Sections

Sections Systemic Lupus Erythematosus (SLE)
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
Media Gallery
Tables
References

Treatment

Approach Considerations

Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations,^[8]although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in patients given hydroxychloroquine, making it the cornerstone of SLE management.^[122]

In general, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may wax and wane with disease activity. These are often controlled with nonsteroidal anti-inflammatory drugs (NSAIDS) or low-potency immunosuppression medications beyond hydroxychloroquine and/or short courses of corticosteroids. More prolonged steroid use is generally reserved for patients with involvement of vital organs. For example, central nervous system involvement and diffuse proliferative kidney disease must be recognized as more severe disease manifestations, and these are often treated with more aggressive immunosuppression. Evidence suggests a relative undertreatment of SLE patients with end-stage renal disease (ESRD), because the extent of lupus activity may be underestimated.^[123]

Assessing response and defining remission

A number of instruments have been devised for the standardized assessment of disease activity in SLE; however, none can be considered the "gold standard".^[124]From the clinician’s perspective, an assessment of disease activity that represents the ideal treatment target for SLE has not yet been found. From the patient’s perspective, improvement in fatigue, joint pain, and quality of life appear to be the ideal treatment goals.^[125]

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), which consists of 24 weighted clinical and laboratory variables of nine organ systems, was developed and introduced in 1985 as a clinical index for the assessment of lupus disease activity in the preceding 10 days.^[124]A modification of the SLEDAI, the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), was introduced in 2002. The SLEDAI-2K allows consideration of persistent active alopecia, mucous membrane ulcers, rash, and proteinuria—disease features that the original SLEDAI considered only as new or recurrent. See the SLEDAI-2K calculator.

A newer approach, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS), includes 17 clinical and laboratory features (see the SLE-DAS calculator) and has demonstrated higher sensitivity to change as compared with the SLEDAI-2K.^{[126, 125]}

The SLE Responder Index (SRI) is a tool that was developed following phase II trials and is composed of the following scores^[127]:

SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus Erythematosus Disease Activity Index)
BILAG (British Isles Lupus Assessment Group)
PGA (physician global assessment)

SRI response is defined by the following^[127]:

A 4-point or greater reduction in the SELENA-SLEDAI score
No new BILAG A or no more than 1 new BILAG B domain score
No deterioration from baseline in the PGA by 0.3 or more points.

European League Against Rheumatism (EULAR) definitions of treatment goals in SLE are as follows^[80]:

Complete remission - Absence of clinical activity with no use of glucocorticoids or immunosuppressive drugs
Low disease activity - SLEDAI score ≤3 with antimalarial therapy, or SLEDAI ≤4, PGA ≤1 with glucocorticoids at ≤7.5 mg of prednisone equivalent and well-tolerated immunosuppresisive agents
Partial renal remission - Reduction in proteinuria by ≥ 50% to subnephrotic levels and serum creatinine within 10% from baseline by 6–12 months
Complete renal remission - Proteinuria < 500 mg/24 hours and serum creatinine within 10% from baseline

EULAR recommendations

EULAR released recommendations for the treatment of SLE in 2008 and updated them in 2019.^{[72, 80]}EULAR recommends that treatment in SLE aim at remission, or at low disease activity in all organ systems if remission cannot be achieved. Specific medication recommendations include the following:

Hydroxychloroquine is recommended for all patients with SLE.
Glucocorticoids can provide rapid symptom relief, but the medium- to long-term aim should be to minimize the daily dose to ≤7.5 mg/day prednisone equivalent or to discontinue them.
Subsequent initiation of immunosuppressive drugs facilitates more rapid tapering of glucocorticoids and may prevent disease flares. The choice of agent depends on prevailing disease manifestation(s), patient age and childbearing potential, safety concerns, and cost.

EULAR recommendations regarding immunosuppressive drugs for SLE are as follows:

Consider methotrexate and azathioprine in patients with poor symptom control with glucocorticoids and hydroxychloroquine, or when hydroxychloroquine alone is unlikely to be sufficient.
Mycophenolate mofetil (MMF) is a potent immunosuppressant with efficacy in renal and non-renal SLE (but not in neuropsychiatric lupus), but its teratogenic potential and higher cost limit its recommendation in women of reproductive age with non-renal manifestations.
Cyclophosphamide can be considered in organ-threatening disease (especially renal, cardiopulmonary, or neuropsychiatric) and as rescue therapy in patients with non–major organ manifestations refractory to other agents. Due to its gonadotoxic effects, it should be used with caution in women and men of fertile age; concomitant use of gonadotropin-releasing hormone (GnRH) analogues is recommended in premenopausal patients.

EULAR recommendations regarding biologic agents for SLE are as follows:

Consider belimumab in patients with extrarenal disease inadequately controlled by first-line treatments.
Off-label use of rituximab may be considered in patients with severe renal or extrarenal (mainly hematologic and neuropsychiatric) disease refractory to multiple other agents.

EULAR recommendations for specific SLE manifestations are as follows:

