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Broad Concepts in Management of Systemic Lupus Erythematosus

  • Vaidehi R. Chowdhary
    Correspondence
    Correspondence: Address to Vaidehi R. Chowdhary, MD, Division of Rheumatology, Department of Medicine, Mayo Clinic, 200 First SW, Rochester, MN 55905.
    Affiliations
    Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester MN
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      Abstract

      Systemic lupus erythematosus is a multisystem autoimmune disease with protean manifestation. Although commonly seen in young women, it can affect men as well as elderly patients. Approach to treatment is multidisciplinary, involves defining the extent of organ involvement, and distinguishing between active manifestations and damage. The mainstay of therapy is judicious use of immunosuppressive medications. Long-term follow-up to address morbidity arising from treatment complications, disease damage, and increased cardiovascular risk is essential.

      Abbreviations and Acronyms:

      ACR (American College of Rheumatology), COC (combined oral contraceptive), CQ (chloroquine), Cy (cyclophosphamide), HCQ (hydroxychloroquine), IV (intravenous), IVMP (intravenous methyl prednisone), LE (lupus erythematosus), LMWH (low-molecular-weight heparin), MMF (mycophenolate mofetil), NP (neuropsychiatric), NSAID (nonsteroidal anti-inflammatory drug), SC (subcutaneously), SLE (systemic lupus erythematosus)
      Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease capable of affecting any organ system. Systemic lupus erythematosus is rare, with an incidence of 2.2 to 5.6 cases per 100,000 person-years and a prevalence of 24 to 207 cases per 100,000 person-years, and it is more common in women.
      • Pons-Estel G.J.
      • Alarcón G.S.
      • Scofield L.
      • Reinlib L.
      • Cooper G.S.
      Understanding the epidemiology and progression of systemic lupus erythematosus.
      It presents earlier and in a more severe form in African Americans, Hispanics, Native Americans, and Asians. The diagnosis of SLE should be suspected in any patient with multiorgan symptoms, and after exclusion of infectious and other causes. The 1997 American College of Rheumatology (ACR) classification criteria can be helpful for diagnosis if 4 of 11 criteria are present; the sensitivity of these is 86% and specificity is 93%.
      • Petri M.
      • Orbai A.M.
      • Alarcón G.S.
      • et al.
      Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.
      The criticism of ACR criteria is that they place emphasis on mucocutaneous manifestations and do not take into account important neurologic manifestations or isolated lupus nephritis. Furthermore, disease manifestations may accrue over time, making it difficult to make a diagnosis early. To address some of these deficiencies, the Systemic Lupus International Collaborating Clinics classification criteria
      • Petri M.
      • Orbai A.M.
      • Alarcón G.S.
      • et al.
      Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.
      were proposed. A diagnosis of lupus can be made if patients meet 4 or more criteria, with at least 1 clinical and 1 laboratory criteria. Patients with biopsy-proven lupus nephritis with either positive antinuclear or anti-double stranded deoxyribonucleic acid (dsDNA) antibodies can now be classified as having lupus nephritis, which was not possible with the ACR criteria. The sensitivity of Systemic Lupus International Collaborating Clinics criteria is 94% and specificity 92%.

      Treat-to-Target Strategy for SLE

      A group of international experts proposed a “treat-to-target” strategy for lupus. Such a concept is already effective for the management of diabetes and hypertension, in which treatment is tailored to a goal level of glycosylated hemoglobin or target blood pressure, respectively. The international task force
      • van Vollenhoven R.F.
      • Mosca M.
      • Bertsias G.
      • et al.
      Treat-to-target in systemic lupus erythematosus: recommendations from an international task force.
      put forth 4 overarching principles and 11 recommendations for management on the basis of extensive literature review. Broad goals include achieving remission or low disease activity, preventing flares, minimizing the use of corticosteroids, not treating patients who are serologically active (high anti–double-stranded DNA and hypocomplementemia) but clinically quiescent and addressing factors affecting health-related quality of life such as depression and pain. Early recognition of lupus nephritis and maintaining immunosuppressive therapy for at least 3 years is recommended. Hydroxychloroquine (HCQ) therapy is recommended for all patients with lupus because of its substantial benefits as discussed below.
      There are, however, challenges in implementing such a strategy, including lack of a unified definition of remission and a paucity of effective immunosuppressive agents. Clinical heterogeneity of lupus makes a single disease activity assessment instrument difficult, and many available instruments are cumbersome to use in clinical practice. Nevertheless, the treat-to-target strategy is a promising concept. Many organizations
      • Bertsias G.
      • Ioannidis J.P.
      • Boletis J.
      • et al.
      Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics
      EULAR recommendations for the management of systemic lupus erythematosus: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics.
      • Bertsias G.K.
      • Tektonidou M.
      • Amoura Z.
      • et al.
      European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association
      Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.
      • Bertsias G.K.
      • Ioannidis J.P.
      • Aringer M.
      • et al.
      EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs.
      American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines
      Guidelines for referral and management of systemic lupus erythematosus in adults.
      • Hahn B.H.
      • McMahon M.A.
      • Wilkinson A.
      • et al.
      American College of Rheumatology
      American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.
      such as the ACR and European League against Rheumatism have published guidelines for the evaluation and management of patients with SLE and of lupus nephritis.

      Treatment Principles

      Key Points

      • Treatment decisions are often based on the type and severity of organ involvement.
      • There is a paucity of clinical trials and evidence-based recommendations for the treatment of many of the lupus manifestations as well as doses of corticosteroids used.
      • Distinction should be made between symptoms manifesting from active disease vs disease-related damage.
      • Management of comorbidities, attention to bone health, increased cardiovascular risk, and immunization status should be part of general medical care.
      • Active discussion about contraception and preconception planning should be undertaken with patients of childbearing potential.
      The treatment approach can be summarized as follows.

      General Medical Care

      Patients with SLE are at an increased risk of several comorbidities secondary to active disease, damage, or treatment-related complications. The risk of cerebrovascular accidents and ischemic heart disease is increased 2.3-fold in patients with SLE.
      • Singh A.G.
      • Crowson C.S.
      • Singh S.
      • et al.
      Risk of cerebrovascular accidents and ischemic heart disease in cutaneous lupus erythematosus: a population-based cohort study.
      We have reported a 2- to 3-fold increased risk of cerebrovascular accident and peripheral arterial disease in patients with cutaneous lupus as well.
      • Singh A.G.
      • Crowson C.S.
      • Singh S.
      • et al.
      Risk of cerebrovascular accidents and ischemic heart disease in cutaneous lupus erythematosus: a population-based cohort study.
      There is an increased risk of infections, osteoporosis, and malignant tumors, especially non–Hodgkin lymphoma, lung, liver, vulvar/vaginal, and thyroid malignancies. Attention should be paid to immunization status, diet, physical activity, and management of fibromyalgia and fatigue. It is critical to take a look at the medication list to identify drugs that can either induce lupus or aggravate lupus skin rashes. The drugs we have commonly noted in our medical practice inducing systemic lupus are minocycline, nitrofurantoin, hydralazine, interferons, and tumor necrosis factor inhibitors. (For a comprehensive review of drug-induced systemic and cutaneous lupus, please refer to Chang and Gershwin.
      • Chang C.
      • Gershwin M.E.
      Drug-induced lupus erythematosus: incidence, management and prevention.
      )
      Table 1 summarizes general medical issues relevant to primary care in these patients.
      Table 1General Medical Care: What the Primary Care Physician Needs to Know
      Medical issuesComments
      1. Infection prevention
       A. Review immunization per CDC guidelines

      a. Annual influenza vaccination and TDap every 10 y

      b. Pneumococcal vaccination

      c. HPV vaccination (young patients aged <26 y)
      Anecdotal reports of SLE flares in patients receiving immunization; however, multiple studies have shown vaccines to be safe and should not be withheld
      • Salemi S.
      • D'Amelio R.
      Are anti-infectious vaccinations safe and effective in patients with autoimmunity?.
       B. Screen for hepatitis B, hepatitis C, and HIV before immunosuppression
       C. Consider PJP prophylaxisLow incidence of 1% of PJP in patients with SLE

      Number needed to treat is 112 and number needed to harm is 32 owing to adverse reactions to TMP-SMX
      • Green H.
      • Paul M.
      • Vidal L.
      • Leibovici L.
      Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials.


