American College of Rheumatology revised SLE classification criteria
Systemic Lupus International Collaborating Clinics (SLICC) criteria
Classification as SLE requires 4 out of 11 criteria
Classification as SLE requires either 4 out of 17 criteria (including ≥1 clinical and ≥ 1 immunological) OR biopsy-confirmed lupus nephritis
Criteria
Definition
Criteria
Definition
Clinical criteria
1. Malar rash
Erythematous rash in malar distribution, spares nasolabial folds, flat or raised, non-scarring
1. Acute cutaneous lupus erythematosus (ACLE)
Malar rash, photosensitive rash, or maculopapular lupus rash OR subacute cutaneous lupus manifestations (annular raised erythematous lesions with central areas of scaling)
2. Photosensitivity
Erythematous rash after sunlight exposure, in sun-exposed areas of body, non-scarring
2. Chronic cutaneous lupus erythematosus (CCLE)
Discoid lupus, lupus tumidus, lupus profundus (also known as lupus panniculitis), or chilblain lupus lesions
3. Discoid rash
Erythematous patches with central area of atrophy and depigmentation, scarring
3. Alopecia
Diffuse hair thinning, non-scarring
4. Oral ulcers
Painless oral (palate, buccal mucosa, tongue) or nasal ulcers
4. Oral or nasal ulcers
Painless ulcers on palate, buccal mucosa, tongue OR painless nasal ulcers
5. Arthritis
Tenderness, swelling, or effusion in at least 2 peripheral joints
5. Joint disease
At least 2 peripheral joints with synovitis (swelling or effusion) OR tenderness and morning stiffness ≥30 minutes
6. Serositis
Evidence of pleuritis (pleuritic-type chest pain, pleural friction rub, or pleural effusion)
OR evidence of pericarditis (friction rub, pericardial effusion, or EKG changes consistent with pericarditis)
6. Serositis
Evidence of pleuritis (pleuritic-type chest pain for ≥1 day or pleural friction rub or pleural effusion)
OR evidence of pericarditis (friction rub or pericardial effusion or EKG changes consistent with pericarditis)
7. Renal disorder
Proteinuria of ≥500 mg/24 hours (per urine protein/creatinine ratio or 24-hour urine protein) or ≥ 3+ on urine dipstick test
OR presence of cellular casts (such as RBC, granular, tubular casts)
7. Renal
Proteinuria of ≥500 mg/24 hours (per urine protein/creatinine ratio or 24-hour urine protein) OR presence of RBC casts
8. Neurologic disorder
Seizures OR psychosis
8. Neurologic
Psychosis, seizures, mononeuritis multiplex, neuropathy OR acute confusional state
9. Hematologic disorder
Hemolytic anemia with reticulocytosis OR at least 2 occasions with leukopenia (WBC <4000/mm3) OR at least 2 occasions with lymphopenia (lymphocytes <1000/mm3) OR thrombocytopenia (platelets <100,000/mm3)
9. Hemolytic anemia
Positive direct Coombs test
10. ANA
Abnormally elevated titer of ANA
10. Leukopenia or lymphopenia
At least 1 occasion of WBC <4000/mm3 OR at least 1 occasion of lymphocytes <1000/mm3
11. Immunologic disorder
Either positive anti-dsDNA OR positive anti-Sm OR positive antiphospholipid antibody (anticardiolipin, or lupus anticoagulant or false-positive RPR)
11. Thrombocytopenia
Platelets <100,000/mm3
Immunologic criteria
1. ANA
Anti-nuclear antibody level above lab reference range
2. Anti-dsDNA
Anti-dsDNA antibody level above lab reference range
3. Anti-Sm
Presence of anti-Sm antibody
4. Antiphospholipid antibody
Either positive lupus anticoagulant or false-positive RPR or medium to high titers of anticardiolipin antibody (either IgG, IgM, or IgA) or positive anti-beta-glycoprotein I antibody (either IgG, IgM, or IgA)
5. Low complement
Low levels of C3, C4, or CH50
6. Direct Coombs test
Positive direct Coombs test without evidence of hemolytic anemia
Drug-Induced SLE
Medications may cause a condition with lupus-like symptoms referred to as drug-induced lupus. The most common inciting medications are hydralazine, procainamide, penicillamine, quinidine, minocycline, isoniazid, antitumor necrosis factor inhibitors, diltiazem, interferon-alpha, methyldopa, and chlorpromazine [4, 5]. Manifestations of drug-induced lupus are limited primarily to cutaneous and arthritic manifestations. Organ involvement such as lupus nephritis or neurological manifestations is very rare [4].