Skin disease - First-line treatment includes topical agents (glucocorticoids and/or calcineurin inhibitors) and antimalarials (preferably hydroxychloroquine); the addition of systemic glucocorticoids may be considered, with the starting dose dependent on the severity of skin involvement.
Neuropsychiatric disease - Consider glucocorticoids and/or immunosuppressive agents if the underlying pathophysiologic mechanism is presumed to be inflammatory; if antiphospholipid antibodies are present, anticoagulant/antithrombotic treatment is favored; if the mechanism is uncertain, or both mechanisms appear to coexist, combined immunosuppressive therapy and anticoagulant/antithrombotic therapy may be considered.
Hematologic disease - First-line treatment of significant lupus thrombocytopenia (platelet count below 30,000/mm³) is with moderate to high doses of glucocorticoids in combination with a steroid-sparing immunosuppressive agent (azathioprine, MMF, or cyclosporine; the last having the least potential for myelotoxicity). Initial therapy with pulses of intravenous methylprednisolone for 1–3 days is encouraged. Intravenous immunoglobulin (IVIG) may be considered in the acute phase.
Lupus nephritis - Treatment consists of an initial induction phase followed by a more prolonged maintenance phase. MMF and (preferably low dose) cyclophosphamide are the immunosuppressive agents of choice for induction treatment. MMF plus high-dose cyclophosphamide may be considered for patients with severe lupus nephritis at increased risk for progression to end-stage renal disease. Maintenance treatment is with MMF or azathioprine, with the choice depending on the agent used for induction and on patient characteristics, including age, race, and wish for pregnancy; rituximab may be considered in refractory or relapsing disease. Calcineurin inhibitors may be considered as second-line agents for induction or maintenance therapy, mainly in membranous lupus nephritis, podocytopathy, or in proliferative disease with refractory nephrotic syndrome despite standard-of-care within 3–6 months; in refractory cases, calcineurin inhibitors may be combined with MMF.

American College of Rheumatology guidelines

In 2009, an American College of Rheumatology (ACR) Task Force generated a quality indicator set.^[128]In 2012, the ACR published "Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an evidence report for lupus nephritis. In 2020, the ACR published a Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases, which includes recommendations tailored to patients with SLE.^[129]These and other guidelines are available at the ACR's Clinical Practice Guidelines Web site.

Adjunctive therapies

Vitamin D insufficiency and deficiency are more common in patients with SLE than in the general population.^[130]Vitamin D supplementation may decrease disease activity and improve fatigue.^{[131, 132]}In addition, supplementation may improve endothelial function, which may reduce cardiovascular disease.^{[133, 134, 135]}

No diet-based treatment of SLE has been proven effective. Patients with SLE should be reminded that activity may need to be modified as tolerated. Specifically, stress and physical illness may precipitate SLE flares. Additionally, persons with SLE should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.

Consultations

The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved. Consultation with any of the following specialists may be necessary:

Rheumatologist
Infectious disease specialist
Neurologist
Pulmonologist
Cardiologist
Gastroenterologist
Nephrologist
Dermatologist
Hematologist
High-risk obstetrician

Hydroxychloroquine

Hydroxychloroquine (HCQ; Plaquenil) is an antimalarial drug that has been used in autoimmune infectious diseases, specifically in SLE. HCQ is an inexpensive, generally available, well-tolerated immunomodulator. HCQ is one of the most valuable therapies in SLE and the cornerstone in lupus management, as it has survival benefits in lupus and reduces overall disease flare risk and accrued damage over time. Thus, all patients with SLE should be given HCQ unless there are contraindications or adverse effects.

The main alkaloids of quinine and cinchonine were isolated from cinchona bark in 1820 and soon quinine was used in 1894 for patients with cutaneous lupus. Subsequently, chloroquine (CQ) was obtained in 1934. HCQ, a hydroxylated analogue of CQ, was synthesized in 1946. Due to a better safety profile, HCQ was approved in 1955 as an alternative to CQ for lupus symptoms including fatigue, rashes, joint pain, and mouth sores.

The mechanisms of action for HCQ are not completely understood. However, it is hypothesized that HCQ—a highly lipophilic, lysosomotropic drug—can pass through cell membranes and accumulate into lysosomes, where it disrupts key important cellular functions via inhibition of the Toll-like receptors (TLRs) and of the Cyclic GMP-AMP synthase–Stimulator of Interferon Genes (cGAS-STING) pathway. This in turn leads to inhibition of enzyme and cytokine release, receptor recycling, antigen presentation, T-cell polarization, and natural killer (NK) cell activation and increases photoprotection against ultraviolet (UV)-A and B light.

HCQ use is encouraged in all patients with lupus because it reduces the risk of disease flares by 20-40%.^[136]It reduces the risk of accrued organ damage, and further HCQ use has been associated with reduced damage progression.^{[137, 138]}This protective effect of antimalarials against damage development is probably due to their role in preventing disease flares, corticosteroid-sparing properties, and favorable effects on different metabolic risk factors. Finally, studies have shown that HCQ can significantly reduce risk of kidney disease progression and thrombosis/cardiovascular disease, and prolong survival in patients with lupus.^{[139, 140]}

Importantly, HCQ passes the placenta, and fetal serum concentrations equal those measured in the maternal blood. During lactation, HCQ passes in the maternal milk, but with lower concentrations than in maternal blood, estimated to be 0.2 mg/kg/day.^[141]HCQ use during pregnancy and breastfeeding is considered safe and reduces lupus flare risk, as well as neonatal lupus or heart block risk with SS-A/B antibodies. Consequently, HCQ use during pregnancy and breastfeeding should be encouraged.^{[142, 143, 144]}

Belimumab

The monoclonal antibody belimumab (Benlysta), a B-lymphocyte stimulator–specific inhibitor, has been found to reduce disease activity and possibly decrease the number of severe flares and steroid use in patients with SLE when used in combination with standard therapy.^[145]In 2011, the US Food and Drug Administration (FDA) approved the use of belimumab in combination with standard therapies (including steroids, nonbiologic disease-modifying antirheumatic drugs (DMARDS; eg, HCQ, azathioprine, methotrexate) to treat active autoantibody-positive SLE.^[146] In 2017, a subcutaneous (SC) formulation was approved that allows patients to self-administer a once-weekly dose.^[147]

Patients of African-American or African descent did not show significant responses to belimumab in phase III post-hoc analysis, but those studies were not powered to assess for this effect; in a phase II trial, Black participants had a greater treatment response. Those results indicate that the benefits of belimumab in patients with SLE remain inconclusive and that further investigation is needed. Patients with severe active lupus nephritis or CNS lupus or patients previously treated with other biologics or cyclophosphamide have been excluded from participation in early trials.

