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![RISK FACTORS FOR SLE
Female sex
Oestrogen containing OCP or HRT (1.2- to 2-fold)
XXY karyotype (Klinefelter’s syndrome)
Exposure to UV light causes SLE flares in approx. 70% patients.
Epstein-Barr virus (EBV) can trigger SLE in susceptible individuals
Current tobacco smoking (odds ratio [OR] 1.5)
Prolonged occupational exposure to silica (OR 4.3)](https://image.slidesharecdn.com/systemiclupuserythematosus-myppt-160827102639/85/Systemic-lupus-erythematosus-6-320.jpg)
![Poor Prognostic Factors
High serum creatinine levels (>124 μmol/L [>1.4 mg/dl])
Hypertension
Nephrotic syndrome (24-h urine protein excretion >2.6 g)*
Anemia (haemoglobin <124 g/L [<12.4 g/dl])
Hypoalbuminemia
Hypocomplementemia
Antiphospholipid antibodies
Male sex
Ethnicity (african american, hispanic with mestizo heritage)
Low socioeconomic status](https://image.slidesharecdn.com/systemiclupuserythematosus-myppt-160827102639/85/Systemic-lupus-erythematosus-57-320.jpg)
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Systemic lupus erythematosus
- 1. Systemic Lupus Erythematosus DR.KOUSTAV JANA DR. BABASAHEB AMBEDKAR MEMORIAL HOSPITAL, MUMBAI
- 2. INTRODUCTION Systemic lupus erythematosus(SLE) is an autoimmune disease Ninety percent of patients are women of child-bearing years people of all genders, ages, and ethnic groups are susceptible highest prevalence is in African-American and Afro- Caribbean women, and lowest prevalence is in white men.
- 3. History of Lupus Lupusmeans “wolf” in Latin 10th century- case reports appeared in writings Late 1800s- Sir William Osler initially described the systemic nature and linked rashes to organ involvement 1949- LE cell described by Malcolm Hargraves at Mayo Clinic 1954- ANA described 1971- First set of classification criteria proposed for Lupus 1983- Antiphospholipid antibody syndrome described
- 4.
- 5. ABNORMAL IMMUNE RESPONSES: (1)activation of innate immunity (dendritic cells, monocyte/ macrophages) by immune complexes or viral DNA / RNA (2) lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (mature T and B lymphocytes) (3) ineffective regulatory CD4+ and CD8+ T cells, B cells, and myeloid-derived suppressor cells (4) reduced clearance of immune complexes and apoptotic cells
- 6. RISK FACTORS FORSLE Female sex Oestrogen containing OCP or HRT (1.2- to 2-fold) XXY karyotype (Klinefelter’s syndrome) Exposure to UV light causes SLE flares in approx. 70% patients. Epstein-Barr virus (EBV) can trigger SLE in susceptible individuals Current tobacco smoking (odds ratio [OR] 1.5) Prolonged occupational exposure to silica (OR 4.3)
- 7. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Systemic: Fatigue, malaise, fever, anorexia, weight loss 95 Musculoskeletal 95 Arthralgias/myalgias 95 Nonerosive polyarthritis 60 Hand deformities 10 Myopathy/myositis 25/5 Ischemic necrosis of bone 15
- 8. ARTHROPATHY & HANDDEFORMITY IN SLE Jaccoud's arthopathy
- 9. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Cutaneous 80 Photosensitivity 70 Malar rash 50 Oral ulcers 40 Alopecia 40 Discoid rash 20 Vasculitis rash 20 Other(e.g.,urticaria, subacute cutaneous lupus) 15
- 10. CUTANEOUS MANIFESTATIONS OFSLE 1 2. 3. 4. 5. 6. 7.
