Lupus Erythematosus (SLE)


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


The anti-nuclear antibody is the hallmark laboratory test for SLE. Although 98% sensitive, it is not specific for SLE and can also be found in other autoimmune diseases such as hypothyroidism, hyperthyroidism, celiac disease, scleroderma, and dermatomyositis. Approximately 30% of normal healthy patients have a positive ANA test and do not develop SLE over time [9]. Autoantibodies (Table 9.2) can be detected as early as 10 years prior to the diagnosis of SLE [9].


Table 9.2

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)


The cutaneous manifestations of SLE can be subdivided into three categories which include acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE) lesions. The most common acute cutaneous lupus lesions include a malar rash (“butterfly rash”) and photosensitive rash.

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Fig. 9.1

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


Renal involvement in lupus patients is collectively described as “lupus nephritis” and can affect the glomeruli, tubules, interstitial tissue, and blood vessels. In 2004, the Society of Nephrology and Renal Pathology Society (ISN/RPS) classified lupus nephritis according to six classes (Table 9.3) based on glomerular pathology [5, 11].


Table 9.3

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

 


aClass IV lesions are further categorized into IV-S for segmental disease and IV-G for global disease


bClass III and Class IV lesions are further subclassified into active lesions (A), chronic lesions (C), or both (A/C)


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


Oct 24, 2020 | Posted by in RHEUMATOLOGY | Comments Off on Lupus Erythematosus (SLE)
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