Autoantibodies in SLE
Autoantibodies in SLE
Autoantibody substrate | Clinical utility |
|---|---|
dsDNA (double-stranded DNA) | High specificity for SLE Correlates with disease activity |
Sm | High specificity for SLE Does not correlate with disease activity |
Ribosomal P proteins | High specificity for SLE Associated with neuropsychiatric manifestations |
Histones | Associated with SLE and drug-induced lupus |
Ro/SS-A | Associated with neonatal lupus (see Fig. 9.1e), photosensitvity, Sjogren’s syndrome, subacute cutaneous lupus, and neuromyelitis optica (NMO) |
La/SS-B | Associated with presence of anti-Ro/SS-A antibodies, neonatal lupus, and Sjogren’s syndrome |
Phospholipid (lupus anticoagulant, cardiolipin antibody, B2-glycoprotein 1) | Associated with hypercoagulable state and thrombosis, recurrent spontaneous abortions, and focal neurologic deficits |
U1-RNP | Associated with mixed connective tissue disease (unless occurring with anti-Sm antibody) |
Cell surface antigens of red blood cells, platelets, lymphocytes, neuronal cells | Hemolytic anemia, thrombocytopenia, lymphopenia, and diffuse neurologic deficits, respectively |
Cutaneous Manifestations of SLE (See Fig. 9.1a–j)
Mucocutaneous manifestations of SLE. (a) Malar (“butterfly”) rash 1. (b) Malar (“butterfly”) rash 2. (c) Malar rash and photosensitive rash. (d) Subacute cutaneous lupus erythematosus (SCLE) rash. (e) Neonatal lupus rash. (f) Discoid rash of lip. (g) Discoid rash of ear. (h) Scarring discoid alopecia. (i) Small-vessel digital vasculitis. (j) Painless hard palate oral ulcer
Malar Rash
A malar rash is one of the most common initial manifestations in SLE. It is a photosensitive erythematous rash that can be flat or raised, spares the nasolabial folds, and resolves without scarring. However, it must be differentiated from rosacea, dermatitis, and seborrhea [5] (see Fig. 9.1a–c).
Photosensitive Rash
Another common acute cutaneous rash is a photosensitive rash , which can occur in any sun-exposed region of the body. It is usually a flat maculopapular erythematous rash that resolves without scarring. It must be differentiated from medication-induced photosensitive rashes, such as those induced by hydrochlorothiazide and NSAIDs [5] (see Fig. 9.1c).
Subacute Cutaneous Lupus Erythematosus (SCLE)
Less common are SCLE rashes, which are annular raised erythematous lesions with areas of scaling in the center. These must be differentiated from medication-induced SCLE-like rashes, caused by terbinafine, hydrochlorothiazide, angiotensin-converting enzyme inhibitors, and calcium channel blockers [5] (see Fig. 9.1d).
Chronic Cutaneous Lupus Erythematosus (CCLE)
Chronic cutaneous lesions include discoid lupus, lupus tumidus, lupus profundus (also known as lupus panniculitis), and chilblain lupus lesions.
Discoid Rash
Discoid lesions are chronic scarring erythematous plaques or papules that have a central area of atrophy and depigmentation. They can occur on the face, neck, ears, and upper extremities. Skin biopsy will demonstrate inflammation and vacuolization at the junction between the dermis and epidermis (“interface dermatitis”) with deposition of IgG, IgM, C3, and IgA (“positive lupus band test”). Discoid rash can occur in isolation without systemic manifestations of lupus. Approximately 10% of patients with discoid rash who are ANA negative eventually develop systemic lupus. The presence of a positive ANA test, discoid lesions on the trunk, or cytopenias increases the risk of developing SLE within the subsequent 5 years [5] (see Fig. 9.1f–h).