- 11. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Hematologic 85 Anemia (chronic disease) 70 Hemolytic anemia 10 Leukopenia (<4000/μL) 65 Lymphopenia (<1500/μL) 50 Thrombocytopenia (<100,000/μL) 15 Lymphadenopathy 15 Splenomegaly 15
- 12. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Neurologic 60 Cognitive disorder 50 Mood disorder 40 Headache 25 Seizures 20 Mono/ polyneuropathy 15 Stroke, TIA 10 Acute confusion /movement disorder 2–5 Aseptic meningitis, myelopathy <1
- 13. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Cardiopulmonary 60 Pleurisy, pericarditis, effusions 30–50 Myocarditis, endocarditis 10 Lupus pneumonitis 10 Coronary artery disease 10 Interstitial fibrosis 5 Pulmonary hypertension,ARDS,hemorrhage <5 Shrinking lung syndrome <5
- 14. LIBMAN-SACKS ENDOCARDITIS Noninfective thromboticendocarditis involving mitral valve in SLE. Note nodular vegetations along line of closure and extending onto chordae tendineae
- 15. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Renal 30–50 Proteinuria ≥500 mg/24 h, cellular casts 30–50 Nephrotic syndrome 25 End-stage renal disease 5–10 Nephritis is usually the most serious manifestation of SLE
- 16. CLASSIFICATION OF LUPUSNEPHRITIS
- 17. CLASSIFICATION OF LUPUSNEPHRITIS CONTD…
- 18. ON RENAL BIOPSY Inflammationcan be: Focal Diffuse
- 19. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Gastrointestinal 40 Nonspecific(nausea, mild pain, diarrhea) 30 Abnormal liver enzymes 40 Vasculitis 5
- 20. CLINICAL MANIFESTATIONS OFSLE & PREVALENCE OVER THE ENTIRE DISEASE COURSE Manifestation Prevalence(%) Thrombosis 15 Venous 10 Arterial 5 Ocular 15 Sicca syndrome 15 Conjunctivitis, episcleritis 10 Vasculitis 5
- 21.
- 22.
- 23. ANA patterns Staining Patterns •Observer dependent • Not sensitive • Not specific • Only LOOSELY associated with certain disease states HENCE ANA PATTERN HAS NO CINICAL SIGNIFICANCE
- 24. What other diagnosesshould clinicians consider in patients with possible lupus? Chronic fatigue syndrome Fibromyalgia Rheumatoid arthritis Small or medium vessel vasculitides Thrombotic thrombocytopenic purpura Viral arthritis Hematopoietic cancer Malignant lymphoproliferative syndromes
- 25. DIAGNOSIS The diagnosis ofSLE is based on characteristic clinical features and autoantibodies.
- 26. 2012 SLICC ClassificationCriteria NO SEROSITIS in criteria
- 27. Should clinicians screenpatients for asymptomatic lupus if they are at increased risk? Not recommended Including those with a family history Test for ANA produces too many false-positives Detected in 3-5% of healthy individuals or patients with other autoimmune or infectious diseases Serologic evidence may precede clinical manifestations By 3 to 9 years Treating during this clinically ‘silent’ period doesn’t halt or delay development
- 28. Drug- Induced Lupus syndromeappears during therapy with certain medications and biologic agents predominant in whites Production of autoantibodies more common than clinical symptoms commonly associated with antibodies to histones Rarely associated with anti-dsDNA 99% disappear within 3 months of stopping the medicine. Has less female predilection than SLE Rarely involves kidneys or brain
- 29. DIL COMMON ASSOCIATIONS Antiarrhythmics: procainamide, disopyramide, and propafenone Anti hypertensives: hydralazine; several ACE inhibitors and beta blockers Antithyroid: propylthiouracil Antipsychotics: chlorpromazine and lithium Anticonvulsants: carbamazepine and phenytoin Antibiotics: isoniazid, minocycline, and nitrofurantoin Antirheumatic: sulfasalazine Diuretic: hydrochlorothiazide Antihyperlipidemics: lovastatin and simvastatin IFNs and TNF inhibitors ANA usually appears before symptoms
- 30. Neonatal Lupus Rare condition nottrue lupus, passively transferred autoimmune disease Occurs when mother is SSA/SSB positive Transplacental transfer of IgG anti SSA or SSB antibodies 5-7% babies will have a transient rash, resolves by 6-8 months 2% of babies will have cardiac complications with congenital heart block
- 31.
- 32. Treatment There is nocure for SLE, and complete sustained remissions are rare. Treatment Plan: to induce remissions of acute flares and then suppress symptoms to an acceptable level and prevent organ damage. Therapeutic choices depend on: (1) whether disease manifestations are life-threatening or likely to cause organ damage, justifying aggressive therapies (2) manifestations are potentially reversible (3) the best approaches to preventing complications of disease and its treatments. Evaluate for organ involvement SSA/SSB ab: pregnancy risks APL ab: clotting, pregnancy risks
- 35. Treatment: Analgesics/Anti-inflammatory Acitaminophen, NSAIDS Used in lupus over for symptom relief particularly for arthritis/ arthralgias Acetaminophen may be a good strategy for its favourable side effect profile, but NSAIDs are more effective in some patients. However, two major issues indicate caution in using NSAIDs: SLE patients are at increased risk for NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction. All NSAIDs, particularly those that inhibit cyclooxygenase-2 specifically may increase risk for myocardial infarction.
