SLE

• • Epidemiology: 20 - 40 years age group; 1:2500; m:f ratio 9:1; children and older adults the m: f is same; common in African Americans.

    • Risk factors: Genetics and environment

  • Pathology:

    • Type III hypersensitivity reaction (due to deposition of immune complex and subsequent activation of complement cascade)

    • Morphology of SLE: LE cells in tissue (neutrophils containing phagocytosed nuclei.

      • SLE in renal disease has 5 classes:

        • Class I: no disease

        • Class II: Mesangial - increase in mesangial matrix due to deposition of immune complexes.

        • Class III: Focal proliferative glomerulonephritis - few glomeruli have proliferation of endothelial and mesangial cells; associated with increased number of neutrophils and possibly fibrinoid necrosis.

        • Class IV: Diffuse proliferative glomerulonephritis - most if not all glomeruli have changes seen in Class III.

        • Class V: Membranous glomerulonephropathy - glomeruli have thickened basement membranes, producing a "wire-loop" pattern.

  • Clinical presentation: Mnemonic: MD SOAP BRAIN

    • Malar rash

    • Discoid rash

    • Serositis: pericarditis, pleural effusion, peritonitis, synovitis

    • Oral ulcers

    • Arhtralgias: include myalgia, arthritis, arthralgia are often the first complain of Pts diagnosed with SLE.

    • Photosensitivity

    • Blood d/o: hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia

    • Renal dysfunction: proteinuria >0.5 g/dL; cellular casts

    • ANA abs

    • Immunologic d/o: anti-dsDNA ab, anti-Smith ab, antiphospholipid ab (+ve lupus anticoagulant, abnormal level of IgM, IgG anticardiolipin, false positive test for syphilis. Cardiolipin is a constituent material used in a syphilis test (which one?)

    • Neurological d/o: sz, psychosis, including chorea

    • Other features: Sx: fever, wt. loss, malaise, Raynaud's phenomenon, miscarriages, meds (INH, hydralazine, procainamide)

    • Two conditions commonly associated with SLE are antiphospholipid antibody syndrome (APA or APLAS), and drug-induced lupus.

  • Opportunistic infections are the most common cause of death. Renal (ESRD) and CNS diseases are the 2nd most common cause of death.

  • ANA is a sensitive screening test, anti-dsDNA is specific. Anti-Sm  is also specific. Complement levels become depressed during active dz, but returns to normal during remissions.

Clinical and Immunologic Criteria Used in the Systemic Lupus International Collaborating Clinics Classification Criteria:

Classification Rule:  Classify a patient as having SLE if

The patient satisfies four of the criteria listed including at least one clinical and one immunologic criterion

OR

The patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies

Clinical Criteria:

1. Acute cutaneous lupus including:

• Lupus malar rash (do not count if malar discoid)

• Bullous lupus

• Toxic epidermal necrolysis variant of systemic lupus erythematosus

• Maculopapular lupus rash

• Photosensitive lupus rash

• In the absence of dermatomyositis

OR

• Subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias)

2. Chronic cutaneous lupus including:

• Classic discoid rash

  • Localized (above the neck)

  • Generalized (above and below the neck)

• Hypertrophic (verrucous) lupus

• Lupus panniculitis (profundus)

• Mucosal lupus

• Lupus erythematosus tumidus

• Chilblains lupus

• Discoid lupus/lichen planus overlap

3. Oral ulcers

• Palate

• Buccal

• Tongue

OR

Nasal ulcers

In the absence of other causes, such as vasculitis, Behçet disease, infection (herpes), inflammatory bowel disease, reactive arthritis, and acidic foods.

4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs)

In the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia.

5. Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness in two or more joints and 30 minutes or more of morning stiffness

6. Serositis

• Typical pleurisy for more than 1 day

OR

• Pleural effusions

OR

Pleural rub

• Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day

OR

• Pericardial effusion

OR

• Pericardial rub

OR

• Pericarditis by ECG

In the absence of other causes, such as infection, uremia, and Dressler syndrome

7. Renal

• Urine protein/creatinine (or 24-hour urine protein) representing 500 mg of protein per 24 hours

OR

• Red blood cell casts

8. Neurologic

• Seizures

• Psychosis

• Mononeuritis multiplex

  • In the absence of other known causes such as primary vasculitis

• Myelitis

• Peripheral or cranial neuropathy

  • In the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus

• Acute confusional state

  • • In the absence of other causes, including toxic-metabolic, uremia, or drugs

9. Hemolytic anemia

10. Leukopenia (<4000/mm3 at least once)

In the absence of other known causes such as Felty syndrome, drugs, or portal hypertension

OR

• Lymphopenia (<1000/mm3 at least once)

  • In the absence of other known causes such as corticosteroids, drugs, or infection

11. Thrombocytopenia (<100,000/mm3 at least once)

In the absence of other known causes such as drugs, portal hypertension, or TTP

Immunologic Criteria

1. ANA above laboratory reference range

2. Anti-dsDNA above laboratory reference range, except ELISA: twice above laboratory reference range

3. Anti-Sm

4. Antiphospholipid antibody as determined by any of the following

• Lupus anticoagulant

• False-positive RPR

• Medium or high titer anticardiolipin (IgA, IgG, or IgM)

• Anti-beta2 glycoprotein I (IgA, IgG, or IgM)

5. Low complement

• Low C3

• Low C4

• Low CH50

6. Direct Coombs test in the absence of hemolytic anemia

The recent guidelines for the clinical use of antinuclear antibody tests issued by a Committee of the College of American Pathologists (CAP), suggest widespread misunderstanding of the clinical value of testing for the level of anti-ssDNA (single-stranded DNA or total DNA) IgG antibodies. This misunderstanding may stem from misconceptions about the manner in which clinicians use, in clinical context, immunoassays that have results expressed on a wide numerical scale. 

When the anti-ssDNA antibody (Ab) test is used for the differential diagnosis of new patients suspected of an inflammatory rheumatic disease the clinical sensitivity for systemic lupus erythematosus (SLE) is close to 100%, and the specificity about 85%. Since anti-dsDNA (double stranded DNA) is present in only about 65% of new SLE patients, an abnormal anti-ssDNA Ab test in the remaining 35% provides the clinician with a valuable clue to search for other criteria for SLE. Contrary to a widely held belief that anti-ss-DNA Ab occurs frequently in patients with rheumatoid arthritis (RA), anti-ssDNA is present only in 10–15% of this patient population and then at relatively low levels. There is evidence that anti-ssDNA, like anti-dsDNA, is involved in the pathogenesis of lupus nephritis. Moreover, the increase in anti-ssDNA Ab level appeared to be the best predictor of forthcoming increase in anti-dsDNA and SLE flare. In a context of symptoms different from those of rheumatic diseases, anti-ssDNA antibodies may be elevated in a relatively high proportion of patients with any of several diseases; leukemia, preeclampsia, chronic hepatitis, renal complications of diabetes, and some inflammatory neurological diseases. In conclusion, anti-ssDNA helps to rule out SLE, helps in the diagnosis of SLE when anti-dsDNA is not present and is useful in follow-up of SLE patients. Like most other quantifiable laboratory indicators of abnormality, anti-ssDNA Ab test is also useful in clinical context for the diagnosis and prognosis of several other condition.

SLE and Neurological manifestations:

Look for evidence of constitutional symptoms, alopecia, photosensitive rash, serositis, synovitis, renal dysfunction,  Raynaud phenomenon, cutaneous vasculitis, hematologic abnormalities, and thromboembolic disease.  

SLE is strongly associated with increased risk of stroke, CNS demyelinating syndromes.  It is also associated with meningoencephalitis, vasculitic neuropathy, peripheral neuropathy.  There is no association with myopathy.

