an affected muscle to biopsy (increasing the yield of the biopsy), and give insight into the response to immunotherapy.  MRI is helpful for visualizing muscle edema (an early finding of active disease), muscle atrophy, and fatty replacement (seen in chronic disease), as well as subcutaneous edema and fasciitis.   Short tau inversion recovery (STIR) sequences are best used to detect muscle or fascial edema, whereas axial T1-weighted images are helpful in visualizing fatty atrophy.  Distinct patterns of muscle involvement have been described to aid in early diagnosis of the idiopathic inflammatory myopathies.

In dermatomyositis, STIR images commonly demonstrate hyperintensity or edema in a patchy distribution in the muscle, along with edema of the subcutaneous tissues and fascia (an uncommon finding in other inflammatory myopathies) and may mirror the distribution of skin involvement.  Fatty infiltration in dermatomyositis is reportedly mild.   MRI has also been useful in detecting the calcinosis deposits seen in dermatomyositis as well as in evaluating patients with dermatomyositis who are designated to have clinically amyopathic dermatomyositis because muscle MRI may occasionally show subtle edema along the fascia or subtly affecting the muscle, indicating that there may indeed be mild muscle involvement.

Muscle MRI in patients with immune-mediated necrotizing myopathy is useful in demonstrating the distribution of affected muscle and disease burden of both active and chronic disease.  Patients with active immune-mediated necrotizing myopathy have MRI findings of generalized muscle edema (seen as hyperintensities on STIR sequences that are associated with ongoing inflammation or myofiber necrosis) atrophy and fatty infiltration (seen on T1-weighted images and that can begin early after onset of the disease), with minimal fascial edema (in contrast to patients with dermatomyositis).  Additionally, patients with immune-mediated necrotizing myopathy may have less involvement of the anterior compartment of the thigh, in comparison to patients with inclusion body myositis.  In comparison with patients with anti–HMG-CoA reductase myopathy, the muscle MRIs of patients with anti-SRP myopathy reveal higher rates of fatty replacement and atrophy, demonstrating a more severe form of myopathy.

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 

Bohan and Peter Criteria for Diagnosis of DM and PM

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.

Myositis-Associated Antibodies

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.

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.

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, and anti-Ha) directed against different tRNA synthetases have been recognized.  

Antisynthetase syndrome

This syndrome includes two or more of the following: myositis, interstitial lung disease, arthritis, 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.

Muscle biopsies in patients with antisynthetase syndrome share feature similar to those of dermatomyositis biopsies (eg, perifascicular atrophy,  microvasculature abnormalities).  However, other 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.

Dermatomyositis specific Myositis-specific autoantibodies

IMNM  (NAM) 

IBM autoantibodies

Treatment Link:  

Inclusion body myositis (IBM)

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

European Neuromuscular Centre diagnostic criteria for inclusion body myositis. 

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

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

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. 

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 hypokalemic. 

Methotrexate, 5 mg/week PO with 2.5 mg/week increments up to 20 mg/week, given in 3 divided doses 12 hours apart.  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 utp 60 mg qwk. 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. 

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

Azathioprine, 2-3 mg/kg PO daily or bid. Begin with a low initial dose. Onset of action: 4-10 mo, max effect: 1-2 years

Mycophenolate mofetil 500 mg PO bid

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.   Patient 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. 

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 weekk for 4 weeks.  Repeat 6-18 months depending on the patient clinical exam.  

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

Algorithim approach in treatment of Myositis

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 caveat is what about turnaround time for Abs vs 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.

Therefore, it is important to know:

Muscle Biopsy Guidelines 

Idiopathic inflammatory myopathy (IIM)

 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: 

 

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.  

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

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

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

Parathyroid dysfunction

Other endocrinopathies

Metabolic disorders and muscle disease

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

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).

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.

Hematological disorders

Hematological disorders are rarely associated

with muscle disease. Muscle involvement has been

particularly reported in sickle cell anemia (182).

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.

Neoplasms

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 (183). They have been long

recognized in association with cancer (183).