- 36. Treatment: Antimalarials hydroxychloroquine, chloroquine Preventactivation of toll like receptors 7 & 9 Used in lupus over 50 years for dermatitis, arthritis FDA approved Prevents relapses Reduces risk for congenital heart block in neonatal SLE Reasonably safe, potential retinal toxicity Eye exam once yearly
- 37. Hydroxychlorquine Takes 6 weeksto kick in, up to 6 months for maximal effect Dose is 200-400 mg/day Reduces intensity of flares Increases time to flare Treats skin and joint manifestations Safe in pregnancy(?)
- 38. Corticosteroids Mainstay for organ/lifethreatening disease Work quickly and effectively; action starts within 24 hours Starting dose: Oral: Prednisone- 0.5-1mg/kg/day; taper over 4-6 weeks, by 10% q week; low dose: 0.07-0.3 mg/kg/day For life/ organ threatening conditions: IV Methylprednisolone 0.5-1 gm/day * 3-5 days followed by oral tapering Maintenance dose of 5-10 mg prednisone after tapering Add a steroid sparing imunosuppresant Long term AE: hyperglycemia, hyperlipidemia, hypertension, accelerated atherosclerosis, osteoporosis, AVN, cataracts, glaucoma, PUD, skin thinning, emotional lability
- 39. Immunosuppressive agents Methotrexate: usedfor arthritis and skin Leflunomide: used for arthritis Azathioprine: useful for renal disease, autoimmune hepatitis, pulmonary disease, myositis, cutaneous manifestations Mycophenylate Mofetil: lupus nephritis Cyclosporine: membranous nephritis, aplasias Cyclophosphamide: used for severe disease- nepritis, CNS involvement, vasculitis Rituximab: used for severe organ threatening disease Belimumab: FDA Approved for Lupus
- 40. Doses of Immunosuppressiveagents Methotrexate: 10–25 mg once a week, PO or SC Leflunomide: 10–20 mg/d Azathioprine:2–3 mg/kg per day PO for induction; 1– 2 mg/kg per day for maintenance Mycophenylate Mofetil: 2–3 g/d PO for induction therapy, 1–2 g/d for maintenance therapy
- 41. Doses of Immunosuppressiveagents Cyclosporine:2.5 mg/kg/day orally in 2 equally divided doses. maximum dose of 5 mg/kg/day Cyclophosphamide: Low dose: 500 mg every 2 weeks for 6 doses, then begin maintenance with MMF or AZA. High dose: 7–25 mg/kg or 500-1000 mg/m2 q month × 6 doses Rituximab:375 mg/m2 q wk × 4 doses or 1 g q 2 wks × 2
- 42. What new medicationsare available for treating systemic lupus? Belimumab (10 mg/kg dose) wks 0,2,and 4, then monthly Monoclonal antibody targeting B lymphocyte stimulator FDA approved for treatment Improves musculoskeletal, mucocutaneous manifestations Improves immunological parameters Fewer patients had worsening hematological parameters Trials excluded patients with severe lupus nephritis or severe CNS manifestations
- 43. On the horizon… Studiesof highly targeted experimental therapies for SLE are in progress 1. Agents that target activated B lymphocytes with anti-CD22 or TACI-Ig 2. Agents that inhibits of IFN-α 3. Agents that inhibits of B/T cell second signal coactivation with CTLA-Ig 4. Agents that inhibits innate immune activation via TLR7 or TLR7 and 9 5. Agents that induces regulatory T cells with peptides from immunoglobulins or autoantigens 6. Agents that suppresses T cells, B cells, and monocyte/macrophages with laquinimod 7. inhibition of lymphocyte activation by blockade of Jak/Stat
- 44. On the horizon… Onlyfour FDA approved medications for lupus- prednisone, hydroxychloroquine, aspirin, belimumuab Many clinical trials ongoing looking at innovative biologic therapies
- 45. How should clinicianschoose therapy for a patient who is having a flare? IV glucocorticoids + immunosuppressive medications For severe manifestations (lupus nephritis, alveolar hemorrhage, CNS vasculitis) Withdraw glucocorticoids once remission achieved Oral prednisone or methlyprednisolone For arthritis, pleuropericarditis, cutaneous vasculitis, uveitis
- 46. How should clinicianschoose and dose drug therapy for lupus nephritis? Class I or II: no immunosuppressive therapy Standard therapy: cyclophosphamide + IV glucocorticoids Newer regimen: mycophenolate mofetil + glucocorticoids Class V: prednisone 0.5 mg/kg/d + mycophenolate mofetil If overlap with III/IV or having nephrotic range proteinuria: treat aggressively as Class III or IV Class VI: preparation for renal replacement therapy Class III or IV: treat aggressively