A multinational phase III study (BLISS-52) that evaluated the efficacy and safety of intravenous (IV) belimumab, in 867 patients with a minimum SELENA-SLEDAI score of 6, reported that patients given belimumab had significantly higher SRI scores at 52 weeks than did those given placebo.^[148]All groups had similar rates of adverse events.

Similarly, a phase III trial of 819 SLE patients who were positive for either antinuclear antibody or anti–double-stranded DNA at baseline screening found that belimumab at 10 mg/kg plus standard therapy resulted in a significantly greater SRI score (43.2%) than placebo (33.5%) at 1 year (those who received IV belimumab 1 mg/kg plus standard therapy had a 40.6% response rate).^[149]Overall, the addition of belimumab to standard therapy reduced SLE disease activity and severe flares, and the medication was well tolerated.^[149]

Approval for SC belimumab was based on the BLISS-SC phase III study (n=839), which documented reduction in disease activity at week 52 in patients receiving belimumab plus standard of care, compared with those receiving placebo plus standard of care. SRI response with belimumab versus placebo was 61.4% vs 48.4%, respectively (P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171 days vs 118 days; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% vs 11.9%; P = 0.0732), compared with placebo.^[150]

Finally, Urowitz et al compared organ damage progression in SLE patients treated with belimumab in the BLISS long-term extension trial with propensity score–matched patients treated with standard SLE therapy from the Toronto Lupus Cohort. They found that patients receiving belimumab had significantly less organ damage progression compared with patients receiving standard SLE therapy.^[151]These effects of belimumab on damage accrual may be partly due to its role in reducing flares and its corticosteroid-sparing effects.

Rituximab

B-cell depletion with rituximab (Rituxan) has been used successfully for rheumatoid arthritis, but studies have shown mixed results in SLE. An open study found benefit of B-cell depletion with rituximab, cyclophosphamide, and methylprednisolone as rescue therapy for patients with active SLE that was unresponsive to standard immunosuppressant therapy.^[152]

There have also been case series of patients with severe refractory SLE in which off-label use of rituximab showed benefits and tolerable safety profiles.^{[153, 154, 155]}For example, in a retrospective study of 115 patients with severe or refractory SLE, 40% of patients had a complete response and 27% had a partial response, as measured by BILAG scores recorded 6 months after the first rituximab treatment.^[156]

However, three placebo-controlled studies, including the Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER] trial and the Lupus Nephritis Assessment with Rituximab [LUNAR] trial,^{[157, 158]}failed to show an overall significant response. Despite the negative results in these trials, rituximab continues to be used to treat patients with severe SLE disease that is refractory to standard therapy.

Pharmacologic agents targeting specific pathways such as cytokines and complement, as well as combinations of rituximab with costimulatory inhibition with anti-CD40L or CTLA-4Ig, may prove to be more effective in treating SLE.^[159]

Anifrolumab

SLE has been associated with high serum levels of type 1 interferon (IFN) and increased type 1 IFN gene signature. Anifrolumab (Saphnelo) is a human IgGk monoclonal antibody that binds to the type 1 IFN receptor and inhibits activity of all type 1 IFNs. The blockade of the type 1 IFN receptor inhibits IFN-responsive gene expression as well as downstream inflammatory and immunologic processes. In August 2021, the FDA approved anifrolumab for the treatment of moderate-to-severe SLE.

Approval was based on combined data from the TULIP-1 and TULIP-2 phase III trials and the MUSE phase II trial. The TULIP-1 trial randomized 457 patients with moderate-to-severe SLE to receive anifrolumab 150 mg IV, 300 mg IV, or placebo every 4 weeks, in addition to standard therapy. The primary endpoint was not reached. However, certain secondary endpoints (eg, reduction in oral corticosteroid dose, CLASI responses, British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA] responses) suggest clinical benefit of anifrolumab compared with placebo.^[160]

The randomized TULIP-2 trial used response to treatment with BICLA as its primary endpoint, and found a higher BICLA response in the anifrolumab group than in the placebo group (47.8% vs 31.5%, respectively). Response to anifrolumab was superior to placebo in patients with high and low IFN gene signature (48% vs 30.7% in high-signature patients, 46.7% vs 35.5% in low-signature patients). The occurrence of herpes zoster was higher in the anifrolumab group than with placebo.^[161]

Like the TULIP-1 trial, the MUSE trial compared 2 doses of anifrolumab (300 mg or 1000 mg) with placebo. Anifrolumab substantially reduced disease activity compared with placebo across primary and secondary endpoints in patients with moderate-to-severe SLE.^[162]

Volcosporin

Voclosporin is a novel calcineurin inhibitor (CNI) that was developed for the treatment of lupus nephritis and has several advantages over traditional CNIs. These include a consistent pharmacokinetic profile, which eliminates the need for therapeutic drug monitoring required for other CNIs, and a more favorable effect on lipids and glucose concentrations.^{[141, 142]} Additionally, voclosporin has no effect on concentrations of mycophenolic acid, the active moiety of mycophenolate mofetil (MMF).^[143]

A multicenter placebo-controlled phase III trial in patients with lupus nephritis found that the addition of voclosporin to MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate.^[163]Compared with placebo, voclosporin yielded a significant increase in 6-month complete renal response rate and a 2.7-fold higher 12-month response rate. Additionally, the improved efficacy in the voclosporin group was achieved with steroid tapering that resulted in a significantly lower cumulative steroid dose than in any previous study. Overall, volcosporin had a good safety profile and good tolerance.^[163]

The totality of the data support the addition of a CNI such as voclosporin to background immunosuppressive therapy as a first-line treatment of lupus nephritis. Volcosporin was approved by the FDA in January 2021 for use in patients with lupus nephritis along with mycophenolate. The recommended dosage is 23.7 mg twice daily, along with mycophenolate 1 g twice daily.