      Recommended for those taking ≥16 mg prednisone or equivalent for ≥8 wk, especially those receiving cyclophosphamide
       D. Antibiotic usageSome antibiotics have sun-sensitizing property and potential to flare cutaneous rashes and occasionally systemic disease (tetracyclines, sulfonamides, and fluoroquinolones)

      Cutaneous reactions to sulfa antibiotics is higher; use sparingly and with caution, but use not contraindicated
      • Pope J.
      • Jerome D.
      • Fenlon D.
      • Krizova A.
      • Ouimet J.
      Frequency of adverse drug reactions in patients with systemic lupus erythematosus.
      2A. Toxicity of immunosuppressive medicationFamiliarity with common toxicities and frequency of laboratory monitoring of rheumatic medications reviewed in reference
      • Schmajuk G.
      • Yazdany J.
      Drug monitoring in systemic lupus erythematosus: a systematic review.
      2B. Screening for antimalarial eye toxicityAmerican Academy of Ophthalmology recommendations, revised in 2016 and summarized in reference
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology
      Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      3. Bone health: Assess for fracture risk using clinical data, steroid dose, and calculation of FRAX scoreCalcium (1200-1500 mg/d) and vitamin D supplements to achieve therapeutic levels (generally 800-1000 units/d)

      ACR guidelines for prevention and treatment of glucocorticoid-induced osteoporosis.
      • Grossman J.M.
      • Gordon R.
      • Ranganath V.K.
      • et al.
      American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.
      Treatment should be individualized. Generally if ≥7.5 mg of prednisone is used, treatment with bisphosphonates or teriparatide for high-risk individual is recommended
      4. Cancer screeningIncreased risk of malignant tumors with SLE especially of non–Hodgkin lymphoma, lung, liver, vulvar/vaginal, and thyroid

      Bladder cancer (especially in smokers) and secondary malignancy with cyclophosphamide use
      5. Cardiovascular risk assessment and counseling: Increased risk of cardiovascular diseaseRisk increased because of the high prevalence of conventional risk factors such as hypertension, sedentary lifestyle, dyslipidemia, as well as those related to disease activity

      Counseling to address traditional risk factors is recommended

      Routine statin therapy to prevent atherosclerosis in low-risk patients is not recommended at this time
      ACR = American College of Rheumatology; CDC = Center for Disease Control; FRAX = Fracture Risk Assessment Tool; HIV = human immunodeficiency virus; HPV = human papillomavirus; PJP = Pneumocystis jiroveci pneumonia; SLE = systemic lupus erythematosus; TDap = tetanus, diphtheria, pertussis; TMP-SMX = trimethoprim/sulfamethoxazole.

      Contraception

      Many patients with lupus are young women taking teratogenic medications, and avoidance of pregnancy during active disease is desirable. The main concerns with hormonal methods of contraception are disease flares and risk of thromboembolism. Two large trials
      • Buyon J.P.
      • Petri M.A.
      • Kim M.Y.
      • et al.
      The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial.
      • Sánchez-Guerrero J.
      • Uribe A.G.
      • Jiménez-Santana L.
      • et al.
      A trial of contraceptive methods in women with systemic lupus erythematosus.
      have compared various methods of hormonal contraception in patients with SLE. Petri and coworkers conducted a double-blind, randomized, noninferiority trial comparing a triphasic combined oral contraceptive (COC) with a placebo in 183 women. The risk of total flares was not different between the groups. The trial by Sánchez-Guerrero et al compared a COC with a progestin-only pill and copper-containing intrauterine device. The disease activity remained stable and was comparable among the 3 groups. Thrombotic events were seen in 4 patients, 2 in each hormonal group; all patients had low-titer antiphospholipid antibodies. Severe infections were seen in 3 patients in the COC group, 2 in the group receiving the progestin-only pill, and 5 (including 2 cases of meningitis) in the intrauterine device group. Both trials excluded patients with severe disease, smokers, history of thrombosis, history of gynecologic cancers, myocardial infarction, and liver disease. Patients with positive antiphospholipid antibodies and lupus anticoagulant were excluded in the trial by Petri and coworkers but not by Sánchez-Guerrero et al. Barrier methods of contraception, hormonal intrauterine device, injectable progestin are other options.

      Supportive Therapy

      Patients with lupus are photosensitive, and UV light is associated with flares. It is important for all patients to practice sun protection methods and avoid peak UV-B hours from 10 am to 4 pm. Sunscreens blocking both UV-A and UV-B with a sun protection factor of 50 or more should be applied liberally and at least 20 minutes before sun exposure. Wide-brimmed hats and tightly woven clothing should be worn. Specialized sun protection clothing is made by several companies dealing in outdoor gear, and a UV protection factor ranging from 40 to greater than 50 is associated with excellent protection. With such diligent sun avoidance and protection, patients should be given vitamin D supplements. Low levels of vitamin D have been associated with higher lupus activity. Aerobic exercises along with strength training are helpful in the management of fatigue, and fibromyalgia.

      Immunosuppressive Therapy

      Table 2 lists common drugs used in the treatment of lupus.
      Table 2Drugs Commonly Used in the Management of Lupus
      G6PD = glucose-6-phosphate dehydrogenase; IgA = immunoglobulin A; ITP = immune thrombocytopenia; IV = intravenous; LN = lupus nephritis; MMF = mycophenolate mofetil; MPA = mycophenolic acid; PML = progressive multifocal leukoencephalopathy; REMS = risk evaluation and mitigation strategy; WBC = white blood cell.
      MedicationDosePregnancy categoryAdverse effectsComments
      Glucocorticoids
       1. PrednisoneMild disease: 0.25-0.50 mg/kg per day

      Severe disease: 0.5-1 mg/kg per day
      CWeight gain, edema, hypertension, dyslipidemia, cataract, hyperglycemia, infections, skin fragility, mood changes, osteoporosis, delayed healing, steroid myopathy, and osteonecrosisLife- or organ-threatening lupus, use IVMP
       2. MethylprednisoloneIV, 500-1000 mg for 3 days
      Antimalarial agents
       1. Hydroxychloroquine400 mg/d (or <5 mg/kg of real body weight)Nausea, diarrhea, skin rashes, eye toxicity, neuromyotoxicity, potential for hemolysis in G6PD-positive individuals, cardiomyopathy, heart block, and skin pigmentation
       2. Chloroquine250 mg (<2.3 mg/kg)C
      Hydroxychloroquine can be safely used in pregnancy with no reports of fetal.
      MethotrexateOral or subcutaneous 15-25 mg once a weekXGastrointestinal adverse effects, hepatotoxicity, hematologic toxicity, infections, lung infiltrates, and malignancyAvoid use in renal insufficiency, use folic acid 1 mg/d to reduce toxicity, and discontinue 3-6 mo before pregnancy
      Leflunomide20 mg/d, maintenance 10 mg/dXDiarrhea, infection, hematologic toxicity, hepatotoxicity, and rare risk of cutaneous lupus exacerbationAvoid pregnancy until plasma levels are <0.02 mg/L and administer cholestyramine to hasten removal from the body
      Mycophenolate mofetil (MMF)

      mycophenolic acid
      Oral 2000-3000 mg/d

      720 mg MPA = 1000 mg MMF
      X

      REMS program for prescribers
      Diarrhea, infection, neutropenia, infection, and lymphoproliferative disorderTherapeutic drug level monitoring recommended

