Systemic Lupus Erythematosus PDF

# Epidemiology and Pathophysiology - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a heterogeneous constellation of organ involvement and the presence of antinuclear antibodies (ANA) and other autoantibodies. - In SLE, a complex and varying interaction of genes, environment, and random events leads to a breakdown of self-tolerance and autoimmunity. Defects in cellular apoptosis result in inadequate clearance of intracellular proteins, especially nuclear antigens, promoting the generation of self-directed T and B cells and the initiation/propagation of autoimmunity. Cytokine generation supports auto-reactivity, with type 1 interferons playing a major role. Autoantibodies may directly induce tissue damage or promote the formation of immune complexes that lead to complement activation and tissue inflammation and damage. Inheritance of SLE risk is polygenic, including major histocompatibility complex genes. - The risk for SLE is higher in those with a family history. Incidence increases at puberty and peaks in the third decade. The disease is more common and more severe in Black and Hispanic populations. Approximately 90% of adult patients are women; SLE is frequently more severe in men than women. ## Key Points - Systemic lupus erythematosus is a multisystem autoimmune disease characterized by a heterogeneous constellation of organ involvement and the presence of antinuclear antibodies and other autoantibodies. - Approximately 90% of adult patients with systemic lupus erythematosus are women. # Clinical Manifestations ## Mucocutaneous Involvement - Skin disease occurs in most patients with SLE and is classified as acute, subacute, or chronic. - Acute cutaneous lupus erythematosus (ACLE) presents as an erythematous, macular, patchy eruption, sometimes with desquamation. The facial eruption of ACLE (the classic malar or butterfly rash) is characterized by fixed, rather than transient, erythema/edema over the cheeks and bridge of the nose, sparing the nasolabial folds, but the neck, upper chest, and dorsum of the arms and hands can also be involved. In some patients, a bullous eruption occurs. ACLE usually responds to therapy and heals without scarring or atrophy. - Subacute cutaneous lupus erythematosus (SCLE) is a photosensitive rash occurring especially on the arms, neck, and upper trunk, usually sparing the central face. It consists of erythematous annular/polycyclic or patchy papulosquamous lesions, often with a fine scale, that may leave postinflammatory hypo- or hyperpigmentation. SCLE is associated with anti-Ro/SSA autoantibodies (prevalence >75%) and can occur in isolation or as a manifestation of underlying SLE. ## Figure 29 The facial eruption of acute cutaneous lupus erythematosus (malar or butterfly rash). This patient has fixed erythematous raised lesions over the malar eminences, the bridge of the nose with sparing of the nasolabial folds, and the chin. ## Figure 30 Subacute cutaneous lupus erythematosus is characterized by erythematous, macular, or patchy skin lesions that are scaly and can evolve as (A) annular/polycyclic lesions or (B) papulosquamous plaques. - Discoid lupus erythematosus (DLE) is the most common manifestation of chronic cutaneous lupus erythematosus and can cause scarring, atrophy, and permanent alopecia. DLE presents as hypo- or hyperpigmented patches or plaques, with erythema during active disease, which may be variably atrophic or hyperkeratotic. Like SCLE, DLE can occur as an isolated finding in the absence of SLE and in such cases is typically limited to the neck, face, and scalp. - Painless oral or nasopharyngeal ulcerations occur in 5% of patients with SLE. Involvement of the hard palate is characteristic. Rarely, DLE is associated with painful ulcers. Nonscarring alopecia is a common feature of active SLE, with hair regrowth a sign of disease control. - Raynaud phenomenon occurs frequently, reflecting arterial vasospasm of digital arteries. Other vascular changes, including livedo reticularis or periungual erythema, may be present as well, although these findings are nonspecific. Some patients with SLE may develop cutaneous vasculitis, most often in the distal extremities. ## Figure 31 Discoid lupus erythematosus. This patient has hyperpigmented, raised patches with keratotic scaling and follicular plugging involving the malar and perioral areas as well as the bridge of the