Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder characterized by autoantibody production responsible for antibody-mediated and immune complex deposition tissue damage. SLE involves multiple organ systems and has heterogeneous disease patterns. Relapses and remissions are a common feature.

SLE

Lupus

• Constitutional: Unexplained fever, fatigue (80% to 100% patients), malaise (Table 1)
• Mucocutaneous lesions (more than 80% of patients):
  1. Acute (associated with + Ro antibody): Malar rash (Fig. E1) sparing nasolabial folds (acute cutaneous lupus); annular or papulosquamous rash (subacute cutaneous lupus)

2. Chronic: Raised erythematous patches with subsequent edematous plaques and adherent scales (discoid cutaneous lupus), lupus profundus, lupus tumidus; alopecia, photosensitivity, nasal, or oropharyngeal ulcerations (classically painless, but discoid lesions [Fig. E2] may be painful); Raynaud phenomenon; leukocytoclastic vasculitis, chilblains; livedo reticularis or livedo racemosa (secondary to antiphospholipid antibody syndrome)

1. 3. Skin biopsy hallmark: Interface dermatitis
2. Musculoskeletal (about 90% of lupus patients): Arthralgias are more common than true arthritis, but nonerosive deforming arthritis is not rare; myositis
3. Cardiac: Pericardial rub (pericarditis) is most common; valvular heart disease (e.g., valve sclerosis, Libman-Sacks endocarditis); congestive heart failure, myocarditis, premature atherosclerotic heart disease
4. Pulmonary: Pleuritis (most common), acute or chronic pneumonitis, diffuse alveolar hemorrhage, pulmonary hypertension
5. Gastrointestinal: Dysphagia, mesenteric vasculitis, peritonitis, pancreatitis, hepatitis
6. Neuropsychiatric: Headache, psychosis, seizure, acute confusion states, peripheral or cranial neuropathy, transverse myelitis, stroke (may be associated with antiphospholipid syndrome), cognitive dysfunction
7. Hematologic (about 50% of lupus patients): Anemia (hemolytic, anemia of chronic disease, aplastic anemia), thrombocytopenia, leukopenia, lymphadenopathy, secondary antiphospholipid antibody syndrome
8. Renal: Acute renal failure, proteinuria, nephritic syndrome, nephrotic syndrome

Lupus may develop in genetically susceptible individuals, triggered by endogenous and exogenous factors. SLE susceptibility involves major histocompatibility complex (MHC) class II polymorphism with commonly observed association with HLA-DR-2, DR3, DR4, and DR8. SLE is also associated with inherited deficiencies of C1q, C2, C4a, others. There is predilection for familial clustering of SLE with risk in monozygotic twins-about 25% to 50%-and 5% in dizygotic twins. Environmental factors such as ultraviolet (UV) light, Epstein-Barr virus infection, and tobacco smoking may have a triggering role. Autoantibody production is the hallmark of disease development and diagnosis of SLE. Evidence supports the improper processing of nuclear proteins and nucleic acid from cell death. Impairments in neutrophil cell death via a process termed NET-osis (nuclear extracellular trap) contribute to the accumulation of nuclear debris. This, in turn, can lead to the presentation of self-nuclear material to plasmacytoid dendritic cells. Plasmacytoid dendritic cells propagate antibody and immune complex production via a type I interferon-dependent mechanism (Fig. E3).⁴

• Rheumatoid arthritis, mixed connective tissue disease, systemic vasculitis
• Neoplastic disorder
• Hematologic malignancy, paraneoplastic syndrome
• Systemic infection
• Other: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, primary antiphospholipid antibody syndrome

The diagnosis of SLE is clinical. The 2019 European League Against Rheumatism/American College of Rheumatology (ACR) classification criteria for SLE (Table 2) includes positive antinuclear antibody (ANA) at least once as obligatory entry criterion, followed by additive weighted criteria grouped in seven clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal), and three immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified as having systemic lupus. The new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 (see later) and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.⁵