      Discontinue drug at least 6 wk before pregnancy is contemplated
      AzathioprineOral 1-2.5 mg/kg per dayDNausea, abdominal pain, diarrhea, myelotoxicity, elevated levels of liver enzymes, and malignancyConsider thiopurine S-methyltransferase testing before therapy. Generally safe to use in pregnancy
      Cyclophosphamide500-1000 mg/m2 IV monthly for 6 mo as induction therapy for LN. 500 mg IV every 2 wk × 3 mo as the Euro-Lupus regimenXNausea, vomiting, cytopenias, infections, hemorrhagic cystitis, gonadal failure malignancy, and bladder cancerIV dose titrated to achieve a nadir WBC count between 2000 and 4000 cells/m2 between days 10 and 14. IV Mesna administered to prevent hemorrhagic cystitis. Consider leuprolide therapy for ovarian protection
      Rituximab1000 mg IV for 2 doses separated by 2 wk or 375 mg/m2 weekly × 4 wkCInfusion reaction, anemia, neutropenia, hepatitis B reactivation, and PMLHepatitis B and tuberculosis screening before infusion and complete immunization before administration
      Belimumab10 mg/kg IV every 2 wk × 3 doses and then every 4 wkCInfusion reaction, fever, depression, infection, nausea, and diarrheaUsed for the treatment of arthritis, cutaneous lupus, and hematologic disease. Trials ongoing for LN
      Intravenous immunoglobulin400 mg/kg per day × 5 dCRenal dysfunction, thrombosis, aseptic meningitis, and transfusion-associated acute lung injury. Adequate hydration before infusionUse in patients with concomitant infection, pregnancy, neurologic manifestation, and ITP. Contraindicated in patients with IgA deficiency (use IgA poor preparations).
      a G6PD = glucose-6-phosphate dehydrogenase; IgA = immunoglobulin A; ITP = immune thrombocytopenia; IV = intravenous; LN = lupus nephritis; MMF = mycophenolate mofetil; MPA = mycophenolic acid; PML = progressive multifocal leukoencephalopathy; REMS = risk evaluation and mitigation strategy; WBC = white blood cell.
      b Hydroxychloroquine can be safely used in pregnancy with no reports of fetal.

      Treatment of Mild Disease

      Manifestations such as inflammatory arthritis, serositis, and cutaneous rashes are treated with antimalarial agents, judicious use of nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids (empirical doses used at 0.25-0.5 mg/kg). Mild cutaneous rashes can be treated with topical steroids as discussed below. Persistent disease usually requires addition of agents such as leflunomide, methotrexate, and mycophenolate mofetil (MMF).

      Treatment of Severe Life- or Organ-Threatening Manifestations

      Myocarditis, lupus nephritis, severe thrombocytopenia or hemolytic anemia, mesenteric vasculitis, myositis, and central nervous system lupus are a few examples of this. The treatment approach is usually multidisciplinary and involves a team of subspecialists such as nephrologists, hematologists, and neurologists. Although high-dose corticosteroids form the mainstay of management, there are no clinical trials regarding the effective dose. Prednisone (40-60 mg or 1 mg/kg per day) and parenteral steroids such as intravenous (IV) methylprednisolone, with most regimens using 1 g for 3 days, are used. Steroids are associated with considerable adverse effects, and regimens to minimize their use are being evaluated. Ezeonyeji and Isenberg
      • Ezeonyeji A.N.
      • Isenberg D.A.
      Early treatment with rituximab in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen.
      found the efficacy of combination of cyclophosphamide (Cy) and rituximab in patients with newly diagnosed SLE for considerable reduction in steroid dose. Steroid-free regimen of rituximab followed by MMF was also found to be effective in an open-label trial in patients with lupus nephritis.
      • Condon M.B.
      • Ashby D.
      • Pepper R.J.
      • et al.
      Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids.
      The impressive results have led to this regimen being tested in the RITUXILUP Trial (clinicaltrials.gov identifier: NCT01773616).
      The choice of a second-line immunosuppressive agent depends on the clinical manifestation and is noted in Table 2. Refractory disease is often treated with Cy or rituximab therapy. Intravenous immunoglobulin is helpful for the management of immune thrombocytopenia, lupus-associated Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and congenital heart block. Benefit has also been observed in small reports for autoimmune hemolytic anemia, pregnancy, lupus nephritis, refractory disease, and severe cutaneous rashes.
      • Mulhearn B.
      • Bruce I.N.
      Indications for IVIG in rheumatic diseases.
      Therapeutic plasma exchange or plasmapheresis has been used in the treatment of neuropsychiatric (NP) manifestations such as myelitis, thrombotic thrombocytopenic purpura, and cytopenias.
      • Kronbichler A.
      • Brezina B.
      • Quintana L.F.
      • Jayne D.R.
      Efficacy of plasma exchange and immunoadsorption in systemic lupus erythematosus and antiphospholipid syndrome: a systematic review.

      Antimalarial Therapy

      The beneficial effects of antimalarial agents, namely, HCQ and chloroquine (CQ), in lupus extend beyond their immunomodulatory property, and unless contraindicated, all patients should be receiving antimalarial therapy. Antimalarial agents prevent lupus flares, organ damage, and thrombosis and increase long-term survival. There are beneficial metabolic effects on lipid levels, prevention of diabetes, and improved bone mass.
      • Ruiz-Irastorza G.
      • Ramos-Casals M.
      • Brito-Zeron P.
      • Khamashta M.A.
      Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.
      Hydroxychloroquine use during pregnancy is associated with a lower risk of flare. The risk of eye toxicity with HCQ is 1% at 5 years but increases to 20% at 20 years. Risk factors include dosage (HCQ dose, >5 mg/kg of real body weight; CQ dose, >2.3 mg/kg), longer duration of use, tamoxifen, retinal disease, older age, and renal and liver disease. The American Academy of Ophthalmology has recently published revised guidelines for screening for eye toxicity.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology
      Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      Baseline screening should include a fundus examination, visual fields, and spectral-domain optical coherence tomography. Annual screening is performed in those at high risk but can be deferred to 5 years in low-risk patients. Screening tests should include automated visual fields and also objective tests such as multifocal electroretinogram and fundus autofluorescence. Color testing, Amsler grid testing, and so on, are not recommended for screening.

      Management of Specific Organ Systems

      We discuss below the treatment approach to manifestation that general internists will commonly encounter. Detailed treatment of all manifestations of lupus is beyond the scope of this review.

      Musculoskeletal Manifestations

      Musculoskeletal manifestations of lupus include inflammatory arthritis, inflammatory myopathy, and soft tissue rheumatism. Secondary fibromyalgia can be seen in 22% to 25% of patients and can be a source of significant disability.
      • Morand E.F.
      • Miller M.H.
      • Whittingham S.
      • Littlejohn G.O.
      Fibromyalgia syndrome and disease activity in systemic lupus erythematosus.
      Inflammatory arthritis is symmetric and commonly starts with the involvement of the small joints of hands. Unlike rheumatoid arthritis, many of these deformities are reducible and not associated with bony destruction or erosions. Rheumatoid factor can be positive in 20% of patients with SLE. Rarely, destructive arthritis or overlap with rheumatoid arthritis can be seen and is termed rhupus. Many of these patients have positive anti-cyclic citrullinated peptide antibodies.
      • Amezcua-Guerra L.M.
      • Springall R.
      • Marquez-Velasco R.
      • Gómez-Garcia L.
      • Vargas A.
      • Bojalil R.
      Presence of antibodies against cyclic citrullinated peptides in patients with “rhupus”: a cross-sectional study.
      Jaccoud arthropathy, classically described in rheumatic fever, can also be seen in SLE. It refers to deformities of the hands such as swan-neck and “boutonniere” resulting from laxity of ligaments or capsular fibrosis. Inflammatory arthritis is treated with judicious use of NSAIDs or prednisone (dose, 0.25-0.5 mg/kg) and HCQ. Inability to taper prednisone or persistent disease requires the addition of second-line immunosuppressive therapy such as methotrexate and MMF.
      • Ginzler E.M.
      • Wofsy D.
      • Isenberg D.
      • Gordon C.
      • Lisk L.
      • Dooley M.A.
      ALMS Group
      Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective, randomized, open-label, parallel-group clinical trial.
      • Artifoni M.
      • Puéchal X.
      How to treat refractory arthritis in lupus?.
      Azathioprine, leflunomide, and cyclosporine are effective as well. The new biological agent belimumab was tested in 2 double-blind randomized controlled trials, namely, BLISS-52 (a study of Belimumab in Subjects with Systemic Lupus Erythematosus) and BLISS-76.
      • Furie R.
      • Petri M.
      • Zamani O.
      • et al.
      BLISS-76 Study Group
      A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.
      • Navarra S.V.
      • Guzmán R.M.
      • Gallacher A.E.
      • et al.
      BLISS-52 Study Group
      Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.
      Pooled data from both trials suggested that belimumab (in doses of 1 mg/kg or 10 mg/kg) considerably improved musculoskeletal signs in comparison to placebo.
      • Manzi S.
      • Sánchez-Guerrero J.
      • Merrill J.T.
      • et al.
      BLISS-52 and BLISS-76 Study Groups
      Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials.
      Although the Exploratory Phase II/III SLE Evaluation of Rituximab trial did not meet its primary end point, registry data from the French AutoImmunity and Rituximab registry
      • Terrier B.
      • Amoura Z.
      • Ravaud P.
      • et al.
      Club Rhumatismes et Inflammation
      Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.
      revealed that 26 of 50 patients (52%) displayed a complete response and 10 (20%) displayed a partial response in terms of the severity of joint symptoms to treatment with rituximab combined with steroids. In a phase II, double-blind, randomized controlled trial,
      • Merrill J.T.
      • Burgos-Vargas R.
      • Westhovens R.
      • et al.
      The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial.
      patients treated with abatacept (10 mg/kg IV) had lower flare rates than did the placebo-treated group. We use abatacept only in patients with refractory disease or those who have failed conventional treatment.