nose. Areas of atrophic scarring are also present. ## Figure 32 Active discoid lupus erythematosus of the scalp with scarring hair loss. # Musculoskeletal Involvement - Joints are affected in 90% of patients with SLE. Many patients have arthralgia, and a much smaller group exhibits arthritis. Many patients with SLE may have evidence of synovitis on imaging even with minimal symptoms or swelling on examination. Typical distribution includes small peripheral joints, often resembling rheumatoid arthritis, but large joints are also affected. SLE arthritis is nonerosive, but reducible subluxation of the digits, swan neck deformities, and ulnar deviation (Jaccoud arthropathy) can occur, a result of damage to the tendons and ligaments. # Osteonecrosis - Osteonecrosis is a serious complication of SLE that most commonly affects the hips but can also involve other large joints. It should be suspected in patients with otherwise unexplained pain and/or reduced range of motion. Long-term and higher-dose (>20 mg/d) prednisone treatment, severe/active SLE, and vasculitis are associated with increased risk for osteonecrosis. If plain radiography (anteroposterior and frog-leg lateral) demonstrates hip joint destruction, no further imaging is required for diagnosis. If radiography is unrevealing and clinical suspicion is high, MRI should be pursued; MRI is more sensitive; MRI may be needed to identify early disease. Although small lesions can improve without invasive treatment, larger areas of involvement can lead to bony collapse. Treatment requires extended non-weight-bearing and, in some cases, core decompression of the affected bone. In the wake of collapse, joint replacement may be necessary. # Myalgia and Subjective Weakness - Myalgia and subjective weakness are common, but true myositis is rare. Glucocorticoids often cause muscle weakness, and, rarely, antimalarial agents can affect muscle. Thus, medication effects must be differentiated from active SLE disease. Fibromyalgia is a common comorbidity (30%); symptoms may overlap those of active SLE disease. # Kidney Involvement - Kidney disease occurs frequently among patients with SLE and remains an important source of morbidity. Lupus nephritis can present with minimal laboratory abnormalities (non-nephrotic proteinuria, hematuria), nephritis (hypertension,edema, active urine sediment, and elevated serum creatinine), and/or nephrosis (nephrotic-range proteinuria, edema, hypoalbuminemia, hypercholesterolemia, and, in some cases, thrombosis). Untreated active disease may progress to kidney failure, in severe cases requiring dialysis or transplant. - All patients with SLE should be regularly evaluated for kidney involvement through assessment of serum creatinine and urine for protein and microscopic evaluation. Active kidney disease should be suspected when there is active urine sediment or proteinuria greater than 500 mg/24 h (or a spot urine protein-to-creatine ratio >500 mg/g). Elevated or rising anti-double-stranded DNA antibody titers or complement consumption commonly associated with active kidney disease. - Kidney biopsy defines both the histologic subtype and the activity/chronicity of disease, which are important for therapeutic decisions. Indications for kidney biopsy include an increase in serum creatinine level, unexplained decrease in glomerular filtration rate, or proteinuria greater than 500 mg/24 h (or a spot urine protein-to-creatinine ratio >500 mg/g), especially in the presence of hematuria or an active urine sediment. ## Lupus Nephritis - Lupus Nephritis - 40% affected - Class I: Min. mesangial - Presentation: Normal U/A & eGFR - Treatment: No specific treatment - Class II: Mesangial prolif - Presentation: Micro hematuria/proteinuria - Treatment: No specific treatment ± ACEI - Class III: Focal prolif - Presentation: Hematuria/proteinuria, ± HTN, ↓ GFR, ± nephrotic - Treatment: Induce: MMF or CYC + steroids - Class IV: Diffuse prolif - Presentation: Hematuria/proteinuria and HTN, ↓ GFR, ± nephrotic - Treatment: ACEI - Class V: Membranous (can coexist with class III or IV) - Presentation: Proteinuria, nephrotic - Treatment: If nephrotic-range proteinuria, induce w/ MMF + steroids - Class VI: Adv. Sclerotic - Presentation: ESRD - Treatment: Renal replacement therapy # Neuropsychiatric Involvement - Neuropsychiatric systemic lupus erythematosus (NPSLE) may involve the central and/or peripheral nervous