Only rarely may polymyositis/dermatomyositis

be associated with acute myelocytic leukemia

(183). In single cases, chronic lymphatic leukemia

may go along with inclusion body myositis

(184, 185). Pyomyositis may be the initial presentation

not only of chronic myeloid leukemia

(186) but also of acute lymphocytic leukemia

(187). In a girl with secondary acute myelogenous

leukemia following chemotherapy, tuberculous

myositis developed (188). Chemotherapy

for leukemia may occasionally induce pyomyositis

(189).

Lymphoma – Lymphoma is frequently associated

with muscle disease, particularly with polymyositis

or dermatomyositis (190). B-cell lymphoma,

T-cell-lymphoma, and Hodgkin’s lymphoma have

been reported in association with dermatomyositis

or polymyositis (191). 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 (191). In single cases,

B-cell lymphoma manifested with isolated myositis

of a single extra-ocular muscle (192). 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. Waldenstr€om’s macroglobulinemia

may go along with antidecorin (BJ) myopathy.

Patients with thymoma may develop rippling

muscle syndrome. Patients with paraproteinemia

(M-protein, j > k 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 traceruptake

in myositis (164) 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 (193). Determination of

various muscle-specific antibodies or auto-antibodies,

such as anti-Jo1, anti-PL7, anti-PL12

(ASS) (166), 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 (158). Antidecorin

antibodies (BJ antigen) may indicate

Waldenstr€om’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

(45). Disturbed neuromuscular transmission

may explain muscle weakness and fatigue

during a viral infection (45). 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

(194). Before diagnosing a secondary myopathy,

a primary myopathy needs to be excluded (195).


Treatment

Treatment of muscle involvement in systemic diseases

is mainly based on the treatment of the

underlying disorder. Additionally, symptomatic

measures for pain, muscle cramps, muscle stiffness,

can be applied. Symptomatic measures for

myositis may also include nonsteroidal analgesic

drugs, steroids, immunoglobulin, or immunosuppressants.

Diabetic myonecrosis responds favorably

to bed rest and analgesics. In case of

immune-mediated myasthenia, cholinergic drugs,

steroids, or immuno-suppressants may be necessary.

In case of vasculitis-related myopathy,

immuno-suppression may be beneficial. Infectious

myositis may respond to adequate antibiotic

treatment. Helminthic infections may respond to

antihelmintics with or without steroids. In case of

abscess formation, puncture and drainage or

resection may be indicated. In severe pyomyositis

due to toxocarosis, repeated debridement may be

inevitable (91). In a rare case of myopathy associated

with Whipple disease antibiotics exhibited a

beneficial effect on muscle manifestations (196).

In case of severe rhabdomyolysis with renal insufficiency

diuretics, hemofiltration or hemodialysis

may beneficially influence the muscle pathology.

Most cases of muscle involvement in systemic disease

profit from physiotherapy.

Limitations

Systemic disease is not addressed in this review

because of limited space, to few reports in the literature,

or low frequency of muscle involvement,

include aspergillosis, celiac disease (197), Henoch-

Schoenlein purpura, Crohn’s disease, mucoviscidosis,

sarcoidosis, AMPA-associated immune

encephalitis (198), renal myopathy, and vitamin-

D deficiency (199).

Clinical implications and summary

For treating physician, it is essential to know

about muscular involvement in infectious, endocrine,

metabolic, immunogenic, vascular, hematological

diseases, or neoplasms. As soon as muscle

involvement is suspected, referral to the neurologist

is inevitable, and appropriate diagnostic measures

as outlined above need to be initiated. In

emergency cases due to renal or respiratory compromise,

the treating neurologist must instantly

manage and supervise the diagnostic procedures

to initiate appropriate treatment in due time. In

case of chronic muscle involvement, diagnostic

steps may be taken more slowly but may be more

invasive including abscess puncture or muscle

biopsy. Particularly in infectious diseases, it is

important to precisely determine the causative

agent to apply the most specific antimicrobial

agents with the highest effect. Muscle involvement

in systemic diseases needs to be recognized

and thoroughly investigated, as some cases may

take a rapid or fulminant course with a high

probability of an unfavorable or even fatal outcome.

Cancer associated myositis: 

Eosinophilic Myopathy

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

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.

Subclasses:

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.

GVHD associated polymyositis

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. 

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. INME 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. Differential diagnoses include disorders causing secondary DHS (multiple system atrophy, amyotrophic lateral sclerosis, myasthenia gravis, and polymyositis).  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. 

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.  

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.)