      Cutaneous Lupus

      The Gilliam classification
      • Gilliam J.N.
      • Sontheimer R.D.
      Distinctive cutaneous subsets in the spectrum of lupus erythematosus.
      divides skin lesions in lupus as lupus erythematosus (LE) specific (seen only in lupus) or LE nonspecific (can be seen in other diseases, eg, urticaria). Lupus erythematosus–specific lesions include acute LE with localized (malar) erythema or generalized erythema, subacute cutaneous lupus with papulosquamous or annular and chronic cutaneous lupus such as discoid lesions.
      • Gilliam J.N.
      • Sontheimer R.D.
      Distinctive cutaneous subsets in the spectrum of lupus erythematosus.
      Medications with a potential to flare lupus rashes such as diuretics (hydrochlorothiazide, chlorthiazide, and spironolactone), antihypertensive drugs (diltiazem, verapamil, and nifedipine), NSAIDs (naproxen and piroxicam), antifungal agents (terbinafine, etc), and antirheumatic drugs such as tumor necrosis factor inhibitors should be reviewed.

      Topical Therapy

      Topical steroids are useful for mild cutaneous rashes. High-potency corticosteroid fluocinonide 0.05% is more effective than hydrocortisone 1%.
      • Roenigk Jr., H.H.
      • Martin J.S.
      • Eichorn P.
      • Gilliam J.N.
      Discoid lupus erythematosus. Diagnostic features and evaluation of topical corticosteroid therapy.
      Treatment with steroids should be time-limited and intermittent. Discoid lesions can be treated with intralesional steroids. Topical tacrolimus 0.1% and pimecrolimus 1%, calcineurin inhibitors, result in improvement of lesions of lupus erythematosus tumidus, subacute cutaneous lupus, and acute cutaneous lupus.
      • Barikbin B.
      • Givrad S.
      • Yousefi M.
      • Eskandari F.
      Pimecrolimus 1% cream versus betamethasone 17-valerate 0.1% cream in the treatment of facial discoid lupus erythematosus: a double-blind, randomized pilot study.
      • Tzung T.Y.
      • Liu Y.S.
      • Chang H.W.
      Tacrolimus vs. clobetasol propionate in the treatment of facial cutaneous lupus erythematosus: a randomized, double-blind, bilateral comparison study.
      Tazarotene and tretinoin (Retin A 0.025% and Retin A 0.05% creams) and imiquimod 5% are useful in resistant lesions.

      Systemic Therapy

      Antimalarial agents are the first-line therapy for all types of cutaneous lupus erythematosus. A clinical effect may be seen as early 2 weeks; if there is no change in 12 weeks, therapy should be escalated. Combination therapy of 2 antimalarial agents (HCQ + CQ) or quinacrine can be tried first. Smokers tend to have more resistant cutaneous lesions, and nicotine may interfere with metabolism of HCQ.
      • Jewell M.L.
      • McCauliffe D.P.
      Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment.
      Smoking cessation should be actively encouraged. Patients with resistant skin lesions require additional immunosuppressive therapy with weekly methotrexate (dose, 10-25 mg), azathioprine (1-2.5 mg/kg per day), or MMF (2-3 g/d).
      • Kuhn A.
      • Ruland V.
      • Bonsmann G.
      Cutaneous lupus erythematosus: update of therapeutic options part II.
      Dapsone therapy (25-150 mg) is useful for patients with urticarial vasculitis, oral ulcerations, and bullous rash of SLE. Dapsone therapy can result in hemolysis and methemoglobinemia, and a glucose-6-phosphate dehydrogenase level should be checked before therapy.
      For refractory disease, lenalidomide and thalidomide have been used because of their immunomodulatory and anti-inflammatory characteristics.
      • Cortés-Hernández J.
      • Ávila G.
      • Vilardell-Tarrés M.
      • Ordi-Ros J.
      Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus.
      In patients with discoid lupus and other types of cutaneous lupus, a complete or marked response was noted in 80% to 90%; however, the lesions relapse after cessation of therapy. Both thalidomide and lenalidomide have thrombotic risk, and this may be an issue in patients with high-titer antiphospholipid antibodies. Acitretin may be helpful in hypertrophic forms of discoid lupus erythematosus. Intravenous immunoglobulin or cyclosporine may be beneficial. In severe cases, biological therapy with belimumab or rituximab is advised. We have occasionally used Cy in patients with disseminated active skin rashes that are often coupled with disease activity elsewhere.

      Cardiopulmonary Manifestations

      Pericarditis and pleurisy are the most frequent cardiopulmonary manifestations in patients with SLE. Clinical presentation is similar to other causes of serositis. Effusions may occur and are exudative with lymphocytic or neutrophilic predominance. A negative pleural fluid ANA test has a high negative predictive value, and secondary causes such as malignancy or infections (such as TB) need to be excluded.
      • Toworakul C.
      • Kasitanon N.
      • Sukitawut W.
      • Wichinun R.
      • Louthrenoo W.
      Usefulness of pleural effusion antinuclear antibodies in the diagnosis of lupus pleuritis.
      It is important to think of and exclude pulmonary embolism in patients with chest pain, especially those with positive antiphospholipid antibodies.
      Serositic manifestations usually respond to antimalarial agents; NSAIDs or prednisone 5 to 15 mg can be used for symptomatic relief. Inability to fully control disease or taper steroids requires addition of second-line agents such as azathioprine, methotrexate, or MMF. Serious manifestations that require aggressive immunosuppressive treatment include myocarditis, lupus pneumonitis, diffuse alveolar hemorrhage, and pulmonary hypertension.

      Lupus Nephritis

      Forty-five percent of patients will have some degree of renal involvement over their lifetime, and renal involvement is 3 times more common in men, African Americans, Hispanics, and nonwhites.
      • Hahn B.H.
      • McMahon M.A.
      • Wilkinson A.
      • et al.
      American College of Rheumatology
      American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.
      The presence of nephritis is associated with a 2.38-fold increased risk of overall mortality and a 2.37 increased risk of SLE-related mortality.
      • Ward M.M.
      • Pyun E.
      • Studenski S.
      Mortality risks associated with specific clinical manifestations of systemic lupus erythematosus.
      Treatment decisions are guided by clinical presentation, laboratory abnormalities, and histologic subtype on kidney biopsy. The International Society of Nephrology and the Renal Pathology Society classification
      • Weening J.J.
      • D'Agati V.D.
      • Schwartz M.M.
      • et al.
      International Society of Nephrology Working Group on the Classification of Lupus Nephritis; Renal Pathology Society Working Group on the Classification of Lupus Nephritis
      The classification of glomerulonephritis in systemic lupus erythematosus revisited.
      divide lupus nephritis into 6 histologic subtypes.
      Therapy for diffuse proliferative glomerulonephritis is usually divided into a period of intense immunosuppression to achieve a clinically meaningful and sustained response and is termed induction therapy. Duration usually lasts 3 months but can be extended to 6 months in persistent disease. Induction is followed by a period of less-intensive maintenance immunosuppression for a period of 2 to 3 years, with the aim of keeping the patient free of disease activity.