Lupus Tumidus
Lupus tumidus is a photosensitive rash that presents as red urticarial annular plaques with sharp raised borders and resolves without scarring. It tends to be more common in men. Biopsy would demonstrate a dense perivascular infiltrate that does not involve the dermal-epidermal junction interface and is negative upon immunofluorescence testing. It can occur in patients without systemic lupus, and only 10% of lupus tumidus patients have a positive ANA test [10].
Lupus Profundus (Lupus Panniculitis)
Lupus patients can develop chronic relapsing-remitting inflammation of the subcutaneous fat tissue, leading to deep painful firm nodules. The end result may be dented scars (lipodystrophy) of the fat tissue, caused by dense lymphocytic infiltration. The face is the most commonly affected area, but involvement of the upper arms, thighs, and breasts can also occur. Biopsy is critical to rule out subcutaneous lymphoma, which can have a similar presentation [5, 10].
Chilblain Lupus
This rare form of CCLE resembles frostbite, with its painful, violaceous plaques, and nodules in cold-exposed areas. Examination may reveal a mottled appearance over the fingers, with severe forms leading to digital ulcers. Nailfold capillary exam will show periungal capillary dilations. Biopsy shows epidermal atrophy, interface vacuolization, and perivascular mononuclear infiltrate. Smokers or patients with Raynaud’s phenomenon are at higher risk for chilblain lupus. The majority of patients with chilblain lupus do not have other systemic manifestations of lupus, while approximately 20% of patients develop systemic lupus [10].
Oral or Nasal Ulcers
These ulcers are typically painless and may go unnoticed by the patient. They are commonly found on the upper hard palate, buccal mucosa, or nasal septum. Painful ulcers should raise concern for a herpes simplex infection [5] (see Fig. 9.1j).
Alopecia
Hair thinning or patchy hair loss is a common manifestation of SLE. Once the underlying SLE disease activity is controlled, alopecia typically begins to improve. It is usually non-scarring, unless it occurs in the setting of a surrounding discoid lesion [5] (see Fig. 9.1h).
Musculoskeletal Manifestations
Arthritis in SLE rarely leads to joint erosions and destruction. Patients tend to develop “Jaccoud arthropathy” which affects the tendons around the joints, causing tendon laxity. Patients can develop reversible ulnar deviation, swan-neck deformity, and MCP subluxation. Over time, however, the deformities can become fixed [5].
Serositis
Patients with SLE can develop pleuritis, pericarditis, or less commonly peritonitis. Moderate and severe serositis inflammation can also lead to accumulation of fluid such as pleural or pericardial effusions. Fluid aspiration reveals a sterile, inflammatory exudative fluid, with either a neutrophil or lymphocyte predominance [5, 11].
Cytopenias
There are a number of cytopenias that may present in SLE patients. The most common anemia is anemia of chronic disease, followed by iron-deficiency anemia and hemolytic anemia. Approximately 10% of SLE patients have a Coombs positive anti-erythrocyte antibody, usually of the warm-type IgG. Other causes of hemolytic anemia must be evaluated, including microangiopathic hemolytic anemia in the setting of APLS, medications, and infections. Red cell aplasia, involving serum IgG that inhibits erythrocyte formation in the bone marrow, is a rare cause of anemia in SLE [11].
Leukopenia in SLE is usually the result of peripheral consumption rather than bone marrow production of leukocytes. However, autoantibodies to leukocytes may form that inhibit granulocyte growth colony-forming units in the bone marrow leading to decreased bone marrow production [11].