systems. NPSLE prevalence is high (75%), but most of the common manifestations (headache, mild cognitive dysfunction, and mood disorder) are nonspecific. - Peripheral neuropathy occurs in 10% to 14% of patients. Severe acute presentations, including seizures and psychosis, are uncommon (<5%) but require aggressive symptomatic as well as disease-specific treatment. - Patients suspected of having serious central NPSLE, such as meningitis, stroke, and psychosis, should undergo central nervous system imaging (CT, MRI, or PET) and cerebrospinal fluid analysis as appropriate. # Cardiovascular Involvement - Asymptomatic pericarditis is the most frequent cardiac manifestation of acute SLE (40%). When symptomatic, features include chest pain, exudative effusion, and, rarely, tamponade or chronic constriction. Myocarditis occurs in 5% to 10% of patients with SLE and usually presents as insidious heart failure but can be acute. - Valvular abnormalities occurring in SLE include those associated with antiphospholipid syndrome (nonspecific thickening of the mitral and aortic valve leaflets, vegetations, regurgitation, and stenosis). Libman-Sacks endocarditis (noninfectious verrucous vegetations) preferentially affects the mitral valve and can cause embolic complications. Patients with SLE also have an increased risk for accelerated atherosclerosis leading to coronary heart disease. # Pulmonary Involvement - Pulmonary involvement is common in SLE, with most patients presenting with pleuritis (45%-60%). Pleural effusions occur in approximately half of these patients and are typically exudative; fluid analysis may reveal lymphocytic pleocytosis and mildly depressed glucose levels. - Parenchymal lung involvement occurs in less than 10% of patients with SLE. A nonspecific interstitial pneumonia pattern is most common, and evaluation centers on assessing SLE activity and excluding other causes of diffuse parenchymal lung disease. Two rare but potentially life-threatening complications of SLE lung disease are acute lupus pneumonitis (presenting as fever, cough, dyspnea, hypoxemia, pleuritic chest pain, and infiltrates) and diffuse alveolar hemorrhage (presenting with dyspnea, hypoxemia, diffuse alveolar infiltrates, a dropping hematocrit, and a high DLCO). Both carry a high mortality rate (>50%). Early recognition, rapid evaluation (CT and/or bronchoscopy with bronchoalveolar lavage or biopsy and aggressive respiratory support combined with high-dose glucocorticoids and immunosuppression are required. With new pulmonary infiltrates, differentiation between these disorders and infection can be difficult, and antibiotics and immunosuppressive therapy are often administered simultaneously until the diagnosis is clear. - Shrinking lung syndrome is a rare but characteristic syndrome consisting of pleuritic chest pain and dyspnea, with progressive decrease in lung volumes. The cause is uncertain, but pleuropulmonary disease and/or diaphragmatic dysfunction may contribute. Immunosuppression may reverse the process in some patients. # Hematologic Involvement - In patients with SLE, normocytic, normochromic anemia of inflammation is common; autoimmune hemolytic anemia occurs in approximately 10% of cases and correlates with SLE activity. Lymphopenia/leukopenia is also common but usually mild. Thrombocytopenia occurs in 30% to 50% of cases, and approximately 10% of patients develop severe thrombocytopenia (<50,000/μL [50 × 109/L]) in isolation or in conjunction with hemolytic anemia. - Cytopenia in SLE may be caused by immune and nonimmune destructive mechanisms (including microangiopathy), medications, and kidney and liver disease. Moderate and severe or rapidly progressive cytopenia requires prompt evaluation with serologic studies and/or bone marrow biopsy. An exact cause of cytopenia may be difficult to ascertain, and a trial of medication adjustment in concert with evaluation for other causes is often necessary. # Antiphospholipid Antibodies and Lupus Anticoagulant - Antiphospholipid antibodies and lupus anticoagulant are present in about 40% of patients with SLE and may be associated with a false-positive result on a rapid plasma reagin test for syphilis. Most patients are asymptomatic. Thrombotic events occur in about 30% of patients; these include venous and arterial thrombosis, miscarriage, stillbirth, livedo reticularis, and cardiac valve thickening/vegetations. The