      Induction Regimen

      The drugs commonly used for initial induction therapy are Cy and MMF. Other agents used for treatment include calcineurin inhibitors, azathioprine, and most recently rituximab. The induction regimen also includes oral prednisone (starting at 1 mg/kg and tapered by 5 mg every 2 weeks) and/or IV methylprednisolone (IVMP; 1 g ×3 days) followed by oral prednisone therapy. Table 3 summarizes the various induction regimens.
      Table 3Treatment of LN
      ALMS = Aspreva Lupus Management Study; AZA = azathioprine; BSA = body surface area; CR = complete remission; CsA = cyclosporine A; Cy = cyclophosphamide; ESRD = end-stage renal disease; IV = intravenous; IVCy = intravenous cyclophosphamide; LN = lupus nephritis; MAINTAIN = Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis; MMF = mycophenolate mofetil; NIH = National Institutes of Health; PR = partial remission; SCr = serum creatinine; TAC = tacrolimus.
      TreatmentRegimenComment
      Induction therapy for class III
      Class III = subendothelial immune deposits and proliferative changes in <50% of glomeruli.
      and IV
      Class IV = subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli.
      LN
       1. IVCy

      A. High-dose NIH regimen
      0.5-1 g/m2 monthly × 6 doses and then quarterly × 2 y plus

      IV methylprednisolone (1 g/m2 BSA) × 3 d followed by 12 consecutive monthly infusions
      • Gourley M.F.
      • Austin III, H.A.
      • Scott D.
      • et al.
      Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial.
      Combination therapy achieved remission in 85%

      In follow-up (11 y), Cy therapy superior to methylprednisolone alone in preventing treatment failures and decreasing risk of SCr doubling

      Cy group: infections (32%-45%), herpes zoster (21%-25%), amenorrhea (55%-57%), and avascular necrosis 18%-33%
       2. Low-dose Euro-Lupus Cy regimen500 mg IV every 2 weeks × 6 doses
      • Houssiau F.A.
      • Vasconcelos C.
      • D'Cruz D.
      • et al.
      Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
      Renal remission in 71% vs 54% in those on conventional Cy regimen

      Amenorrhea (2%), zoster (2%), avascular necrosis (0%), and severe infections (11%)

      Long-term follow-up, death, doubling of SCr, and ESRD were similar
      • Houssiau F.A.
      • Vasconcelos C.
      • D'Cruz D.
      • et al.
      The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.
       3. MMFIVCy monthly pulses (0.5-1 g/m2 monthly) vs oral MMF 3 g
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Aspreva Lupus Management Study Group
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      Response rates with MMF (56.2%) was similar to those in the IVCy group (53%)

      No differences with respect to improvement in renal function, nonrenal parameters, rates of adverse events, infection, or mortality
      • Houssiau F.A.
      • Vasconcelos C.
      • D'Cruz D.
      • et al.
      The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.
       4. TACMaintenance therapy: 150 Chinese patients, TAC (0.06-0.1 mg/kg per day) or MMF (2-3 g/d) in combination with prednisone for 6 mo followed by AZA × 5 y
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Aspreva Lupus Management Study Group
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.


      Combination therapy: TAC (4 mg/d) + MMF (1 g/d) vs IVCy 0.75 (adjusted to 0.5-1.0 g/m2 monthly × 6 mo)
      • Mok C.C.
      • Ying K.Y.
      • Yim C.W.
      • et al.
      Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up.
      At 6 mo, CR similar in the TAC (62%) and MMF (59%) groups

      A nonsignificant trend of higher incidence of renal flares and renal function decline in the TAC group

      More remissions in the combination group (45.9%) than in the IVCy group (25.6%) at the end of 24 wk

      Overall response incidence was higher in the multitarget group than in the IVCy group (83.5% vs 63.0%)
      Maintenance therapy for class III and IV LN
       1. CyIVCy monthly followed by IVCy quarterly (0.5-1 g/m2; n=20), or AZA (1-3 mg/kg; n=19) or MMF (0.5-3 g; n=20)
      • Liu Z.
      • Zhang H.
      • Liu Z.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      72-mo event-free survival rate for the composite end point of death or chronic renal failure higher in the MMF and AZA groups than in the CYC group (P=.05 and P=.009, respectively)

      Rate of relapse-free survival higher in the MMF group than in the Cy group (P=.02)

      Cy associated with an increased incidence of hospitalization, amenorrhea, infections, nausea, and vomiting

      Practice of quarterly IVCy pulses for 2 years is obsolete
       MMF vs AZA
      1. Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis studyMMF 2 g/d or AZA 2 mg/kg after receiving the low-dose Euro-Lupus Cy regimen
      • Contreras G.
      • Pardo V.
      • Leclercq B.
      • et al.
      Sequential therapies for proliferative lupus nephritis.
      Long-term follow-up of up to 10 y did not show any difference in rates of renal and extrarenal flares or doubling of SCr in this predominantly white cohort
      • Tamirou F.
      • D'Cruz D.
      • Sangle S.
      • et al.
      MAINTAIN Nephritis Trial Group
      Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.


      Trial was underpowered to show the difference
      2. ALMS, maintenance phaseMMF (2 g/d) or AZA (2 mg/kg) as maintenance showed superiority of MMF over AZA in preventing renal flare, doubling of SCr, or death
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      ALMS Group
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      The ALMS patient group was racially more diverse

      Nonwhites respond better to MMF; unlike MAINTAIN, only patients who achieved remission were entered into the maintenance phase
       Treatment of class V
      Class V = subepithelial immune deposits and membranous thickening of glomerular capillaries.
      LN
      1. IVCy vs CsAIVCy (0.5-1 g/m2 every 2 mo × 6 doses) + prednisone (1 mg/kg per day × 8 wk and then tapered to 0.25 mg/kg per day) or CsA (5 mg/kg per day; duration 11 mo) + prednisoneHigher probability of renal CR + PR: 60% with CYC, 83% with CsA vs 27% with prednisone alone
      • Austin III, H.A.
      • Illei G.G.
      • Braun M.J.
      • Balow J.E.
      Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy.


      Adverse effects were similar; relapses were more common after discontinuation of cyclosporine
      2. IVCy vs MMFPooled data from 2 trials (n=84)
      • Radhakrishnan J.
      • Moutzouris D.A.
      • Ginzler E.M.
      • Solomons N.
      • Siempos I.I.
      • Appel G.B.
      Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis.
      Similar rates of remission, relapses, and overall response
       Treatment of class VI
      Class VI = advanced sclerosis of >90% glomeruli.
      LN
      Renal replacement and supportive therapy, no immunosuppression
      a ALMS = Aspreva Lupus Management Study; AZA = azathioprine; BSA = body surface area; CR = complete remission; CsA = cyclosporine A; Cy = cyclophosphamide; ESRD = end-stage renal disease; IV = intravenous; IVCy = intravenous cyclophosphamide; LN = lupus nephritis; MAINTAIN = Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis; MMF = mycophenolate mofetil; NIH = National Institutes of Health; PR = partial remission; SCr = serum creatinine; TAC = tacrolimus.
      b Class III = subendothelial immune deposits and proliferative changes in <50% of glomeruli.
      c Class IV = subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli.
      d Class V = subepithelial immune deposits and membranous thickening of glomerular capillaries.
      e Class VI = advanced sclerosis of >90% glomeruli.