- 47. Maintenance therapy Mycophenolatemofetil Azathioprine Both superior to cyclophosphamide For patients who don’t respond to either Calcineurin inhibitors (cyclosporine, tacrolimus) Rituximab (monoclonal antibody against CD20) Either in combination with glucocorticoids
- 48. How should clinicianschoose therapy for neuropsychiatric lupus? Treatment relatively empirical IV glucocorticoids, immunoglobulin, cyclophosphamide Relapse may be more common in glucocorticoid vs cyclophosphamide treatment Rituximab may be beneficial, but relapse rate seems high
- 49. How should clinicianschoose therapy for respiratory manifestations? Pleuritis NSAIDs, low- to moderate-dose glucocorticoids Abrupt diffuse alveolar hemorrhage IV glucocorticoids + immunosupressants; consider plasmapheresis Pulmonary hypertension PDE-5 inhibitors, ERAs, and prostacyclin analogs may be used; with or without immunosuppressants In interstitial lung disease: glucocorticoids, and, if poor response, cyclophosphamide or azathioprine Acute lupus pneumonitis High doses of glucocorticoids and cyclophosphamide
- 50. How should clinicianschoose therapy for ocular manifestations? Depends on severity and disease activity Antimalarials NSAIDs Oral or IV glucocorticoids Scleral or retinal involvement Concomitant use of pulse glucocorticoids Then 1 mg/kg prednisone equivalent + immunosuppressants Retinal vasculitis and arterial or venous retinal occlusion with antiphospholipid antibodies IV glucocorticoids + Immunosuppressants + antiplatelet agents / anticoagulation
- 51. How should cliniciansmonitor patients who are being treated for lupus? Routinely test: CBC,KFT, LFT, urinalysis Allows evaluation of target-organ manifestations In impending flare: dsDNA antibodies + C3 & C4 levels Controversial for clinically stable patients Treatment with prednisone of clinically stable but serologically active patients may avert severe flare Monitor individual disease manifestations Monitor for immunosuppressant toxicity If treated with hydroxychloroquine: ophthalmological evaluation annually (particularly if >40y and treated for a long time) Monitor for osteoporosis, osteonecrosis Consider periodic lipid testing, ECHO
- 52. What should cliniciansdo about immunizations in people with lupus? All patients with SLE should receive Influenza vaccine Pneumococcal vaccine Consider quadrivalent HPV vaccine Well-tolerated, reasonably effective in stable SLE No live attenuated vaccines if immunocompromised If on >20mg/d prednisone or immunosuppressants Including: herpes zoster, Flumist, MMR, smallpox Tuberculin skin test recommended If glucocorticoids or immunosuppressive use prolonged
- 53. How should cliniciansmodify treatment for pregnant patients? Treat active lupus manifestations Use hydroxychloroquine and prednisone Discontinuation associated with increased flare risk If severe, consider IV glucocorticoids + azathioprine Contraindicated: mycophenolate mofetil, methotrexate, cyclophosphamide
- 54. When should patientswith lupus be hospitalized? Severe thrombocytopenia Severe or rapidly progressive renal disease Suspected lupus pneumonitis or pulmonary hemorrhage Chest pain or severe cardiovascular manifestations CNS and neurological manifestations Unexplained fever
- 55. Prognosis Has dramatically improvedover time Normal life expectancy for patients with drug induced lupus cutaneous lupus lupus without organ involvement Possible increased risk of NHL
- 56.
- 57. Poor Prognostic Factors High serum creatinine levels (>124 μmol/L [>1.4 mg/dl]) Hypertension Nephrotic syndrome (24-h urine protein excretion >2.6 g)* Anemia (haemoglobin <124 g/L [<12.4 g/dl]) Hypoalbuminemia Hypocomplementemia Antiphospholipid antibodies Male sex Ethnicity (african american, hispanic with mestizo heritage) Low socioeconomic status
- 58. Mortality Bimodal mortality Early deaths:infection and renal involvement Later deaths: atherosclerotic disease Premenopausal women with lupus have 30-50x higher risk of CAD than their non-lupus counterparts
- 59. SLEDAI SLEDAI is awidely used measure of SLE disease activity scores >3 reflect clinically active disease.
- 60.