1997 ACR Criteria:

• Malar rash
• Discoid rash
• Photosensitivity (recurrence of unusual skin rash in sun-exposed areas)
• Oral or nasopharyngeal painless ulceration, observed by physician
• Arthritis (nonerosive)
• Serositis (pleuritis, pericarditis)
• Renal disorder (persistent proteinuria >0.5 g/day, or ≥3+ on dipstick if quantification not performed; cellular casts)
• Neurologic disorder (seizures, psychosis [in absence of offending drugs or metabolic derangement])
• Hematologic disorder:
  1. Hemolytic anemia with reticulocytosis
  2. Leukopenia (<4000/mm³ total on two or more occasions)
  3. Lymphopenia (<1500/mm³ on two or more occasions)
  4. Thrombocytopenia (<100,000/mm³ in the absence of offending drugs)
• Immunologic disorder:
  1. Anti-double-stranded DNA antibody (anti-dsDNA)
  2. Anti-Smith antibody (anti-Sm)
  3. Antiphospholipid antibodies (anticardiolipin immunoglobulin M [IgM] or IgG, lupus anticoagulant, antibeta-2 glycoprotein IgM or IgG, or false-positive fluorescent treponemal antibody absorption test or Treponema pallidum immobilization for 6 mo)
• ANA: An abnormal titer of ANA by immunofluorescence or equivalent assay at any time in the absence of drugs known to be associated with drug-induced lupus syndrome

2012 SLICC Criteria: SLE can be diagnosed if⁶:

• Biopsy-proven nephritis with either ANA or anti-dsDNA antibodies or
• Patient satisfies four clinical criteria, requiring at least one clinical and at least one immunologic criterion
• Clinical criteria:
  1. Acute cutaneous lupus (malar rash, bullous lupus, toxic epidermal necrolysis, photosensitive lupus rash, maculopapular lupus, subacute cutaneous lupus)
  2. Chronic cutaneous lupus (discoid, hypertrophic verrucous, panniculitis, mucosal lupus, lupus tumidus, chilblains lupus, lichen planus)
  3. Oral ulcers or nasal ulcers
  4. Nonscarring alopecia
  5. Synovitis (more than two joints or inflammatory arthralgias of more than two joints)
  6. Serositis (pleurisy for more than 1 day, pericardial pain for more than 1 day)
  7. Renal (>500 mg proteinuria/24 h or RBC casts)
  8. Neurologic (seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, acute confusion state)
  9. Hemolytic anemia
  10. Lymphopenia (<1000/mm³ at least once)
  11. Thrombocytopenia (<100,000/mm³ at least once)
• Immunologic criteria:
  1. ANA
  2. Anti-dsDNA (>2× laboratory reference range)
  3. Anti-Smith
  4. Antiphospholipid antibodies (lupus anticoagulant, rapid plasma reagin [RPR], anticardiolipin IgA, IgG, IgM, anti-β2 glycoprotein IgA, IgG, IgM)
  5. Low complement
  6. Direct Coombs test in the absence of hemolytic anemia

Definitions of SLE classification criteria are included in Table 3.

Suggested initial laboratory evaluation of suspected SLE:

• ANA by immunofluorescence or similar high-quality method
  1. CBC with differential, blood urea nitrogen and serum creatinine, urinalysis, erythrocyte sedimentation rate (ESR), partial thromboplastin time (PTT), complements (C3, C4)

Consider additional laboratory testing in a patient with strong suspicion for systemic lupus:

• Anti-dsDNA, anti-Smith, anti-SSA, anti-SSB, anti-RNP antibodies. Table 4 summarizes autoantibodies and clinical significance in SLE
• Lupus anticoagulant, RPR, anticardiolipin antibodies, anti-beta-2 glycoprotein antibodies especially in patients with thrombotic events or recurrent miscarriages
• Urinalysis for red blood cell (RBC), cellular casts
• Random spot urine protein: Urine creatinine ratio, 24-h urine protein collection if proteinuria; >0.5 or >500 mg/24 h is abnormal, respectively. Evaluation of renal biopsy specimens in lupus nephritis (LN) is summarized in Table E5

Direct Coombs test

• Chest x-ray examination for evaluation of pulmonary involvement (pleural effusion, infiltrates)
• Electrocardiogram for chest pain
• Echocardiogram if murmur, evidence of new or unexplained congestive heart failure, or suspected pericarditis

• Avoidance of sunlight and use of high-SPF sunscreen (>35).
• Screening and counseling for modifiable cardiovascular risk factors such as cigarette smoking, diet, exercise, cholesterol, and uncontrolled hypertension (HTN).
• Counseling for pregnancy planning for patients of childbearing age.
• Calcium and vitamin D supplementation for prevention of early osteoporosis (see “Osteoporosis”).⁷