      Cyclophosphamide

      There are 2 regimens for the administration of IVCy: the high-dose National Institutes of Health regimen and the lower-dose Euro-Lupus Nephritis Trial (ELNT) regimen.
      • Gourley M.F.
      • Austin III, H.A.
      • Scott D.
      • et al.
      Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial.
      • Houssiau F.A.
      • Vasconcelos C.
      • D'Cruz D.
      • et al.
      Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
      The original high-dose National Institutes of Health regimen, although effective, is associated with considerable adverse effects and the practice of quarterly IVCy pulses for 2 years is obsolete (Table 2). The Euro-Lupus regimen was developed to combat these adverse effects and decrease the cumulative dose of Cy. Although oral Cy is effective in induction treatment of lupus nephritis, we do not use it in clinical practice because of the high incidence of toxicity.

      Mycophenolate Mofetil

      Recently MMF in doses of 2 to 3 g has been tested as an induction therapy for lupus nephritis and is equivalent to IVCy in inducing remission with fewer adverse effects.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Aspreva Lupus Management Study Group
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Ginzler E.M.
      • Dooley M.A.
      • Aranow C.
      • et al.
      Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.
      • Moore R.A.
      • Derry S.
      Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis.
      • Walsh M.
      • James M.
      • Jayne D.
      • Tonelli M.
      • Manns B.J.
      • Hemmelgarn B.R.
      Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis.
      • Zhu B.
      • Chen N.
      • Lin Y.
      • et al.
      Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials.
      • Touma Z.
      • Gladman D.D.
      • Urowitz M.B.
      • Beyene J.
      • Uleryk E.M.
      • Shah P.S.
      Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis.
      • Henderson L.K.
      • Masson P.
      • Craig J.C.
      • et al.
      Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials.
      Table 3 summarizes results of the large international trial.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Aspreva Lupus Management Study Group
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      The Aspreva Lupus Management Study
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Aspreva Lupus Management Study Group
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Isenberg D.
      • Appel G.B.
      • Contreras G.
      • et al.
      Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study.
      has found better response to MMF than to IVCy in African American and Hispanic patients.
      Pharmacokinetic properties vary widely among individuals, and Asians are particularly susceptible to drug toxicity.
      • Isenberg D.
      • Appel G.B.
      • Contreras G.
      • et al.
      Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study.
      Studies have found that a trough mycophenolic acid level of greater than 3 to 3.5 μg/L (to convert to μmol/L, multiply by 3.12) or mycophenolic acid area under the curve greater than 35 mg/h per liter is associated with lower disease activity and flares; however, more studies are needed in this field.
      • Łuszczyńska P.
      • Pawiński T.
      Therapeutic drug monitoring of mycophenolic acid in lupus nephritis: a review of current literature.
      We choose MMF as initial therapy and, for reserve, the use of IVCy in patients with rapidly progressive kidney failure, with severe lupus nephritis (creatinine clearance level <30 mL/min; serum creatinine level >3 mg/dl [to convert to μmol/L, multiply by 88.42]), or with widespread (>50%) segmental glomerular necrosis or crescents on biopsy or in those in whom drug compliance may be an issue.

      Tacrolimus

      Tacrolimus is a calcineurin inhibitor that binds FK506-binding protein 12 and inhibits the phosphatase activity of calcineurin. Most studies on its effectiveness are in Asians, and longer-term follow-up and studies in other racial groups are needed.

      Other Agents

      Rituximab. Although the Lupus Nephritis Assessment with Rituximab trial,
      • Rovin B.H.
      • Furie R.
      • Latinis K.
      • et al.
      LUNAR Investigator Group
      Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.
      a phase III randomized controlled trial involving anti-CD20 antibody, rituximab plus MMF, and glucocorticoids, did not meet its primary and secondary efficacy end points, the response rate was numerically higher in the rituximab arm than in the MMF arm (57% vs 46%) and highest in African American patients. The negative results were surprising and in contrast to those of several open-label trials and registry studies
      • Moroni G.
      • Raffiotta F.
      • Trezzi B.
      • et al.
      Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study.
      • Mok C.C.
      Current role of rituximab in systemic lupus erythematosus.
      that have found efficacy of resistant SLE treatment with rituximab. The criticism of the Lupus Nephritis Assessment with Rituximab trial is that it was underpowered and that the placebo arm (which was glucocorticoid, MMF 2 g, and placebo infusion) was an effective therapy. An observation period longer than 12 months is sometimes required to see benefit of therapy, and the study did not include patients with refractory lupus nephritis.
      Both Cy and MMF are teratogenic, and tacrolimus or azathioprine can be considered during pregnancy. An induction treatment regimen with azathioprine 2 mg/kg plus IVMP 1 g × 3 days at weeks 0, 2, and 6 and oral prednisone exhibited comparable efficacy with IVCy at 2 years. However, the azathioprine arm exhibited significant relapses, sustained doubling of creatinine, and worsening chronicity scores on kidney biopsy on long-term follow-up.
      • Arends S.
      • Grootscholten C.
      • Derksen R.H.
      • et al.
      Dutch Working Party on systemic lupus erythematosus
      Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis.

      Maintenance Therapy for Class III and IV Lupus Nephritis

      Maintenance therapy is recommended to consolidate renal response and prevent flares. There are no data to guide duration of immunosuppressive therapy beyond 3 years, and continuing treatment should be individualized. Agents that have been used for maintenance include Cy (Table 2); however, this is not a favored agent because of cumulative toxicity. Mycophenolate mofetil and azathioprine have been compared head to head in the Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis study and the Aspreva Lupus Management Study
      • Tamirou F.
      • D'Cruz D.
      • Sangle S.
      • et al.
      MAINTAIN Nephritis Trial Group
      Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      ALMS Group
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      (Table 2), and MMF is found to be equivalent or superior to azathioprine, respectively.
      • Tamirou F.
      • D'Cruz D.
      • Sangle S.
      • et al.
      MAINTAIN Nephritis Trial Group
      Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      ALMS Group
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      Small studies
      • Mok C.C.
      Towards new avenues in the management of lupus glomerulonephritis.
      have used cyclosporine (2.5-3 mg/kg) or tacrolimus as maintenance regimen; however, more long-term data are needed.

      Supportive Therapy

      The use of HCQ is associated with lower nephritis flare rates, and a reduced risk of developing renal disease and thrombotic complications.
      • Bertsias G.K.
      • Tektonidou M.
      • Amoura Z.
      • et al.
      European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association
      Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.
      • Lee S.J.
      • Silverman E.
      • Bargman J.M.
      The role of antimalarial agents in the treatment of SLE and lupus nephritis.
      Renal failure is associated with an increased risk of HCQ toxicity, and dose adjustments may need to be made. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is recommended in nonpregnant patients with hypertension or proteinuria levels of 0.5 g/24 h or more for their renoprotective effect. Target blood pressure of 130/80 mm Hg or lower is recommended to delay progression of renal disease. Attention to cardiovascular risk factors and appropriate management is recommended. Statin therapy for low-density lipoprotein level greater than 100 mg/dL (to convert to mmol/L, multiply by 0.0259) is recommended, although its benefit in patients with SLE has not been proven.