risk for thrombosis is highest in the presence of triple positivity for lupus anticoagulant, anti-ẞ2-glycoprotein, and anticardiolipin antibodies. Patients with SLE are at increased risk for thrombotic events even in the absence of antiphospholipid antibodies. See MKSAP 19 Hematology for more information. # Gastrointestinal Involvement - Gastrointestinal involvement is a common (40%) and underrecognized SLE manifestation. Sefositis presents as abdominal pain, is usually associated with active disease, and improves with treatment. Mesenteric vasculitis, inflammation of the small and large bowel, pancreatitis, protein-losing enteropathy, and diffuse peritonitis are uncommon but may be severe and associated with cutaneous vasculitis. - Noninfectious hepatitis can occur and is associated with the presence of antiribosomal P antibodies. Patients with SLE who have Raynaud phenomenon and anti-U1-ribonucleoprotein antibodies are at increased risk for esophageal disease and reflux. - Medications used to treat SLE (NSAIDs, prednisone, mycophenolate, azathioprine) also frequently affect the gastrointestinal system and may cause esophagitis, gastritis, pancreatitis, and other manifestations. ## Key Points - The facial eruption of acute cutaneous lupus erythematosus (malar or butterfly rash) is characterized by erythema/edema over the chin, cheeks, and bridge of the nose, sparing the nasolabial folds. - Many patients with systemic lupus erythematosus have arthralgia, and a much smaller group exhibits arthritis. - All patients with systemic lupus erythematosus should be regularly evaluated for kidney involvement through assessment of serum creatinine and urine for protein and microscopic evaluation. - The most common manifestations of neuropsychiatric systemic lupus erythematosus are headache, mild cognitive dysfunction, and mood disorder. # Comorbidities - Patients with SLE have a higher overall risk for malignancies (particularly hematologic); the risk for non-Hodgkin lymphoma is at least two to three times higher than in the general population. Malignancy risk in SLE is tied to the use of immunosuppressive agents. Higher cumulative cyclophosphamide doses are associated with increased risk for solid organ tumors, and azathioprine use is associated with an increased risk for myeloproliferative syndromes. Cervical cancer is also increased in patients with SLE, especially those receiving immunosuppressive therapies. Hydroxychloroquine use does not appear to increase malignancy risk and may be protective. - Patients with SLE have a 2- to 10-fold increased prevalence of coronary artery disease. It is the most common cause of death among older patients with SLE, even those whose lupus has become quiescent. A history of high SLE disease activity (especially nephritis) and prednisone dosages greater than 10 mg/d are independent risk factors for coronary artery disease. Patients with SLE are also at increased risk for ischemic stroke. ## Key Points - Patients with systemic lupus erythematosus are at increased risk for malignancy; immunosuppressive use contributes to this increased risk. - Patients with systemic lupus erythematosus have a 2- to 10-fold increased prevalence of coronary artery disease; high SLE disease activity and prednisone dosages greater than 10 mg/d are independent risk factors for coronary artery disease. # Diagnosis ## General Considerations - The diagnosis of SLE should be considered in patients, especially young women, with any individual manifestation of SLE or with symptoms affecting multiple organ systems. The most common presenting clinical features that differentiate patients with SLE from those with other mimicking conditions include malar rash, photosensitivity, inflammatory arthritis, weight loss, and fever, along with such laboratory features as positivity for ANA, low complement levels, and presence of lupus-specific antibodies. Patients with subjective reports of fatigue, myalgia, and/or arthralgia but lacking objective findings most likely have an alternative diagnosis and should not be evaluated for SLE. - Several classification criteria for SLE have been used; although intended for recruitment of homogenous SLE populations for research studies, they can also be used to suggest a clinical diagnosis of SLE. A 2019 update of these criteria from the European League Against Rheumatism/American College of Rheumatology includes the requirement