Other DMARDs, including methotrexate, mycophenolate, steroids, and cyclophosphamide, are recommended for use in SLE and are discussed in Medication.

Investigational Therapies

Despite mixed results from prior anti-CD20 studies in lupus, recent case reports and case series have reported a possible role for B-cell–depleting anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in severe treatment-refractory SLE.^{[164, 165]}CAR T-cells genetically engineered to recognize CD19, a specific B-cell marker that can also target CD20-negative plasma cells, had shown efficacy in treating refractory B-cell cancers, which raised interest in this approach in lupus. In a compassionate use study, five patients with treatment-refractory lupus who received anti-CD19 CAR T-cell therapy showed B-cell depletion, double-stranded DNA seroconversion, and drug-free remission for a median of 8 months.^[165]Those findings merit further investigation of this approach.

Emergency Department Management

Acute emergencies in patients with SLE include the following:

Severe neurologic involvement
Systemic vasculitis
Profound thrombocytopenia with a thrombotic thrombocytopenia (TTP)–like syndrome
Rapidly progressive glomerulonephritis
Diffuse alveolar hemorrhage ^[166]

These conditions may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide. Strokes, acute myocardial infarctions, and pulmonary emboli occurring as complications of SLE are managed in the same way as they are in patients without SLE. In patients who present with fever, it may be necessary to limit immunosuppression to steroids and to empirically treat for an infection until culture results have been received.

In rare cases, diffuse alveolar hemorrhage may require plasma exchange, or profound steroid-refractory thrombocytopenia may require therapy with intravenous immunoglobulin (IVIG). Catastrophic antiphospholipid antibody syndrome also requires aggressive acute management. For more information, see the Medscape article Antiphospholipid Syndrome.

Hospitalization

Fever in patients with SLE is grounds for hospital admission because of the difficulty of distinguishing a disease flare from infection in these immunocompromised hosts. Patients with SLE are often complement deficient and functionally asplenic; therefore, they are at particular risk for infections with encapsulated organisms. For example, meningococcemia in young females with lupus may be catastrophic.

Although it is known that chronically low complement levels and functional asplenia may increase susceptibility to infection, it is not known to what degree.^{[167, 168]}Overall, the primary reason patients with SLE die of infections is probably the use of immunosuppressive medications. Stress-dose steroid protocols should be used in patients who are receiving maintenance corticosteroids when they are admitted with infectious or perioperative stress.

Central nervous system lupus with depressed consciousness or alveolar hemorrhage may prompt transfer to an intensive care unit and consideration of protective intubation. Thrombotic thrombocytopenic purpura and catastrophic antiphospholipid antibody syndrome should prompt transfer to a center capable of offering plasma exchange therapy.

For more information, see the Medscape articles Neurologic Manifestations of Systemic Lupus Erythematosus and Thrombotic Thrombocytopenic Purpura.

Lupus Nephritis

The 2012 American College of Rheumatology (ACR) guidelines for lupus nephritis recommend that treatment of this condition be largely based on classification by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) histologic criteria (see Workup/Biopsies and Histologic Features).^[113]

Lupus nephritis is managed with a combination of glucocorticoids^[169]and immunosuppressive agents to slow the progression to end-stage renal disease (ESRD), along with maintaining normal blood pressure levels (ie, target of ≤130/80 mm Hg).^{[80, 113]}In general, individuals with class I or II lupus nephritis do not require immunosuppression.^[113]

Patients with class III or IV disease, as well as those with a combination of class V and class III or IV disease, generally undergo aggressive therapy with glucocorticoid drugs and immunosuppressants.^[113]Immunosuppressive therapy consists of induction and maintenance therapy. Induction therapy involves potent immunosuppressive drugs (eg, mycophenolate mofetil [MMF], cyclophosphamide) to achieve remission; these drugs are generally used for 3 months to 1 year, with an average of 6 months’ treatment having been shown to be more efficacious and safer than long-term therapy.^[170]

A large randomized trial that compared induction therapy consisting of oral MMF with cyclophosphamide therapy in patients with lupus nephritis showed that MMF was not inferior to cyclophosphamide.^[171]The investigators suggested that MMF was associated with both a trend toward greater complete remissions and a greater safety profile.^[171]This study’s findings were confirmed with the large, international Aspreva Lupus Management Study (ALMS) trial (see Maintenance therapy, below).^[172]

Two newer therapies, belimumab and volcosporin, have been approved for use in combination with MMF for patients with lupus nephritis. Experts recommend adding voclosporin or belimumab to standard therapy (eg, MMF or cyclophosphamide) in lupus nephritis that is unresponsive to standard therapy.^[173]In clinical trials, voclosporin responses were better in patients who were already receiving mycophenolate and belimumab showed a larger beneficial effect in patients experiencing a relapse than in those with de novo lupus nephritis.^[174]These observations suggest that both of these novel therapies improve response rates in patients who have already been exposed to some immunosuppression.

Of note, experts advise that belimumab may be less effective in patients with proteinuria ≥3 g/day, and voclosporin should be used cautiously or not at all in patients with a significantly impaired glomerular filtration rate (ie, < 45 ml/min). If voclosporin is not available, tacrolimus should be considered, given the CNI class effect.

For refractory or therapy-resistant lupus nephritis, defined as partial or no response to the above therapies, B-cell targeted therapies such as rituximab should be considered. There are data to support rituximab use in patients with refractory disease, but the quality of this data is low-modest. In patients who have no or only partial response to rituximab, the addition of other immunosuppression or combination immunosuppression could be considered, although the risk versus benefit must be assessed. Additionally, one might consider repeating kidney biopsy to assess activity vesus chronicity, which to examine the risk vs. benefit of intensifying immunosuppression in such cases.