      Neuropsychiatric Lupus

      Neuropsychiatric manifestations constitute severe complications of SLE, contributing substantially to increased morbidity and mortality in these patients. In most patients, NPSLE presents early in disease course in the first 2 years, and in 39% to 50%, it can be the first manifestation of disease. The ACR
      The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes.
      has published a set of case definitions for 19 NPSLE syndromes that include central nervous system manifestation, psychiatric manifestation, and peripheral nervous system manifestation of SLE. Patients presenting with longitudinal transverse myelitis, involving at least 3 vertebral segments, and optic neuritis commonly have antineuromyelitis optica antibodies directed against aquaporin-4.
      • Nardone R.
      • Fitzgerald R.T.
      • Bailey A.
      • Zuccoli G.
      Longitudinally extensive transverse myelitis in systemic lupus erythematosus: case report and review of the literature.
      Coexistent Sjögren syndrome may be present. Identification of antineuromyelitis optica antibodies has important prognostic significance and portends a severe disease course with frequent relapses.
      The diagnostic and therapeutic approach consists of determining whether the event is a manifestation of SLE (primary NPLE), a complication of disease or therapy, a coincidental association, or secondary to other causes such as drugs, infections, and metabolic. Treatment is often directed by whether the manifestations are inflammatory or thrombotic or mixed (Figure 1). Patients with a predominantly inflammatory process (acute confusional state, aseptic meningitis, and optic neuritis) are often treated with immunosuppressive therapy, whereas predominantly thrombotic manifestations (eg, stroke due to antiphospholipid antibody syndrome) require antiplatelet and/or anticoagulation therapy.
      Figure thumbnail gr1
      Figure 1Treatment of primary NPLE. APL = antiphospholipid antibody; CsA = cyclosporine A; CV = cardiovascular; INR = international normalized ratio; IVCy = intravenous cyclophosphamide; IVIG = intravenous immunoglobulin; MMF = mycophenolate mofetil; NPLE = neuropsychiatric lupus erythematosus; ? = indicates unclear efficiency.
      There is a paucity of evidence-based guidelines, and most recommendations are based on small cohorts or case series. Steroids including IV methylprednisolone (1 g × 3 days) form first-line treatment. Several case series
      • Boumpas D.T.
      • Yamada H.
      • Patronas N.J.
      • Scott D.
      • Klippel J.H.
      • Balow J.E.
      Pulse cyclophosphamide for severe neuropsychiatric lupus.
      • Neuwelt C.M.
      • Lacks S.
      • Kaye B.R.
      • Ellman J.B.
      • Borenstein D.G.
      Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus.
      • Ramos P.C.
      • Mendez M.J.
      • Ames P.R.
      • Khamashta M.A.
      • Hughes G.R.
      Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus.
      • Mok C.C.
      • Lau C.S.
      • Wong R.W.
      Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study.
      • Stojanovich L.
      • Stojanovich R.
      • Kostich V.
      • Dzjolich E.
      Neuropsychiatric lupus favourable response to low dose i.v. cyclophosphamide and prednisolone (pilot study).
      have found good improvement in NP manifestation with Cy. The dose and route used have been variable; Mok et al
      • Mok C.C.
      • Lau C.S.
      • Wong R.W.
      Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study.
      used a combination of prednisone and oral Cy (1-2 mg/kg for 6 months) followed by azathioprine maintenance and reported complete response in all 13 patients. A retrospective review
      • Neuwelt C.M.
      • Lacks S.
      • Kaye B.R.
      • Ellman J.B.
      • Borenstein D.G.
      Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus.
      of use of IVCy monthly (dose, 250-1000 mg/m2) in 31 patients reported response in 61% of patients. In patients with mild manifestations, improvement was seen as early as 4 days but on average 4 monthly IVCy infusions (range, 2-9 months) were required for response. Cyclophosphamide is the only therapy that has been tested in a small controlled clinical trial that compared IVCy and IV methylprednisolone in patients with severe NP manifestations.
      • Barile-Fabris L.
      • Ariza-Andraca R.
      • Olguín-Ortega L.
      • et al.
      Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus.
      Patients received either IVCy (0.75 g/m2 body surface area, monthly × 1 year and then quarterly for additional year, plus oral prednisone) or IVMP (1 g × 3 days, monthly × 4 month, bimonthly × 6 months and then every 3 months × 1 year). There was a lesser number of treatment failures in the Cy group (1 of 19) than in the IVMP group (7 of 13). Cyclophosphamide was more effective than MP in the management of seizures, optic neuritis, brainstem lesions, and peripheral neuropathy, but a clear benefit over MP was not apparent for transverse myelitis and coma; however, the numbers were extremely small.
      Isolated case reports or series
      • Lhotta K.
      • Würzner R.
      • Rosenkranz A.R.
      • et al.
      Cerebral vasculitis in a patient with hereditary complete C4 deficiency and systemic lupus erythematosus.
      • Jose J.
      • Paulose B.K.
      • Vasuki Z.
      • Danda D.
      Mycophenolate mofetil in neuropsychiatric systemic lupus erythematosus.
      • Tomietto P.
      • D'Agostini S.
      • Annese V.
      • De Vita S.
      • Ferraccioli G.
      Mycophenolate mofetil and intravenous dexamethasone in the treatment of persistent lupus myelitis.
      • Saison J.
      • Costedoat-Chalumeau N.
      • Maucort-Boulch D.
      • et al.
      Systemic lupus erythematosus-associated acute transverse myelitis: manifestations, treatments, outcomes, and prognostic factors in 20 patients.
      have found good response of MMF (combined with IV dexamethasone) in a patient with myelitis and cerebral vasculitis or for psychotic manifestation (with IV immunoglobulin). Others
      • Mok C.C.
      • Mak A.
      • To C.H.
      Mycophenolate mofetil for lupus related myelopathy.
      • Mok C.C.
      Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review.
      have reported only modest results of mycophenolate in NP lupus. Rituximab was used as an initial therapy in 6 patients with myelopathy, with complete response seen in 4 patients
      • Ye Y.
      • Qian J.
      • Gu Y.
      • Chen X.
      • Ye S.
      Rituximab in the treatment of severe lupus myelopathy.
      ; most published reports have been in patients with refractory disease. In a systematic review,
      • Narváez J.
      • Ríos-Rodriguez V.
      • de la Fuente D.
      • et al.
      Rituximab therapy in refractory neuropsychiatric lupus: current clinical evidence.
      complete remission or partial remission was seen in 85% of patients after 1 cycle of treatment; however, relapses were noted in 45% (median, 9.5 months; range, 4-22 months) despite a maintenance regimen. Intravenous immunoglobulin has been used as adjunctive therapy, and the response is usually rapid.
      • Milstone A.M.
      • Meyers K.
      • Elia J.
      Treatment of acute neuropsychiatric lupus with intravenous immunoglobulin (IVIG): a case report and review of the literature.
      • Vina E.R.
      • Fang A.J.
      • Wallace D.J.
      • Weisman M.H.
      Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: prognosis and outcome.
      Plasmapheresis has also been used in patients with manifestations such as acute confusional state, seizure disorder, cerebrovascular disease, cognitive dysfunction, demyelinating syndrome, intractable headache, myelopathy, aseptic meningitis, and psychosis.
      • Neuwelt C.M.
      The role of plasmapheresis in the treatment of severe central nervous system neuropsychiatric systemic lupus erythematosus.
      Improvement occurred in 54% to 74% and usually in the first week of treatment.
      • Neuwelt C.M.
      The role of plasmapheresis in the treatment of severe central nervous system neuropsychiatric systemic lupus erythematosus.
      • Bartolucci P.
      • Bréchignac S.
      • Cohen P.
      • Le Guern V.
      • Guillevin L.
      Adjunctive plasma exchanges to treat neuropsychiatric lupus: a retrospective study on 10 patients.
      A daily or every other day course, 3 to 6 times, is sufficient to see response in lupus.
      • Schwartz J.
      • Winters J.L.
      • Padmanabhan A.
      • et al.
      Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue.
      It is commonly combined with immunosuppressive therapy, with published series on cyclosporine and Cy.
      • Bambauer R.
      • Schwarze U.
      • Schiel R.
      Cyclosporin A and therapeutic plasma exchange in the treatment of severe systemic lupus erythematosus.
      Azathioprine was not found to be useful in short-term treatment, but may be useful as a maintenance agent in NPLE.
      • Mok C.C.
      • Lau C.S.
      • Wong R.W.
      Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study.
      • Ginzler E.
      • Sharon E.
      • Diamond H.
      • Kaplan D.
      Long-term maintenance therapy with azathioprine in systemic lupus erythematosus.
      Further studies are needed to define the differences among various second-line drugs.

