Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a multisystem, pleomorphic disease in which inflammation, antibody production, and complement-fixing immune complex deposition result in tissue damage. Some regard it as a syndrome in that many patients have only a few aspects of the process (e.g., nephritis, thrombocytopenia) and are otherwise healthy and normal. In 1971, the American Rheumatism Association (forerunner of the American College of Rheumatology [ACR]) published preliminary criteria for the classification of SLE for clinical trials and population studies rather than for diagnostic purposes. Updated three times since, this definition has evolved as new insights and autoantibodies have become known. Nevertheless, it appears that SLE is part of a spectrum of lupus-associated disorders. This section will attempt to categorize and define these subsets. The breakdown of different types of lupus is shown in Table 2.1.
The last revision of the ACR criteria (Table 2.2) defines SLE as being inclusive of four cutaneous, four systemic, and three laboratory components. Four of the 11 are required for a diagnosis.1 The 1997 criteria are over 90% sensitive and specific but have several inherent weaknesses: (1) many patients with biopsy-documented lupus nephritis do not meet the criteria; (2) the central nervous system definition has been made obsolete as advances in imaging, serological, and cerebrospinal fluid testing have become available; (3) issues of ANA-negative lupus are not adequately addressed; and (4) one can have cutaneous lupus without systemic features and still fulfill the criteria. The Systemic Lupus International Collaborative Clinics (SLICC) proposed new criteria in 2012 to address these concerns. As sensitive and specific as the ACR criteria, for research studies and epidemiological surveys, either classification system can be used (Table 2.2b).
Cutaneous Lupus
Chronic cutaneous lupus erythematosus (CCLE; formerly known as discoid lupus) accounts for an overwhelming majority of cases of cutaneous lupus.2 Although many CCLE patients have SLE, pure CCLE is defined by a biopsy demonstrating pathological changes consistent with the disorder in someone who does not fulfill the ACR criteria for SLE. Approximately half of all lupus is pure cutaneous; determining its true prevalence is difficult because many of these patients never see a rheumatologist and are managed by dermatologists; they are rarely hospitalized, as a person is not likely to die from a “rash.” Gilliam’s classification of lupus, put forth in the late 1970s, has been modified by some more recent advances, shown in Table 2.3.
Table 2.1 Types of lupus erythematosus
|
Cutaneous lupus, 40% • Chronic cutaneous lupus erythematosus is 90% of this grouping |
|
Systemic lupus erythematosus (SLE), 50% • Organ-threatening disease, 25% • Non-organ-threatening disease, 25% |
|
Overlap syndrome/mixed connective tissue disease, 10% (involves fulfilling criteria for SLE and another rheumatic disease) |
|
Drug-induced lupus erythematosus, <1%Neonatal Lupus,<1% |
Table 2.2 The 1982/1997 American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus
|
Cutaneous 1. Malar rash: fixed malar erythema, flat or raised 2. Discoid rash: erythematous-raised patches with keratic scaling and follicular plugging; atrophic scarring may occur 3. Photosensitivity: skin rash as an unusual reaction to sunlight; diagnosed by patient history or physician observation 4. Oral ulcers: oral or nasopharyngeal ulcers, usually painless; observed by physician |
|
Systemic 1. Arthritis: non-erosive, involving two or more peripheral joints; characterized by tenderness, swelling, effusion 2. Serositis: pleuritis (convincing history of pleuritic pain or rub heard by physician, or evidence of pleural effusion) or pericarditis (documented by electrocardiogram, rub, or evidence of pericardial effusion) 3. Renal disorder: persistent proteinuria (>0.5 g/day or >3+) or cellular casts of any type 4. Neurological disorder: seizures or psychosis in the absence of other causes |
|
Laboratory 1. Hematological disorder: hemolytic anemia or leukopenia (<4000 on two occasions), lymphopenia (<1500 on two occasions), or thrombocytopenia (<100,000 in the absence of offending drugs) 2. Immunological disorder: anti-ds DNA, or anti-Sm, or antiphospholipid antibodies (abnormal IgM or IgG anticardiolipin antibody, lupus anticoagulant, or false-positive syphilis serology) 3. Antinuclear antibody in the absence of drugs known to be associated with the “drug-induced lupus syndrome” For identifying patients in clinical studies, a person shall be said to have SLE if any four or more of the 11 criteria are present either serially or simultaneously, during any interval of observation. |
Table 2.2b SLICC (Systemic Lupus Erythematosus International Collaborating Clinics) Classification For SLE
|
I. Biopsy documented nephritis excluding other causes, OR II. One clinical and one immunological criterion from those listed below A. Clinical criteria in the absence of other causes: 1. Acute cutaneous rash (malar, sun-sensitive, maculopapular, toxic epidermal necrolysis variant) 2. Chronic cutaneous lupus (discoid, hypertrophic, profundus, tumidus, chilblains, mucosal, lichenoid) 3. Oral ulcers (buccal, tongue, or nasal) 4. Non-scarring alopecia 5. Non-erosive inflammatory arthritis 6. Serositis (pleural, pericardial) 7. >0.5 G/day equivalent proteinuria or red blood cell urinary casts 8. Neurological (seizures, psychosis, mononeuritis multiplex, myelitis, peripheral/cranial neuropathy, acute confusional state) 9. Hemolytic anemia 10. Leukopenia (<4K) or lymphopenia (<1K) 11. Thrombocytopenia (<100 K) B. Immunological criteria: 1. Antinuclear antibody present above reference range 2. Anti double-stranded DNA >2 times reference range 3. Antiphospholipid antibody (lupus anticoagulant, false-positive syphilis serology, anticardiolipin antibody >twice normal range, or anti beta-2 glycoprotein) 4. Anti Sm 5. Low C3, C4, or CH50 (total hemolytic complement) 6. Positive direct Coombs without hemolytic anemia |
|
Petri MA, Orbai AM, Alarcon GS, et al. Derivation and validation of the SLICC Classification Criteria for SLE. Arthritis Rheum. 2012;64:2677-2686.6 |
Table 2.3 Modified Gilliam classification for histologically specific lupus erythematosus-associated skin lesions
|
1. Acute cutaneous lupus: localized or generalized 2. Subacute cutaneous lupus: annular papulosquamous 3. Chronic cutaneous lupus: classical discoid lupus (localized or generalized), hypertrophic (verrucous), lupus profundus (panniculitis), mucosal lupus, lupus tumidus, toxic epidermal necrolysis, chilblains lupus (perniotic LE) |
Neonatal Lupus
This rare condition occurs when a child of a mother who is anti-Ro (SSA) positive is born with a transient lupus rash that lasts several weeks before disappearing (the baby cannot make anti-Ro) or has congenital heart block. One anti-Ro-positive mother in 14 has a child with a rash; 2% of children born to these mothers have cardiac complications. It is not true lupus.