Other therapies have been studied, with diverse results. In one study, azathioprine combined with methylprednisolone pulses provided a short-term renal response rate comparable to that from prednisolone combined with standard-dose IV cyclophosphamide; however, patients had more infections and extended follow-up data showed a higher relapse rate and greater progression of chronic kidney disease. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that while therapies such as azathioprine plus glucocorticoids may be considered in lieu of the recommended initial drugs for proliferative lupus nephritis in cases of intolerance, lack of availability, and/or excessive cost of standard drugs, these alternatives may have inferior efficacy.^[174]

Maintenance therapy

MMF and azathioprine were directly compared as maintenance agents in 2 major clinical trials. In ALMS, which included 227 ethnically diverse patients with lupus nephritis, treatment failure over 3 years of follow-up was observed in 16% of MMF-treated patients and 32% of azathioprine-treated patients (P= 0.003). Treatment failure was defined by the composite endpoint of death, ESRD, lupus nephritis flare, sustained doubling of serum creatinine, or requirement for rescue therapy.^[175] Lupus nephritis flares occurred in 12.9% of MMF-treated patients and 23.4% of azathioprine-treated patients. In addition, a higher proportion of patients in the azathioprine group had adverse events leading to withdrawal of therapy (39.6% vs. 25.2%)

The Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis (MAINTAIN) trial found no difference in time to kidney flare with MMF or azathioprine; cumulative kidney flare rate was around 20% in both groups after 36 months. However, patients receiving MMF experienced a significantly lower incidence of cytopenias than did those receiving azathioprine; they also experienced fewer renal flares, although the difference did not reach statistical significance. MAINTAIN comprised 105 predominantly White patients who received baseline treatment with IV methylprednisolone followed by oral glucocorticoids and IV cyclophosphamide.^[176]

Consequently, the 2021 KDIGO guidelines recommend MMF as the maintenance drug of choice for class III and IV lupus nephritis.^[174]Alternatives, such as azathioprine or leflunamide, may be considered in situations of intolerance, lack of availability, and/or excessive cost of standard drugs, but these alternatives may be associated with inferior efficacy.

Adjunctive therapy

Unless contraindicated, hydroxychloroquine should be used as adjunctive therapy in lupus nephritis because of the potential for reduction in rates of disease flare; damage accrual, including kidney damage; and risk of thrombotic events.^[113]

Administer angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to all patients with lupus nephritis (except pregnant women) who have proteinuria of 0.5 g or more per 24 hours (or equivalent by protein/creatinine ratios on spot urine tests).^[113]This treatment has been reported to not only reduce proteinuria by about 30% but also significantly delay the doubling of serum creatinine and the progression to ESRD (in patients with nondiabetic chronic kidney disease).^[177]

Statin therapy is recommended in patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL because both renal dysfunction alone and SLE alone are independent risk fac tors for accelerated atherosclerosis.^[113]

End-stage renal disease

Patients with SLE and nephritis who progress to ESRD may require dialysis and kidney transplantation; those treatments have rates of long-term patient and graft survival that are similar to those observed in patients without diabetes and SLE.^[80]However, transplantation is considered the treatment of choice because of improved survival rates.^[80]

For more information, see Lupus Nephritis.

Antiphospholipid Syndrome

In patients with SLE, the presence of antiphospholipid antibodies is common; depending on the assay, these antibodies have been reported in up to 30-50% of SLE patients.^[178]Therefore, it is important to evaluate these patients for risk factors for thrombosis, such as use of estrogen-containing drugs, tobacco smoking, immobility, previous surgery, and the presence of severe infection or sepsis.^[80]The European League Against Rheumatism (EULAR) has noted that low-dose aspirin in individuals with SLE and antiphospholipid antibodies is potentially useful for primary prevention of thrombosis and pregnancy loss.^[80]

Secondary prevention of thrombosis in nonpregnant patients with SLE and thrombosis associated with antiphospholipid syndrome can be managed with long-term use of oral anticoagulants.^[80]In pregnant patients with SLE and antiphospholipid syndrome, unfractionated or low-molecular-weight heparin and aspirin may reduce the risk of pregnancy loss.

For additional information, see Antiphospholipid Syndrome and Systemic Lupus Erythematosus and Pregnancy.

SLE in Pregnancy

Fertility rates in women with SLE may be similar to those in the general population. However, the incidence of spontaneous abortion, premature labor, early preeclampsia/eclampsia, fetal growth restriction, and intrauterine death are somewhat higher in women with SLE,^{[80, 179]}especially in those with SSA(Ro)/SSB(La) antibodies, antiphospholipid antibodies,^[105]or lupus nephritis.^[177]One study suggested that women with SLE have fewer live births than the general population.^[180]In this study, decreased live births were associated with exposure to cyclophosphamide and high SLE disease activity.

SLE can also flare during or after pregnancy. Whether flares of SLE are more frequent during pregnancy is controversial. The flares do not seem to be exceedingly more serious than those in nonpregnant patients, although pregnancy outcomes are generally more likely to be complicated. Increased rates of hypertension during pregnancy, premature delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism are all more frequent in women with SLE.

To minimize complications in pregnancy, SLE ideally should be well controlled for at least 4-6 months before conception. Obstetricians who handle high-risk pregnancies should optimally offer pregnancy planning consultation and monitor all pregnancies in patients with SLE. Suggestions for treatment of SLE during pregnancy are also included in the European League Against Rheumatism (EULAR) recommendations. High-dose aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in later pregnancy.