SLE is associated with various neuropsychiatric syndromes, collectively referred to as neuropsychiatric SLE.  The American College of Rheumatology has described standard case definitions identifying 19 central and peripheral neuropsychiatric SLE syndromes.   Although these definitions have provided stricter reporting nomenclature and consequently narrower prevalence estimates of neuropsychiatric SLE (20% to 40% of patients with SLE), they do not imply  direct causation.  While neurologic injury can be caused by the SLE disease process (sometimes referred to in the literature as primary neuropsychiatric SLE), neuropsychiatric symptoms often arise from complications of SLE such as infection, metabolic derangements, or medication toxicity (secondary neuropsychiatric SLE) but can also be caused by comorbid neural autoimmunity.

In addition, the pathophysiology underlying primary neuropsychiatric SLE is heterogeneous, including both inflammatory and vascular mechanisms, and remains ill-defined.  As such, clinicians must be careful when attributing neuropsychiatric symptoms to SLE.  Evidence of systemic disease activity can be supportive but is neither necessary nor sufficient to establish a diagnosis of primary neuropsychiatric SLE.  For those without a preexisting diagnosis of SLE, the presence of multisystem disease and detection of autoantibodies associated with SLE can suggest the diagnosis.  The patient’s age can also be helpful as the risk of SLE flares decreases with age, and neuropsychiatric involvement is less common in late-onset SLE.  Patients with neurologic complications due to the SLE process are considered to have severe disease, resulting in higher morbidity and mortality and possibly necessitating escalation of therapy. Ultimately, it is imperative to systematically exclude alternative etiologies before ascribing a specific neuropsychiatric syndrome to SLE and deciding on the most appropriate management strategy.  

Neuropsychiatric Syndromes Encountered in Systemic Lupus Erythematosus

CNS Manifestations

Headache and mood disorders are the most commonly reported neuropsychiatric SLE syndromes. Still, recent studies suggest that the prevalence of headache is not significantly higher in patients with SLE compared with the general population, and neither headache nor mood disorders track disease activity. Therefore, whether headache or mood disorders are causally linked to SLE remains unclear.   Changes in cognitive function are also commonly reported by patients with SLE.  Severity ranges from nonspecific subjective cognitive clouding, or “brain fog,” to more marked impairment captured on objective testing. There is conflicting evidence on whether SLE is associated with an increased risk of dementia or whether cognitive impairment remains stable or even improves over time.  Factors outside the SLE disease process likely contribute to cognitive dysfunction, although microvascular injury and loss of white matter integrity secondary to SLE-associated vasculopathy may play a role in some cases.  This conjecture is supported by the observation that objective cognitive impairment is associated with the detection of antiphospholipid antibodies (aPLs; specifically anticardiolipin/anti–β-2-glycoprotein antibodies and lupus anticoagulants).  SLE is associated with an increased risk of stroke compared with the general population, with a reported frequency between 5% and 18%.  Ischemic stroke is far more common than hemorrhagic stroke.  Beyond conventional stroke risk factors (which are present at a higher frequency in patients with SLE), high disease activity scores, the presence of aPLs, a prior history of neuropsychiatric SLE, and African descent are associated with increased stroke risk.  About 65% of patients with SLE and ischemic stroke have coexisting antiphospholipid syndrome, and aPL levels should be obtained in all patients with SLE presenting with stroke.  Stroke mechanisms in these patients include in situ thrombosis and cardioembolism in the setting of nonbacterial thrombotic endocarditis, although the latter can occur in patients with SLE without antiphospholipid syndrome.  Anticoagulation with warfarin is administered for secondary stroke prevention in these patients.  Direct oral anticoagulants are non-inferior to warfarin in reducing the risk of recurrent venous thromboembolism in patients with antiphospholipid syndrome.  However, they have been associated with a relatively increased risk of recurrent arterial thromboembolism and are therefore not a therapeutic alternative in patients with antiphospholipid syndrome and a history of arterial thrombosis.  Acute changes in mentation can be the result of primary or secondary neuropsychiatric SLE.  Acute psychosis is a rare but well-described form of primary neuropsychiatric SLE that occurs in 1.5% of patients with SLE.  This is sometimes referred to as lupus psychosis and generally occurs early in the disease course, often in association with increased systemic disease activity.  An immune-mediated mechanism is suspected, and hypercytokinemia has been reported in these patients; however, no clinically useful biomarkers are currently available.