Drug-Induced Lupus Erythematosus
Approximately 15,000 cases of drug-induced lupus erythematosus (DILE) are reported annually in the United States. They do not generally fulfill the ACR criteria for SLE. Over 80 offending agents can induce DILE; 99% of cases disappear within three months of withdrawing the offending agent.
Mixed Connective Tissue Disease
One patient in 20 who fulfill criteria for SLE has Raynaud’s phenomenon, an antibody to RNP (ribonucleoprotein), and also satisfies the ACR criteria for scleroderma, rheumatoid arthritis, or inflammatory myositis.3 Once thought to have a benign condition, mixed connective tissue disease (MCTD) patients have a high prevalence of pulmonary hypertension and a poorer prognosis. A classification system is shown in Table 2.4.
Crossover and Overlap Syndromes
Individuals who do not have antibodies to anti-RNP but who have SLE and fulfill criteria for another rheumatic inflammatory disorder are thought to have a crossover or overlap syndrome. The prognosis is superior to that of MCTD.
Undifferentiated Connective Tissue Disease
For every patient with SLE, there are six or seven who display lupus-like symptoms without meeting SLE criteria. The presence of a positive anti-nuclear antibody or rheumatoid factor with certain inflammatory or vas-culopathy features (e.g., Raynaud’s phenomenon) is consistent with an undifferentiated connective tissue disease (UCTD).4 One patient in three with a UCTD has spontaneous resolution of the process, one-third continue to have UCTD, and for one-third the disease will evolve into rheumatoid arthritis or SLE. Palindromic rheumatism also falls into this category. There is some evidence that hydroxychloroquine can prevent UCTD from progressing (Table 2.5).5
Table 2.4 Criteria for mixed connective tissue disease
|
Clinical criteria: Three of the following must be present: synovitis OR myositis (one must be present), hand edema, Raynaud’s, acral sclerosis AND Serological criteria: Positive anti-RNP into at least a moderate titer |
Table 2.5 Criteria for undifferentiated connective tissue disease
|
1. Mandatory: inflammatory arthritis in >1 joint, OR Raynaud’s, OR keratoconjunctivitis sicca 2. Mandatory: positive antinuclear antibody, rheumatoid factor, or anti-CCP 3. Need three of the following: myalgias, autoimmune rash, serositis, persistent fever without infection, adenopathy, elevated sedimentation rate or C-reactive protein, antiphospholipid antibody |
Table 2.6 Criteria for the classification of the antiphospholipid syndrome
|
Clinical criteria: • Vascular thrombosis: one or more episodes within 5 years • Pregnancy morbidity: one or more unexplained deaths of a morphologically normal fetus after at least 10 weeks of gestation; OR before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency; OR 3 or more unexplained spontaneous abortions before the 10th week of gestation Laboratory criteria: • IgG or IgM isotype anticardiolipin antibodies on two occasions at least 3 months apart • Lupus anticoagulant on two occasions at least 6 weeks apart • Antibodies to β2-glycoprotein (IgG or IgM isotypes) on two occasions 12 weeks apart One clinical criterion plus one laboratory criterion must be present |
Antiphospholipid Syndrome
One-third of persons with SLE have antiphospholipid antibodies; one-third of these (or about 11% of persons with SLE) sustain thromboembolic events or recurrent miscarriages as a consequence. The revised definition for antiphospholipid syndrome (APS) is presented in Table 2.6. One percent of persons with APS have recurrent thromboembolic episodes despite adequate therapy. This is referred to as catastrophic antiphospholipid syndrome (CAPS).
References
1. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725.
2. Gilliam JN, Sontheimer RD. Skin manifestations of SLE. Clin Rheum Dis. 1982;8:207–218.
3. Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989;16:328–334.
4. Alarcon GS, Williams GV, Singer JZ, et al. Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol. 1991. 18:1332–1339.
5. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.
6. Petri MA, Orbai AM, Alarcon GS, et al. Derivation and validation of the SLICC Classification Criteria for SLE. Arthritis Rheum. 2012.64:2677–2686.