for a positive ANA result at least once, with the addition of clinical and/or immunologic criteria totaling at least 10 points on a weighted scale. These criteria compare favorably to prior published criteria, with a sensitivity of about 96% and specificity of about 93%. ## Entry Criterion - Antinuclear antibody at a titer ≥1:80 on Hep-2 cells or equivalent positive test result - If absent, do not classify as SLE - If present, apply additive criteria ## Additive Criteria - Do not count a criterion if there is a more likely explanation than SLE. Occurrence of a criterion on at least one occasion is sufficient. SLE classification requires at least one clinical criterion and ≥10 points. Criteria need not occur simultaneously. - Within each domain, only the highest weighted criterion is counted toward the total score. ### Clinical Domains and Criteria - **Constitutional** - Fever (temperature >38.3 °C): 2 - **Hematologic** - Leukopenia (<4000/μL [4.0 × 109/L]): 3 - Thrombocytopenia (<100,000/μL [100 × 109/L]): 4 - Autoimmune hemolysis (with positive direct antiglobulin test result): 4 - **Neuropsychiatric** - Delirium: 2 - Psychosis (delusions and hallucinations in absence of delirium): 3 - Seizure (primary generalized or focal seizure): 5 - **Mucocutaneous (observed by clinician)** - Nonscarring alopecia: 2 - Oral ulcers: 2 - Subacute cutaneous or discoid lupus: 4 - Acute cutaneous lupus: 6 - **Serosal** - Pleural or pericardial effusion: 5 - Acute pericarditis: 6 - **Musculoskeletal** - Joint involvement (synovitis in ≥2 joints or tenderness of ≥2 joints with ≥30 minutes of morning stiffness): 6 - **Renal** - Proteinuria >0.5 g/24 h (or equivalent spot urine protein-to-creatinine ratio): 4 - Renal biopsy showing class II or V lupus nephritis: 8 - Renal biopsy showing class III or IV lupus nephritis: 10 ### Immunologic Domains and Criteria - **Hematologic** - Antiphospholipid antibodies: - Anticardiolipin antibodies or - Anti-ß2-glycoprotein I antibodies or - Lupus anticoagulant: 2 - **Complement proteins** - Low C3 or low C4: 3 - Low C3 and low C4: 4 - **SLE-specific antibodies** - Anti-dsDNA antibody or - Anti-Smith antibody: 6 - **Classify as systemic lupus erythematosus with a score of 10 or more if entry criterion is fulfilled.** ## Classification Criteria (Ann Rheum Dis 2019;78:1151) - **Required criteria:** ANA titer ≥1:80 AND ≥10 points (at least one clinical) ### Clinical domains (points) - **Renal** - proteinuria >0.5 g/d (4) - class II or V nephritis (8) - class III or IV nephritis (10) - **Mucutaneous** - non-sclarring alopecia (2) - oral ulcers (2) - discoid lupus (4); subacute (4) or acute (6) cutaneous lupus - **Hematologic** - leukopenia (3) - thrombocytopenia (4) - autoimm. hemolytic anemia (4) - **Serosal** - pleural/pericardial effusion (5) - acute pericarditis (6) - **Neuropsychiatric** - delirium (2) - psychosis (3) - seizure (5) - **Musculoskeletal** - joint involvement (6) - **Constitutional** - fever (2) ### Immunology domains (points) - **Antiphospholipid antibodies** - anti-CL, anti-B2GP1, or a lupus anticoagulant (2) - **Complement proteins** - low C3 or C4 (3) - low C3 and C4 (4) - **SLE-specific Abs** - anti-dsDNA or anti-Smith (6) - **Within each domain only the bigbest weighted criterion is counted toward the total score** # Laboratory Studies - Initial evaluation for SLE includes routine laboratory testing to establish organ-specific involvement, including complete blood count, chemistry panel, and urinalysis with microscopy. - ANA should be obtained to screen for nuclear-directed autoantibodies. The most appropriate method for testing ANA is the indirect immunofluorescence assay, which is highly sensitive (>95%) for SLE but not specific. ANA tests should be interpreted in the context of the probability of disease because ANA may be present in patients with other autoimmune diseases as well as in healthy individuals. Low-titer ANA (<1:80) is considered negative; even ANA at a more positive titer in the absence of specific features of SLE may be noninformative. - If the ANA result is positive and the clinical context supportive, SLE-specific autoantibodies (anti-double-stranded DNA, anti-Smith, anti-U1-ribonucleoprotein, anti-Ro/SSA, and anti-La/SSB), as well as tests for other autoimmune diseases under consideration, should be obtained to further characterize the disease. ## Autoantibodies in SLE - **Autoantibody** | **Frequency