MRI of the head is frequently unremarkable, and CSF can be normal but may demonstrate a mild pleocytosis, an elevated IgG index, or raised CSF-unique oligoclonal bands.  

Both focal and generalized seizures have been reported in patients with SLE, with an estimated frequency between 4% and 35%.  The wide range likely reflects various potential underlying mechanisms for seizures among the different SLE populations studied.  Posterior reversible encephalopathy syndrome (PRES), which presents with encephalopathy and seizures, occurs in 0.7% to 1.8% of patients with SLE.  PRES may be a direct complication of SLE or, more likely, a complication of renal disease or immunosuppression.

Demyelinating syndromes, primarily optic neuritis and myelitis but occasionally cerebral disease, occur in about 1% of patients with SLE.  Although this may represent a direct manifestation of SLE in some cases, the demyelinating events frequently reflect comorbid neural-specific autoimmunity such as neuromyelitis optica spectrum disorders (NMOSD).  Given the similar at-risk population, relapsing demyelinating events may also represent comorbid multiple sclerosis. Myelitis frequently presents with longitudinally extensive lesions (>3 segments) on MRI imaging, but short segmental lesions can occur as well.  One study suggested that SLE myelitis presents with two distinct phenotypes: a gray matter pattern of injury characterized by flaccid myelitis and associated with prominent systemic symptoms, and a white matter pattern with spasticity and hyperreflexia.  Most patients with white matter myelitis met the criteria, including the detection of anti–aquaporin-4 (AQP-4) antibodies, for NMOSD, whereas those with gray matter myelitis did not.  Later studies have not reproduced these findings but do suggest that patients with SLE myelitis without coexisting multiple sclerosis or NMOSD score higher on indices of systemic disease activity.  Myelin oligodendrocyte glycoprotein antibody-associated disease can present with gray matter–predominant myelitis.  However, recent data suggest that myelin oligodendrocyte glycoprotein IgG antibodies are not as frequently detected in patients with SLE.  

Chorea is a reported rare manifestation of SLE, primarily in patients with aPLs.  A subset of patients have associated basal ganglia infarcts, but imaging is normal in many patients.  Steroid-responsive aseptic meningitis with or without associated meningeal enhancement on MRI is also rarely reported in association with SLE.  The association between these two syndromes and SLE is unclear, and alternative causes need to be strongly considered.

Severe neurologic syndromes presumed to be immune-mediated, including otherwise unexplained psychosis, are treated with high-dose IV methylprednisolone followed by initiation of mycophenolate mofetil or cyclophosphamide, although rituximab can be considered.  In addition to IV methylprednisolone, plasma exchange can be considered acutely in refractory CNS demyelinating syndromes, particularly in cases of NMOSD.  

Cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine can be used in patients without comorbid NMOSD, especially if systemic disease activity is evident, although rituximab, which is favored in NMOSD, can also be considered.  Therapies such as eculizumab, inebilizumab, and satralizumab that were recently approved specifically for NMOSD can be considered in patients with positive AQP-4 testing.  Seizures are usually managed with antiseizure medications.  Anticoagulation can be considered in patients with chorea with associated aPLs.  The utility of immunosuppression in these patients is unclear.

Peripheral nerve complications

Peripheral nerve complications occur in 6% to 14% of patients with SLE, although in approximately 40% of cases, the neuropathy is not directly attributable to SLE.  Distal symmetric primarily sensory axonal polyneuropathies are most common, followed by small fiber neuropathy.  Both acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have rarely been reported.  Vasculitic neuropathy (also known as mononeuritis multiplex), characterized by sequential, painful mononeuropathies, can occur (albeit rarely) in patients with SLE.  Symptomatic management is the mainstay of therapy except in patients with vasculitic neuropathy, in which case high-dose corticosteroids and cyclophosphamide are administered.