The EULAR recommendations indicate that in pregnant women with SLE, prednisolone, azathioprine, hydroxychloroquine (unnecessary discontinuation of hydroxychloroquine (HCQ) during pregnancy may result in lupus flares), and low-dose aspirin may be used.^[80]Prednisone, prednisolone, and methylprednisolone are the corticosteroids of choice during pregnancy because of their minimal placental transfer. However, mycophenolate mofetil, cyclophosphamide, and methotrexate are strictly contraindicated.^[80]

The American College of Rheumatology (ACR) strongly suggests counseling women with SLE who are considering pregnancy regarding the improved maternal and fetal outcomes associated with entering pregnancy with quiescent/low activity disease.^[129]Testing recommendations include the following:

Test for anti‐Ro/SSA and anti‐La/SSB once before or early in pregnancy, as determining the status of these autoantibodies improves counseling regarding pregnancy and fetal risk (strong recommendation)
In women with SLE who are considering pregnancy or are pregnant, test for LAC, aCL, and anti‐β ₂GPI antibodies once before or early in pregnancy; do not repeat these tests during pregnancy (strong recommendation)
During pregnancy, monitor SLE disease activity with clinical history, examination, and laboratory tests at least once per trimester (strong suggestion)

The ACR guideline recommends that all women with SLE take HCQ during pregnancy, if possible. If a patient is already taking HCQ, continuing it during pregnancy is strongly recommended; if she is not taking HCQ, starting it if there is no contraindication is conditionally recommended. The ACR also conditionally recommends treating SLE patients with low‐dose aspirin (81 or 100 mg daily), beginning in the first trimester.

Neonatal lupus erythematosus (NLE) can develop in the babies of mothers with antibodies to SSA/Ro. Neonates with NLE can present with rash around 4-6 weeks of life, elevated liver function test results, thrombocytopenia around 1-2 weeks of life, neutropenia, and hydrocephalus.^[181]NLE can also manifest as a congenital atrioventricular conduction block,^[182]with as many as 1-5% of pregnancies in mothers with anti- SSA/SSB antibodies leading to heart block, rising to a 6-25% risk for subsequent pregnancies after one affected child is born.^[183]

In pregnant women with anti‐Ro/SSA and/or anti‐La/SSB antibodies, the ACR conditionally recommends serial fetal echocardiography, starting between 16 and 18 weeks and continuing through week 26. For women with a history of an infant with complete heart block (CHB) or NLE, the ACR conditionally recommends performing fetal echocardiography weekly; screening can be less frequent than weekly in women without such a history, but a recommended interval has not been determined.

The ACR conditionally recommends treating all women who are positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies with HCQ during pregnancy, to reduce the risk of fetal CHB. For pregnant women with anti‐Ro/SSA and/or anti‐La/SSB antibodies and fetal first‐ or second‐degree heart block shown on echocardiography, the ACR conditionally recommends treatment with oral dexamethasone 4 mg daily. If CHB (without other cardiac inflammation) is present, the ACR conditionally recommends against treating with dexamethasone.^[129]

For additional information, see Systemic Lupus Erythematosus and Pregnancy and Neonatal and Pediatric Lupus Erythematosus.

Prevention

Patients with SLE should be educated to avoid triggers for flare. Persons with SLE should avoid ultraviolet light and sun exposure to minimize worsening of symptoms from photosensitivity. Diet modification should be based on the disease activity. A balanced diet is important, but patients with SLE and hyperlipidemia, for example, should be placed on a low-fat diet. Many patients with SLE have low levels of vitamin D because of less sun exposure; therefore, these patients should take vitamin D supplements. Exercise is important in SLE patients to avoid rapid muscle loss, bone demineralization, and fatigue. Smoking should also be avoided.

Antimalarial therapy (hydroxychloroquine) has been shown to prevent disease flares and to decrease mortality.^[122]In contrast, high rates of sulfa allergy and anecdotal reports of disease flares have led to avoidance of sulfa-based medications in patients with SLE.

Contraception and family planning are important considerations given the risks of disease flare with exogenous estrogens and pregnancy and with the teratogenic risks of some SLE drugs. Estrogen therapies have typically been avoided to prevent disease flares; progesterone-only contraception is more often considered.^[184]However, studies have suggested that oral estrogen-containing contraceptives may not be associated with disease flares or thrombosis risk in patients with mild lupus without antiphospholipid antibodies.^{[63, 185]}

Preventive measures are necessary to minimize the risks of steroid-induced osteoporosis and accelerated atherosclerotic disease.^[186]The American College of Rheumatology (ACR) guidelines for the prevention of glucocorticoid-induced osteoporosis suggest the use of traditional measures (eg, calcium, vitamin D) and the consideration of prophylactic bisphosphonate therapy.

The ACR Quality of Care statement^[187]recommends annual cardiovascular disease risk assessment; some researchers suggest that the cardiovascular risk for SLE is similar to that for diabetes mellitus. The 10-year coronary event rate is 13-15% in patients with active SLE, which is comparable to the 10-year event rate of 18.8% in patients with known coronary artery disease.^[188]African-American patients with SLE may be particularly vulnerable to premature cardiovascular disease and related death.^[189]

Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers may be useful in patients with kidney disease. Aggressive blood pressure and lipid goals may help prevent CAD or kidney disease progression.^[188]

The European League Against Rheumatism (EULAR) vaccination recommendations for rheumatic diseases, including lupus, advocate baseline assessment and delivery of nonlive vaccines during stable disease.^[190]Particularly important is immunization against encapsulated organisms, such as meningococcal vaccine, pneumococcal vaccine, and routine Haemophilus influenzae childhood vaccination. Annual influenza vaccine is also encouraged.

Vitamin D

Studies from around the world have documented a higher prevalence of vitamin D insufficiency and deficiency in patients with SLE, compared with the general population, especially in conjunction with obesity.^{[130, 191, 192, 193, 194, 132]}Studies from Australia,^[191]France,^[194]the Mediterranean region,^[131]and Taiwan^[193]—but not from Mexico^[192]—have shown an association between serum vitamin D levels and SLE disease activity.