Thrombocytopenia may be an isolated manifestation in SLE or may be a component of multisystem disease activity. Antibodies to platelets usually include either autoantibodies against thrombopoietin receptor (TPOR) or against glycoprotein IIb/IIIa (GPIIb/IIIa). Anti-TPOR-induced thrombocytopenia has a poorer response to immunosuppressants compared to anti-GPIIb/IIIa-induced thrombocytopenia. Thrombocytopenia may also occur in the setting of active APLS and is usually associated with hemolytic anemia. Other causes of thrombocytopenia include medications, infections, and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) which may coexist with active SLE. Although treatments differ, TTP-HUS requires plasmapheresis, while active SLE requires immunosuppressant therapy [11].
Rarely, patients with SLE may develop pancytopenia. Pancytopenia in SLE may be due to reversible myelofibrosis with bone marrow hypocellularity that may be responsive to immunosuppressants. Other causes of pancytopenia include hemophagocytic syndrome/macrophage activation syndrome (HLH/MAS) or cytotoxic immunosuppressants [11].
Lupus Nephritis
ISN/RPS 2003 classification of lupus nephritis
Class | Class definition | Subclassesb |
|---|---|---|
I | Minimal mesangial LN | |
II | Mesangial proliferative LN | |
III | Focal LN | III (A) III (A/C) III (C) |
IVa | IV-S: Diffuse LN IV-G: Global LN | IV-S (A) IV-S (A/C) IV-S (C) IV-G (A) IV-G (C) |
V | Membranous LN | |
VI | Advanced sclerosing LN |
Class I: Minimal Mesangial Lupus Nephritis
Light microscopy appears to show normal glomeruli. Immunofluorescence (IFA) and electron microscopy demonstrate immune deposits in the mesangium. Patients have normal urinalysis and normal serum creatinine. No treatment is required [5, 11].
Class II: Mesangial Proliferative Lupus Nephritis
Light microscopy will show increased hypercellularity in the mesangium. Electron microscopy and IFA will show immune deposits in the mesangium. Patients usually have near normal urinalysis and normal serum creatinine. Treatment is rarely required, but patients may benefit from an angiotensin-converting-enzyme inhibitor (ACE inhibitor) if there is elevated proteinuria >0.5 g/day [5, 11].
Class III: Focal Proliferative Lupus Nephritis
Histology demonstrates segmental lesions involving <50% of the glomeruli, with hypercellularity and immune complex deposition in the subendothelial space and mesangium. Patients present with increasing serum creatinine, proteinuria, hematuria, low complement levels, elevated dsDNA antibody, hypertension, and lower extremity edema. Immunosuppressive treatment is required, with high-dose steroids and either mycophenolate mofetil or cyclophosphamide. Without treatment, patients will progress to Class IV lupus nephritis [5, 11].
Class IV: Diffuse Proliferative Lupus Nephritis
Class IV lupus nephritis is a continuum of Class III LN that has extended to affect over 50% of the glomeruli. Class IV LN is further divided into Class IV-S and Class IV-G. Class IV-S is characterized by segmental lesions involving >50% of the glomeruli, and Class IV-G is defined by global glomerular lesions involving >50% of the glomeruli. There is also presence of basement membrane thickening, sclerosis of capillaries, as well as inflammatory infiltrate and areas of necrosis that lead to “crescent” formation. IFA microscopy reveals a “full house pattern” with IgG, IgM, IgA, C3, and C1q deposition in the subendothelial space. Patients will present similarly to Class III LN and require similar treatment [5, 11].
Class V: Membranous Lupus Nephritis
Histology will demonstrate global or segmental immune deposits in the subepithelial space. Patients usually present with significant proteinuria, minimal hematuria, and normal serum creatinine, complements, and anti-dsDNA levels. Treatment usually requires only ACE inhibitors, but may require immunosuppressants if there is extensive proteinuria [5, 11].
Class VI: Advanced Sclerosing Lupus Nephritis
Patients with sclerosis of 90% or more of their glomeruli are classified as having Class VI LN. There is no significantly active glomerular disease, and thus immunosuppression is avoided. These patients are prepared for or are undergoing renal replacement therapy [5, 11].
Indications for Renal Biopsy
- 1.
Proteinuria of ≥1 gm/day
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