• There are only four FDA-approved SLE medications: Aspirin, corticosteroids, hydroxychloroquine (1955), and belimumab (2011).
• Treatment should be targeted toward the involved organ(s). Recommended drugs for the treatment of SLE according to stratification of disease severity are described in Fig. 4. Indications for immunosuppressive therapy in SLE are summarized in Table 6.
• Limited and defined courses of corticosteroids are useful for a variety of SLE symptoms. Steroid therapy should be restricted to acute or subacute control of symptoms, due to the increased cardiovascular risk and increased organ damage associated with chronic steroid use. Recommended drug monitoring in SLE is summarized in Table 7.
• Consider checking G6PD in certain ethnic groups more predisposed to antimalarial- induced hemolytic anemia.
• Hydroxychloroquine has best evidence for reducing flares, organ damage, lipids, thrombosis; improving survival; augmenting action of mycophenolate mofetil (MMF) in LN; and preventing seizures. Currently recommend not to exceed an oral dose of 5 mg/kg/day to decrease risk of retinal toxicity.¹
• Methotrexate and azathioprine are used as steroid-sparing agents. Indications include cutaneous and joint involvement.¹
• Joint pain and mild serositis are generally well controlled with NSAIDs or low-dose corticosteroids. Hydroxychloroquine and methotrexate are also effective for arthritis. Belimumab does well for joint and cutaneous manifestations. Leflunomide and rituximab may be considered for refractory arthritis. Treatment approach for musculoskeletal features of SLE is summarized in Table 8.
• Cutaneous manifestations:
  1. Topical or intradermal corticosteroids are helpful for individual discoid lesions, especially in the scalp.
  2. Hydroxychloroquine alone or in combination with quinacrine and/or chloroquine can be considered for refractory skin disease.
  3. Refractory cases may be treated with belimumab, MMF, dapsone, or combination treatment.^1,8
  4. Fig. E5 and Table E9 summarize general management of cutaneous lesions in SLE.
• Hematologic manifestations:
  1. Corticosteroids are first-line therapy. Table E10 summarizes the treatment and main hematologic features of SLE.

2. Azathioprine can be used for thrombocytopenia or hemolytic anemia. Check for TPMT genetic mutation before the first use.
3. Intravenous immunoglobulin (IVIG) or rituximab may be considered for severe leukopenia, autoimmune hemolytic anemia, or autoimmune thrombocytopenia (Fig. E6).

1. 4. Central nervous system manifestations:
   5. Headaches are treated symptomatically. Most headaches will not be SLE-related and should be treated according to the underlying cause.
   6. Anticonvulsants and antipsychotics may be indicated.
   7. Standard therapy for other neuropsychiatric SLE symptoms is not established.
2. Renal disease: The histologic classification of LN according to the International Society of Nephrology/Renal Pathology Society is summarized in Table E11. Severity of LN is described in Table E12. Treatment recommendations for LN are summarized in Table E13. (Class III, IV, or IV/V with cellular crescents LN; see Table E14.) INDUCTION: 6-mo treatment.

1. 1. The typical treatment induction period is 6 mo. The use of intravenous cyclophosphamide (CYC) with corticosteroids given at monthly intervals is more effective in preserving renal function than is treatment with glucocorticoids alone. Low-dose “Euro-Lupus” protocol may be equally efficacious and less toxic for certain populations (e.g., Caucasians, Blacks) than high-dose regimen. MMF is considered equivalent to CYC based on high-quality studies, with better tolerability and fertility profile. MMF may be preferred in African Americans and Hispanics. MMF and azathioprine are good options for maintenance treatment.
   2. There is interest in and positive data for use of calcineurin inhibitors, such as tacrolimus, for treatment of LN. Newer and possibly less toxic voclosporin has entered phase III trial and when added to MMF showed better results in renal responses compared with MMF alone.⁹
2. Severe nonrenal organ disease:
   1. Evidence from systematic randomized controlled trials for non-renal lupus treatment is comparatively limited.
   2. High-dose intravenous CYC is used as an induction treatment. Azathioprine or MMF may be used as maintenance.
   3. IVIG may be considered in severe disease especially when concomitant infection is present.
   4. Plasmapheresis or plasma exchange may be considered in critical situations: First-line therapy in Guillain-Barré syndrome, thrombotic thrombocytopenic purpura (TTP); second-line for SLE-related hemolytic anemia, cerebritis, and diffuse alveolar hemorrhage (DAH). Infectious complications are common.
3. Fever/infection post-immunosuppressive therapy
   1. Immunosuppressive therapy can result in neutropenia and increased susceptibility to infection
   2. Fig. E7 illustrates an approach to SLE patients with fever and other signs of infection post-immunosuppressive therapy