Limited evidence suggests that supplementation may be clinically beneficial in SLE patients with low levels of vitamin D. In Mediterranean patients, female patients who were not receiving supplemental vitamin D showed more fatigue and received more oral corticosteroids than those with normal levels of vitamin D.^[131]In Australian patients, an increase in serum vitamin D levels was associated with reduced disease activity over time.^[191]

A randomized, double-blind, placebo-controlled trial in 40 patients with juvenile-onset SLE suggests that cholecalciferol supplementation for 24 weeks is effective in decreasing disease activity and improving fatigue in these patients. Compared with the placebo group, patients receiving oral cholecalciferol 50,000 IU/week demonstrated significant improvement in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (P = 0.010) and European Consensus Lupus Activity Measurement (ECLAM) scores (P = 0.006), along with a reduction of fatigue related to social life, as measured by the Kids Fatigue Severity Scale (K-FSS) score (P = 0.008).^[132]

Endothelial dysfunction and increased risk of cardiovascular disease occur in SLE.^[133]In vitro and clinical studies have demonstrated a beneficial effect of vitamin D supplementation on endothelial function in SLE.^{[134, 135]}

Long-Term Monitoring

Periodic follow-up and laboratory testing, including complete blood counts with differential, creatinine, and urinalyses, are imperative for detecting signs and symptoms of new organ-system involvement and for monitoring response and adverse reactions to therapies. At least quarterly visits are recommended in most cases.^[195]Periodic complement levels and dsDNA titers may be used as adjuncts to clinical evaluation for detecting lupus flares.

Up to 83% of patients may be nonadherent to HCQ, the pivotal therapy for lupus.^[196]Similar nonadherence rates may exist for other therapies, such as methotrexate and mycophenolate. It is very important to discuss adherence to medications, including possible barriers to adherence, during clinic visits and to prepare an adherence plan for individual patients. Several tools, including self-report patient and physician-informed questionnaires and objective drug level monitoring, can be used to encourage HCQ and other medication use and maximize efficacy.^{[197, 198, 199]}

Complications

Opportunistic infections can develop, most often in patients receiving long-term immunosuppressive therapy. Another less-common complication is osteonecrosis, especially of the hips and knees after prolonged high-dose corticosteroid usage. More commonly, hyperglycemia and diabetes, premature atherosclerotic disease, and myocardial infarction are long-term complications of chronic inflammation and steroid therapy.

Medication

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Argolini LM, Frontini G, Elefante E, Saccon F, Binda V, Tani C, et al. Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 8 years follow up. J Nephrol. 2021 Apr. 34 (2):389-398. [QxMD MEDLINE Link].

Media Gallery

Systemic lupus erythematosus (SLE). The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds (nasolabial fold sparing is indicated by black arrows).
Dermatomyositis. Acute onset of confluent macular erythema in a periorbital and malar distribution (involving the cheeks and extending over the nasal bridge), with extension to the chin in a female with juvenile dermatomyositis. Note the perioral sparing. In some patients, there may be more extensive involvement of the face, including the perioral region, forehead, lateral face, and ears. In contrast to SLE , in dermatomyositis with malar erythema, the nasolabial folds are often not spared.
Discoid lupus erythematosus.
Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.
In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab) responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity. HLA = human leukocyte antigen; UV = ultraviolet light.
This axial, T2-weighted brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with long-standing systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. Distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to distribution.
Lupus band test. Microphotograph of a histologic section of human skin prepared for direct immunofluorescence using an anti-IgG antibody. The skin is from a patient with systemic lupus erythematosus and shows IgG deposit at 2 different places: the first is a band-like deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (anti-nuclear antibodies).
Microphotograph of a fixed Hep-2 line cell prepared for indirect immunofluorescence. The preparation was exposed to a serum of a patient with systemic lupus erythematosus and labeled using a murine anti-human immunoglobulin G (IgG) antibody. It shows IgG deposit in the nucleus and nonspecific deposit in the cytoplasm.
Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
The chest x-ray from a patient with lupus demonstrates a right-sided pleural effusion (yellow arrow) and atelectasis with scarring in the left lung base (blue arrow). In severe complications, a fibrothorax may develop.
Vasculitis, antiphospholipid antibodies, and renal failure are commonly found in patients with lupus; these conditions greatly increase the risk of developing pulmonary emboli. The diagnosis in a patient with shortness of breath, hemoptysis, and pleuritic chest pain is commonly made with ventilation-perfusion scans or computed tomography (CT) angiography. The CT angiogram demonstrates a filling defect in the left anterior segmental artery (arrow).
Libman-Sacks endocarditis is the most characteristic cardiac manifestation of lupus. It is characterized by clusters of verrucae on the ventricular surface of the mitral valve. These lesions consist of accumulation of immune complexes, platelets, and mononuclear cells. This can lead to heart failure, valvular dysfunction, emboli, and secondary infective endocarditis. Diagnosis is best made via echocardiography, which may reveal the characteristic valvular masses (arrows). IVS = interventricular septum; LA = left atrium; LV = left ventricle.
Histologic image of a normal renal cortex, including the glomerulus (1) and proximal (2) and distal (3) convoluted tubule. [Image from Wikipedia: http://en.wikipedia.org/wiki/File:Histology-kidney.jpg]
Discoid lupus erythematosus is a chronic scarring skin condition causing scaly plaques on the scalp, face, and ears.
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).