in SLE** | **Comments** ---|---|---| Antinuclear | >95% | Useful as an initial screening test; assesses multiple antigens simultaneously Anti-double-stranded DΝΑ | 50%-60% | Found in more severe disease, especially kidney disease; antibody levels commonly follow disease activity and are useful to monitor Anti-Ro/SSA | 30% | Associated with photosensitive rashes, discoid lupus erythematosus, and neonatal lupus erythematosus; also common when secondary Sjögren syndrome is present Anti-U1-ribonucleoprotein | 35% | Associated with Raynaud phenomenon and esophageal dysmotility; also seen in MCTD Anti-Smith | 30% | Specific for SLE; often associated with more severe disease Anti-La/SSB | 20% | Common in Sjögren syndrome; less common in SLE and neonatal lupus erythematosus Antiribosomal P | 15% | Associated with CNS lupus and lupus hepatitis - CNS = central nervous system; MCTD = mixed connective tissue disease; SLE = systemic lupus erythematosus. ## Autoantibodies in SLE (Nat Rev Rheumatol 2020;16:565) - **Auto-Ab** | **Frequency (approx)** | **Clinical Associations** | **Timeline** ---|---|---|---| ANA | 95-99% if active disease 90% if in remission Homogeneous or speckled | Any or all of broad spectrum of clinical manifestations Sensitive but not specific | May appear yrs before overt disease Ro | 15-35% ④ anti-Ro may be seen w/ or low titer ANA | Sjögren's/SLE overlap Neonatal lupus; photosens.; subacute cutaneous lupus | ds-DNA | 70%; ~95% Sp; titers may parallel dis. activity, esp. renal | Lupus nephritis Vasculitis | Appears mos before or at dx, but may become after dx Sm | 30%; very specific for SLE | Lupus nephritis | U1-RNP | 40% | MCTD; Raynaud's; Tend not to have nephritis | Histone | 90% in DLE; 60-80% in SLE | Mild arthritis and serositis | At diagnosis # Disease Activity Markers - Disease activity markers, including complements C3 and C4, should be assessed initially and regularly thereafter. Complement levels are typically reduced during SLE activity, reflecting immune complex formation and complement consumption. - Rising titers of anti-double-stranded DNA antibody levels may be concordant with SLE kidney disease activity. Other SLE autoantibodies, including ANA, do not reflect disease activity and need not be repeated. Erythrocyte sedimentation rate and C-reactive protein are variably associated with disease activity; some patients with SLE have little to no elevation in C-reactive protein during SLE flares, which may help distinguish flares from infection once the individual patient's pattern of responsiveness is established. # Differential Diagnosis - The differential diagnosis of SLE includes multisystem diseases, acute and chronic infections, medication effect, malignancies (particularly hematologic), and neurologic diseases (e.g., multiple sclerosis). Multisystem autoimmune diseases (ANCA-associated vasculitis, rheumatoid arthritis, adult-onset Still disease, dermatomyositis, Sjögren syndrome, and mixed connective tissue disease) have overlapping features but may be distinguished through a careful assessment of their unique manifestations. - SLE should also be distinguished from undifferentiated connective tissue disease, which presents with milder symptoms and objective abnormalities that cannot be categorized or diagnosed as a specific connective tissue disease. - Certain medications can cause drug-induced lupus erythematosus (DILE), which mimics SLE. The syndrome is usually milder; malaise, fever, arthritis, and rash are associated with transient positivity for ANA and antihistone antibodies. Symptoms usually resolve after discontinuation of the offending agent. Kidney and central nervous system disease are uncommon. Patients with SLE are at no more risk for DILE than the general population, and medications associated with DILE are not contraindicated in patients with SLE. ## Medications Commonly Associated With Drug-Induced Lupus Erythematosus - **Medication** | **Antibodies Detected** | **Comments** ---|---|---| Procainamide | ANA (75%); antihistone | 20% develop DILE; fever; arthritis; serositis Hydralazine | ANA (20%); antihistone | 5%-8% develop DILE; fever; arthritis; rare vasculitis and kidney disease Minocycline | ANA; ANCA; anti-dsDNA rare | Arthritis; vasculitis; autoimmune hepatitis Antithyroid drugs | ANA; ANCA; antihistone | Vasculitic rash; rare pulmonary and kidney disease Statins | ANA; antihistone; anti-dsDNA | SLE, SCLE, dermatomyositis, and polymyositis all reported Calcium channel blockers | ANA; anti-Ro/SSA; antihistone rare | SCLE Thiazide diuretics | ANA; anti-Ro/SSA; antihistone rare | SCLE ACE inhibitors | ANA; anti-Ro/SSA; antihistone rare | SCLE TNF inhibitors | ANA (23%-57%); chromatin and anti-dsDNA common; antihistone rare | DILE most common with infliximab, uncommon for etanercept; SLE, SCLE, DLE all reported # Management - SLE most often follows a relapsing-remitting pattern (70%) with periods of inactive disease, although some patients may have a monophasic or persistently active pattern. The most commonly used instrument for monitoring disease activity is the SLE Disease Activity Index (SLEDAI), which incorporates both clinical and laboratory measures. Clinical remission or low disease activity are typical goals of therapy. - Pharmacologic therapy is almost always required; the choice of agents should reflect disease activity and specific organ involvement. Management requires frequent disease assessment and adjustment of treatment to reflect changing conditions. ## Medications Commonly Used to Treat Systemic Lupus Erythematosus - **Medication** | **Common Uses in SLE** | **Important Adverse Effects** ---|---|---| NSAIDS | Arthritis; pain; fever | Hypertension; GI bleeding; AKI Prednisone | Used for all manifestations in varying doses | Hypertension; glucose intolerance; weight gain; infection; osteonecrosis Hydroxychloroquine | Used in almost all patients without contraindications; especially useful for skin involvement and to prevent disease flares | GI intolerance; rash; blurry vision; retinopathy; vacuolar myopathy Mycophenolate mofetil | Moderate to severe disease; as effective as cyclophosphamide for remission induction for nephritis | Bone marrow suppression; elevation of liver enzymes; infection Azathioprine | Moderate to severe disease | Bone marrow suppression; elevation of liver enzymes; hematologic malignancy Voclosporin | Lupus nephritis | GI intolerance; increased risk for malignancy; creatinine elevation Cyclophosphamide | Severe organ- or life-threatening disease | Bone marrow suppression; hemorrhagic cystitis; infection; malignancy; infertility Belimumab | Add-on therapy for moderate to severe disease | Infusion reactions; infections Anifrolumab | Add-on therapy for moderate to severe disease | Infusion reactions; infections - AKI = acute kidney injury; GI = gastrointestinal; SLE = systemic lupus erythematosus. ## Treatment (Ann Rheum Dis. 2019;78:736; Lancet 2019;393:2332; Nat Rev Rheumatol 2019;15:30) - **Drug** | **Indication** | **Adverse Effects** ---|---|---| Hydroxychloroquine (HCQ) | All Ptes/c↓ flares (NEJM 1991;324:150); monoRx for arthritis, serositis, skin disease | Retinal tox (<1%), Stevens-Johnson; myopathy. Not immunosuppressive. NSAIDs | Arthritis, myalgias, serositis | Gastritis, UGIB, renal failure Corticosteroids | Low dose for arthritis, serositis; high-dose (1 mg/kg) ± pulse (1g x 3 d) for major dis. (eg, renal, CNS, heme). Minimize as able. | Adrenal suppression, diabetes, cataracts, necrosis of bone, myopathy, osteopenia, avascular Mycophenolate (MMF) | Nephritis (induction/maint); nonrenal refractory to HCQ | Cytopenias, ↑ LFTs, diarrhea, teratogen Cyclophosphamide (CYC) | Severe organ-threatening nephritis or CNS disease (induction, minimize exposure) | Cytopenias, infertility/teratogen, myeloprolif. dis., hemorrhagic cystitis, bladder cancer Azathioprine (AZA) | Nephritis (maintenance) | Myelosuppr. (✓TPMT), ↑ LFTs, teratogen, lymphoprolif. dis. Methotrexate (MTX) | Non-renal dis. refractory to HCQ | Myelosuppression, alopecia, hepatotoxicity, stomatitis, pneumonitis, teratogen Cyclosporine (CSA) | Arthritis (preferred over MMF/AZA) Skin disease & serositis Renal disease | Hyperplastic gums, HTN, hirsutism, CKD, anemia Voclosporin (calcineurin inhibitor Lancet 2021;397:2070) | Nephritis (induction). Added to MMF+steroids; ↑ complete renal response w/ ↓ steroid. | HTN, ↓ GFR, diarrhea. (Stable PK, .. does not require levels like other calcineurin inhibitors) Belimumab (NEJM 2013;368:1528 & 2020;383:1117) | Arthritis, serositis, skin disease (esp. if ds-DNA or ↓C3/C4). Nephritis (induction). ↑ renal response when added. ITP, AIHA, refractory SLE | B-cell depletion by binding BLYS (less immunosuppressive than RTX) Rituximab (RTX) | | Infusion reaction / serum sickness, PML, infection Baricitinib (Lancet 2018;392:222) | Prelim data: 4 mg w/ efficacy in arthritis, skin disease | Infections (zoster), ↑ LFTs, cytopenias, dyslipidemia Anifrolumab (anti- IFN receptor) | Moderate to severe disease (NEJM 2020;382:211) | Infection (PNA, zoster), hypersensitivity reaction - Hydroxychloroquine is a mainstay of treatment in SLE because it reduces disease-associated damage, prevents disease flares, and improves kidney and overall survival. In addition, hydroxychloroquine may reduce the risk for thrombosis, liver disease, and myocardial infarction; improve lipid profiles; and improve outcomes in high-risk pregnancies. Almost all patients with SLE without contraindications should receive hydroxychloroquine. With very rare exceptions the dosage should be limited to 5 mg/kg/d or less, and patients should receive annual monitoring by an ophthalmologist after 5 years of treatment to reduce the risk for retinal toxicity. Hydroxychloroquine can be used alone for mild disease (especially skin and joints) and in combination with other agents in severe disease. - Glucocorticoids are also used in most patients with SLE, particularly in acute disease. The glucocorticoid dose should be determined by the level of disease activity and organ systems threatened. For severe disease activity (including profound cytopenia, class III/IV nephritis, and NPSLE), high-dose glucocorticoids are recommended. For life- or organ-threatening disease (such as rapidly progressive glomerulonephritis or seizures), high-dose intravenous glucocorticoids are given, typically followed by daily oral glucocorticoids. After disease stability is achieved, glucocorticoids are tapered to the lowest effective dosage, preferably to no more than 7.5 mg/d within 4 to 6 months. Literature supports limiting exposure to glucocorticoids, especially at high doses, because of associated risk for organ damage, infection, and premature mortality. Glucocorticoids should be discontinued entirely when possible. - For moderate or severe disease, immunosuppressive therapy should be initiated concurrently with glucocorticoids to achieve and maintain disease control and to allow tapering of glucocorticoids. The choice of medication should be determined by the organs involved and disease severity. Intravenous cyclophosphamide is used as induction therapy for severe or refractory disease (e.g., acute central nervous system lupus, diffuse alveolar hemorrhage, or myocarditis), followed by maintenance therapy with mycophenolate mofetil or azathioprine. Mycophenolate mofetil or cyclophosphamide is used for lupus nephritis, although combination regimens including other immunosuppressive agents are also options. - The biologic agents belimumab and anifrolumab are FDA approved for patients with incomplete response to conventional treatments and are useful for skin/joint involvement and moderate/severe disease. Experience suggests a possible benefit of belimumab as add-on therapy for more severe organ involvement. - Less commonly used medications include quinacrine, methotrexate, leflunomide, calcineurin inhibitors, and rituximab. Other agents under investigation include proteasome inhibitors, Janus kinase inhibitors, interleukin-12 and interleukin-23 inhibitors, and other B cell-acting agents. - Adjunctive agents may be used for specific clinical features. NSAIDs can be used to treat arthritis and pleuropericarditis but are not disease modifying and may adversely affect kidney function and blood pressure. Statins and antihypertensive agents are often used to reduce cardiovascular risks. ACE inhibitors should be considered in patients with proteinuria. Adequate vitamin D intake is important in patients with SLE. Bone health should be monitored, with treatment for appropriate patients, especially those receiving glucocorticoids. Sun avoidance and regular use of sunscreen that blocks both UV-A and UV-B should be recommended for all patients with SLE. ## Key Points - Almost all patients with systemic lupus erythematosus without contraindications should receive hydroxychloroquine because it can reduce disease-associated damage, prevent disease flares, and improve kidney and overall survival. - Glucocorticoids are used in most patients with systemic lupus erythematosus, particularly in acute disease; after disease stability is achieved, glucocorticoids should be tapered to the

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