• Therapy targeting B cells:
  1. Rituximab: Anti-CD20 monoclonal antibody. Randomized controlled trials for rituximab as an adjunct induction agent were negative in terms of both renal and nonrenal outcomes but were felt to be limited by study design. Some observational studies have shown efficacy in those who have failed other regimens.^1,10
  2. Epratuzumab: An anti-CD22 agent. Studies initially showed positive data, but in July 2015 both phase III trials for SLE failed to meet their primary endpoint, and this medication is no longer studied.
  3. Belimumab: Decreases activation of B cells. When used in addition to standard therapy, patients on belimumab showed improvement in cutaneous and musculoskeletal disease. Belimumab-treated patients had decreased SLE activity, a reduced time to disease flare, and lower glucocorticoid exposure. Patients with central nervous system or serious kidney disease were excluded. There is interest in adding belimumab to standard LN regimen, but data from BLISS-LN are not yet available.^8,11
  4. Abatacept: Downregulates T-cell activation. Data are limited regarding improvement in arthritis, fatigue, sleep if added to routine therapy. Negative data as adjunct agent for lupus arthritis when added to MMF or CYC. Shows limited positive efficacy in patients refractory to other treatments.¹
  5. Interferon therapy: Interferon α (INFα) has been linked to increased disease activity in SLE. INFα blocking therapies are in phase II clinical trials. Sifalimumab, a monoclonal antibody against INFα, reduced moderate to severe mucocutaneous involvement in SLE and decreased active joint count and fatigue scores in preliminary data analysis. Development of sifalimumab has been terminated in favor of anifrolumab, a similar INFα blocking agent. The TULIP-1 study of that molecule did not meet response criteria based on score used in the BLISS trial. TULIP-2 used BICLA as a response measure and showed statistically significant improvement compared to placebo. The phase III trial is ongoing.^12,13
  6. There is continuous interest in studying B-cell and interferon-based treatment, but no FDA approved treatment, other than noted earlier, is currently used clinically.
  7. Novel potential targeted treatment approaches may include blocking interleukin-17 (IL-17), IL-12/23, and JAK inhibitors (early data for 4-mg baricitinib showed positive results). Research remains very active and ongoing to find new therapeutic targets.^14,15
• Recommended assessment and monitoring of patients with SLE with nonrenal, noncentral nervous system manifestations are summarized in Box 1.
• SLE in pregnancy (Table E15): Pregnancy in the setting of SLE is associated with a higher risk of complications compared with healthy women (preterm labor, unplanned cesarean delivery, fetal growth restriction, preeclampsia, and eclampsia). Ideally, conception should be attempted in a state of disease remission or stability. If pregnancy occurs during a period of disease relapse, medications need to be adjusted for maternal and fetal safety. Mothers with active SLE should be tested for anti-Ro/SSA and anti-La/SSB antibodies once before or early in pregnancy, due to their associated increase in risk for neonatal lupus and congenital heart block.¹⁶

1. Recommended during pregnancy: Hydroxychloroquine, low-dose aspirin, antihypertensives (methyldopa, labetalol, nifedipine)
2. Selective use allowed during pregnancy: NSAIDs, glucocorticoids, azathioprine, cyclosporine, tacrolimus, biologics
3. Contraindicated: Cyclophosphamide, mycophenolate mofetil, methotrexate, leflunomide

• Most patients with SLE experience remissions and exacerbations.
• 5-yr survival rate has improved to more than 90% in patients with newly diagnosed SLE since the advent of potent immunosuppressive therapy. The 15-yr survival rate is now 85%.³
• Early death related to SLE activity and infections; late death due to cardiovascular disease.
• LN progression rate to ESRD in 10% to 30% within 15 yr.
• African Americans, Asian Americans, and Hispanic Americans in general have a worse prognosis. The leading cause of death in SLE patients in developed countries is premature atherosclerosis. The quality of life for many SLE patients is poor due to fatigue, chronic pain, and cognitive impairment.²

• Rheumatology consultation for all patients with SLE
• Hematology consultation for patients with significant hematologic abnormalities (e.g., severe hemolytic anemia or thrombocytopenia)
• Nephrology consultation in patients with proteinuria and/or suspected renal involvement
• Dermatology consultation for patients with unexplained or unusual skin rash
• Cardiology consultation for patients with lupus carditis, arrhythmias
• Ophthalmology referral for all patients on hydroxychloroquine and chloroquine

Systemic Lupus Erythematosus (Patient Information)Discoid Lupus (Related Key Topic)Renal Lupus (Related Key Topic)