      Supportive Therapy

      Symptomatic therapy such as anticonvulsants (for seizures), antidepressants/anxiolytic agents (for mood disorders) or antipsychotic agents (for psychosis), and antihypertensive drugs should be used, as indicated. Hydroxychloroquine should be considered for primary prevention of thrombosis in patients with SLE and persistently high-titer positive antiphospholipid antibodies.
      • Tektonidou M.G.
      • Laskari K.
      • Panagiotakos D.B.
      • Moutsopoulos H.M.
      Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies.
      Some studies
      • Ruiz-Irastorza G.
      • Cuadrado M.J.
      • Ruiz-Arruza I.
      • et al.
      Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies.
      have also reported benefits of low-dose aspirin as primary prophylaxis in patients with SLE. Antiplatelet therapy and/or anticoagulation was beneficial for secondary prevention of thrombotic manifestations.
      • Ruiz-Irastorza G.
      • Hunt B.J.
      • Khamashta M.A.
      A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies.
      • Khamashta M.A.
      • Cuadrado M.J.
      • Mujic F.
      • Taub N.A.
      • Hunt B.J.
      • Hughes G.R.
      The management of thrombosis in the antiphospholipid-antibody syndrome.
      These adjunct therapies may be effective for some patients with chorea, transverse myelitis, and ischemic optic neuropathy.
      • Cervera R.
      • Asherson R.A.
      • Font J.
      • et al.
      Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.
      • D'Cruz D.P.
      • Mellor-Pita S.
      • Joven B.
      • et al.
      Transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies.
      • Heinlein A.C.
      • Gertner E.
      Marked inflammation in catastrophic longitudinal myelitis associated with systemic lupus erythematosus.
      • Sivaraj R.R.
      • Durrani O.M.
      • Denniston A.K.
      • Murray P.I.
      • Gordon C.
      Ocular manifestations of systemic lupus erythematosus.

      Hematologic Issues

      Hematologic abnormalities constitute an important manifestation of lupus often paralleling activity of disease. Figure 2 depicts the management of autoimmune hemolytic anemia and cytopenia.
      • Barcellini W.
      • Zanella A.
      Rituximab therapy for autoimmune haematological diseases.
      • Olfat M.
      • Silverman E.D.
      • Levy D.M.
      Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus.
      • Fayyaz A.
      • Igoe A.
      • Kurien B.T.
      • et al.
      Haematological manifestations of lupus.
      • Jung J.H.
      • Soh M.S.
      • Ahn Y.H.
      • et al.
      Thrombocytopenia in systemic lupus erythematosus: clinical manifestations, treatment, and prognosis in 230 patients.
      • Hall S.
      • McCormick Jr., J.L.
      • Greipp P.R.
      • Michet Jr., C.J.
      • McKenna C.H.
      Splenectomy does not cure the thrombocytopenia of systemic lupus erythematosus.
      • Jiang B.
      • Li T.
      • Guo L.
      • Shen H.
      • Ye S.
      • Chen S.
      Efficacy and safety of rituximab in systemic lupus erythematosus and Sjögren syndrome patients with refractory thrombocytopenia: a retrospective study of 21 cases.
      • Maroun M.C.
      • Ososki R.
      • Andersen J.C.
      • Dhar J.P.
      Eltrombopag as steroid sparing therapy for immune thrombocytopenic purpura in systemic lupus erythematosus.
      Figure thumbnail gr2
      Figure 2Management of hematologic lupus manifestations. AZA = azathioprine; Cy = cyclophosphamide; Cy = cyclophosphamide; GM-CSF = granulocyte-macrophage colony-stimulating factor; Hb = hemoglobin; HCQ = hydroxychloroquine; IVIG = intravenous immunoglobulin; MMF = mycophenolate mofetil; TCP = thrombocytopenia; TTP = thrombotic thrombocytopenic purpura. SI conversion factor: To convert hemoglobin value to mmol/L, multiply by 0.0626.

      Reproductive Issues

      Pregnancy

      Active discussion with patients about pregnancy planning should be held. Although most women have successful pregnancy, we discourage pregnancy in patients with active lupus nephritis, severe or symptomatic pulmonary hypertension (estimated systolic pulmonary artery pressure >50 mm Hg), renal failure, heart failure, stroke in past 6 months, and severe restrictive lung disease (forced vital capacity <1 L). Disease flares can be seen in 30% to 50% of patients, with rates being considerably lower when the disease is in remission. Most of these are minor flares. Several studies have found that active disease 6 months before pregnancy, lupus nephritis, and discontinuation of antimalarial agents are a risk factor for adverse maternal outcomes. Medical complications such as sepsis, postpartum bleeding, pulmonary embolism, and deep venous thrombosis are more common in SLE. There is increased incidence of preterm labor, intrauterine growth retardation, premature rupture of membranes, and preeclampsia.
      • Clowse M.E.
      • Jamison M.
      • Myers E.
      • James A.H.
      A national study of the complications of lupus in pregnancy.
      The post-partum period may be characterized by disease flares, failure of lactation, thrombotic complications, and postpartum bleeding.
      • Lateef A.
      • Petri M.
      Management of pregnancy in systemic lupus erythematosus.

      Neonatal Lupus and Congenital Heart Block

      Anti-Ro and anti-La antibodies can be cardiotoxic to the fetus, and varying degrees of congenital heart block can be seen in 1% to 3% of children born to women who are seropositive.
      • Brucato A.
      • Cimaz R.
      • Caporali R.
      • Ramoni V.
      • Buyon J.
      Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies.
      The risk of recurrence increases to 18% in subsequent pregnancies. The heart block can be transient or complete, leading to heart failure in utero and hydrops fetalis. There is no known effective therapy for complete heart block. Corticosteroids, particularly fluorinated steroids such as dexamethasone or betamethasone that can cross the transplacental barrier, are administered. Intravenous immunoglobulin has been used for treatment; however, a recent trial to prevent congenital heart block was negative.
      • Friedman D.M.
      • Llanos C.
      • Izmirly P.M.
      • et al.
      Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial.
      Hydroxychloroquine use during pregnancy is associated with a reduced risk of fetal development of neonatal lupus.
      • Izmirly P.M.
      • Kim M.Y.
      • Llanos C.
      • et al.
      Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine.
      Seropositive women without a previous child born with congenital heart block should undergo serial fetal echocardiograms at 16, 18, 20, 22, and 24 weeks of pregnancy.

      Antiphospholipid Antibody–Positive Mother

      Antiphospholipid antibodies are well-known risk factors for thromboembolism and pregnancy loss. In a large multiethnic cohort,
      • Buyon J.P.
      • Kim M.Y.
      • Guerra M.M.
      • et al.
      Predictors of pregnancy outcomes in patients with lupus: a cohort study.
      the presence of lupus anticoagulant was associated with adverse pregnancy outcomes. The presence of antiphospholipid antibody also increases risk of preeclampsia, hypertension, intrauterine growth restriction, and fetal death. Management goals are to reduce the risk of thromboembolic events and prevent fetal loss. Low-dose aspirin can reduce the risk of preeclampsia, but some studies
      • Buyon J.P.
      • Kim M.Y.
      • Guerra M.M.
      • et al.
      Predictors of pregnancy outcomes in patients with lupus: a cohort study.
      • Amengual O.
      • Fujita D.
      • Ota E.
      • et al.
      Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review.
      have not found a reduction in adverse obstetrical outcome in asymptomatic patients and decision to use aspirin should be individualized. The antiphospholipid antibody–positive patient with history of thrombotic episodes should be warned about its embryotoxicity before conception and switched to low-molecular-weight heparin (LMWH) as soon as pregnancy is confirmed. Although unfractionated heparin and LMWH are equal in efficacy, LMWH is preferred because of lower risk of thrombocytopenia and osteoporosis. Treatment is with low-dose aspirin plus therapeutic dose of LMWH (eg, enoxaparin 1 mg/kg subcutaneously [SC] or dalteparin 100 units/kg SC every 12 hours or enoxaparin 1.5 mg/kg per day or dalteparin 200 units/kg SC every day). Anticoagulation should be continued for 6 weeks after delivery. Women with a positive obstetric history (recurrent early miscarriages, fetal death [>10 weeks], or prior early delivery [<34 weeks] due to severe preeclampsia or placental insufficiency) but no thrombotic episodes are treated with low-dose aspirin and prophylactic LMWH (enoxaparin 40 mg/d or dalteparin 5000 units/d SC).
      • Lateef A.
      • Petri M.
      Management of pregnancy in systemic lupus erythematosus.

      Recommendations

      Management of SLE is exceedingly complex and associated with significant morbidity from disease and medication complications. Development of new effective therapeutics is greatly needed. Current research is focused on targeting the B and long-lived plasma cells, the interferon pathway and receptors, signaling molecules in T and B cells, and epigenetic targets.

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