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Table 1. EULAR/ACR Clinical Domains and Criteria for SLE

Domain	Criteria	Points
Constitutional	Fever	2
Hematologic	Leukopenia Thrombocytopenia Autoimmune hemolysis	3 4 4
Neuropsychiatric	Delirium Psychosis Seizure	2 3 5
Mucocutaneous	Non-scarring alopecia Oral ulcers Subacute cutaneous or discoid lupus Acute cutaneous lupus	2 2 4 6
Serosal	Pleural or pericardial effusion Acute pericarditis	5 6
Musculoskeletal	Joint involvement	6
Renal	Proteinuria > 0.5 g/24 h Kidney biopsy class II or V lupus nephritis Kidney biopsy class III or IV lupus nephritis	4 8 10

Table 2. EULAR/ACR Immunologic Domains and Criteria for SLE

Domain	Criteria	Points
Antiphospholipid antibodies	Anti-cardiolipin antibodies or Anti-β2GP1 antibodies or Lupus anticoagulant	2
Complement proteins	Low C3 or low C4 Low C3 and low C4	3 4
SLE-specific antibodies	Anti-dsDNA antibody or Anti-Smith antibody	6

Table 3. Autoantibody Tests for SLE

Test	Description
ANA	Screening test; sensitivity 95%; not diagnostic without clinical features
Anti-dsDNA	High specificity; sensitivity only 70%; level is variable based on disease activity
Anti-Sm	Most specific antibody for SLE; only 30-40% sensitivity
Anti-SSA (Ro) or Anti-SSB (La)	Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren syndrome; associated with neonatal lupus
Anti-ribosomal P	Uncommon antibodies that may correlate with risk for CNS disease, including increased hazards of psychosis in a large inception cohort, although the exact role in clinical diagnosis is debated^[115]
Anti-RNP	Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective-tissue disease with overlap SLE, scleroderma, and myositis
Anticardiolipin	IgG/IgM variants measured with ELISA are among the antiphospholipid antibodies used to screen for antiphospholipid antibody syndrome and pertinent in SLE diagnosis
Lupus anticoagulant	Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the clotting cascade in antiphospholipid antibody syndrome
Direct Coombs test	Coombs test–positive anemia to denote antibodies on RBCs
Anti-histone	Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide or hydralazine; p-ANCA–positive in minocycline-induced drug-induced lupus)
ANA = antinuclear antibody; CNS = central nervous system; ds-DNA = double-stranded DNA; ELISA = enzyme-linked immunoassay; ENA = extractable nuclear antigen; Ig = immunoglobulin; p-ANCA = perinuclear antineutrophil cytoplasmic antibody; RBCs = red blood cells; RNP = ribonucleic protein; SLE = systemic lupus erythematosus; Sm = Smith; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B.

Table 4. International Society of Nephrology 2003 Revised Classification of SLE Nephritis

Class	Classification	Features
Class I	Minimal mesangial	Normal light microscopy findings; abnormal electron microscopy findings
Class II	Mesangial proliferative	Hypercellular on light microscopy
Class III	Focal proliferative	< 50% of glomeruli involved Class III lupus nephritis is further subclassified as follows: Class III (A), focal proliferative: Active lesions Class III (A/C), focal proliferative and sclerosing: Active and chronic lesions Class III (C ) (focal sclerosing): Chronic lesions
Class IV	Diffuse proliferative	=50% of glomeruli involved; classified segmental or global; treated aggressively Class IV lupus nephritis is also further subclassified, as follows: Class IV-S: Diffuse segmental proliferative Class IV-G: Diffuse global proliferative Class IV-S or IV-G, active (A) or chronic (C) Note: It remains to be determined whether further subcategories have a prognostic difference.^[120]There are conflicting data from studies; some investigators report that class IV-G (A) has a better prognosis relative to class IV-S (A/C), which is less responsive to treatment.
Class V	Membranous	Predominantly nephrotic disease Note: Class V may occur with class III or IV (then, both cases would be diagnosed)^[113]
Class VI	Advanced sclerosing	≥90% of glomeruli involved without residual activity^[113] Chronic lesions and sclerosis
Source (except as noted otherwise) : Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. Feb 2004;15(2):241-50.^[121] SLE = systemic lupus erythematosus.

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Author

Christie M Bartels, MD, MS Division Head, Associate Professor, Division of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health

Christie M Bartels, MD, MS is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Shivani Garg, MD, MS Assistant Professor (CHS), Division of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health; Director, Lupus Clinic, Co-Director, Lupus Nephritis Clinic, UW Health

Shivani Garg, MD, MS is a member of the following medical societies: American College of Rheumatology, American Medical Association, American Society of Nephrology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Daniel Muller, MD, PhD Associate Professor of Medicine, Department of Medicine, Section of Rheumatology, University of Wisconsin School of Medicine and Public Health

Daniel Muller, MD, PhD is a member of the following medical societies: American Holistic Medical Association, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology

Disclosure: Nothing to disclose.

Acknowledgements

Gino A Farina, MD, FACEP, FAAEM Associate Professor of Clinical Emergency Medicine, Albert Einstein College of Medicine; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center

Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Julie Hildebrand, MD Consulting Staff, Department of Internal Medicine, Associated Physicians of Madison, WI

Disclosure: Nothing to disclose.

Richard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Viraj S Lakdawala, MD Clinical Instructor of Emergency Medicine, University of California, San Francisco, School of Medicine; Attending Physician, San Francisco General Hospital

Viraj S Lakdawala, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Mark J Leber, MD, MPH Assistant Professor of Emergency Medicine in Clinical Medicine, Weill Cornell Medical College; Attending Physician, Lincoln Medical and Mental Health Center

Mark J Leber, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and American College of Physicians

Disclosure: Nothing to disclose.

Carlos J Lozada, MD Director of Rheumatology Fellowship Program, Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Pfizer Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Anuritha Tirumani, MD Research Coordinator, Department of Emergency Medicine, Brooklyn Hospital Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors would like to thank Joanna Wong for assistance in preparation of revisions to this topic.

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