Editor's Notes
- #26 Chronic fatigue syndrome and fibromyalgia may present with diffuse musculoskeletal symptoms mimicking lupus, or may be secondary to SLE. SLE can be excluded in the absence of inflammatory pain and negative results on serologic evaluation. Rheumatoid arthritis is characterized by symmetric, intensely inflammatory, erosive arthritis (when advanced), and a positive rheumatoid factor or anti-CCP antibody testing. Such drugs as procainamide, hydralazine, minocycline, isoniazide, and tumor necrosis factor inhibitors can cause drug-induced lupus, a clinical syndrome resembling SLE characterized by fever, serositis, arthritis and rash. Anti-histone antibodies are detected in approximately 75% of patients; however, they can also be seen in SLE and are not pathognomonic. Anti-dsDNA, or antibodies to extractable nuclear antigens, are rare in drug-induced lupus, and symptoms usually abate within days or weeks after drug discontinuation. Small- or medium-vessel vasculitides, thrombotic thrombocytopenic purpura, and viral arthritis, as seen in parvovirus infection and HIV/AIDS, can also mimic SLE. Differential diagnosis relies on laboratory studies, detection of viral serologies, and tissue histopathology. Hematopoietic cancer and malignant lymphoproliferative syndromes may present with positive ANA, anemia, low-grade fever, pleural effusions, and lymphadenopathy and can be misdiagnosed as lupus.
- #45 A monoclonal antibody targeting the B-lymphocyte stimulator (BLys) was recently approved. Two international, double-blind, phase 3 RCTs compared belimumab 1 mg/kg and 10 mg/kg plus standard therapy to placebo plus standard therapy (58,59). In the 52-week study, reduction of ≥4 points on the SLE Response Index (SRI) was 51% and 58% with the belimumab 1-mg/kg and 10-mg/kg dose, respectively, vs. 44% with placebo (P<0.05). In the 76-week study, the SRI-measured response at 52 weeks was 42.8% and 46.5% with the belimumab 1-mg/kg and 10-mg/kg dose and 35.3% with placebo; at 76 weeks, the response rates were 42.1% and 41.4% with the belimumab 1-mg/kg and 10-mg/kg dose, and 33.8% with placebo (P<0.05 and P=NS). Both trials excluded patients with severe lupus nephritis or severe CNS manifestations. Analysis of combined results from both trials showed more improvement of musculoskeletal and mucocutaneous manifestations in patients treated with belimumab and improvement in immunological parameters; in addition, fewer patients had worsening hematological parameters (60). The SRI requires reduction in disease activity scores and no deterioration from baseline in target organ manifestations (58). Further evidence is needed to assess the comparative efficacy of BlyS antagonism in severe lupus manifestations.
- #48 Severe SLE manifestations, such as lupus nephritis, alveolar hemorrhage, or CNS vasculitis, should be treated with glucocorticoids administered intravenously (IV) in conjunction with immunosuppressive medications. Glucocorticoids can be gradually withdrawn once remission is achieved. Oral prednisone or methlyprednisolone is used for arthritis, pleuropericarditis, cutaneous vasculitis, and uveitis. Early studies demonstrated that glucocorticoids could ameliorate SLE, although subsequent controlled trials showed that the therapeutic effect was not sustained (23). Early studies also linked glucocorticoids to improved survival in severe SLE (24), but similar studies have not been done for mild or moderate disease. Current decisions about glucocorticoid dosage and the duration of treatment for specific manifestations rely largely on clinical experience, because too few clinical trials have been done. An early study comparing 100 mg versus 1000 mg IV methylprednisolone, suggested that 3 daily doses of 1000 mg did not have significant advantage over 3 daily doses of 100 mg (25). A more recent randomized study showed that a dose of 1000 mg to 1500 mg over 3 days is as effective as doses ranging from 2000 mg to 5000 mg over 3 days and is associated with a decreased risk for infections (26). Significant overlap exists between lupus manifestations and some glucocorticoid complications, including osteoporosis, avascular bone necrosis, myopathy, and psychosis. Furthermore, despite the abundance of observational data on glucocorticoid toxicity, evidence from randomized controlled clinical trials (RCTs) is limited. Table 2 summarizes the 2002 European League Against Rheumatism recommendations on glucocorticoid treatment (27). These recommendations define a low daily dose of prednisone (or equivalent) as ≤7 mg. Low doses are associated with relatively low risk for toxicity, although monitoring for cushingoid symptoms, osteoporosis, cataracts, glaucoma, hyperglycemia, and hypertension is probably justified. Prolonged treatment with medium to high dose carries higher risk of complications, including myopathy, psychosis, hyperlipidemia, and atherosclerosis. However, the prevalence and incidence of these complications in different corticosteroid regimens are still unclear (28).
- #49 Induction therapy The indications for kidney biopsy are in the Box: Indications for Kidney Biopsy in Patients With SLE; the currently accepted classification system for biopsy results are in the Box: Histopathologic Classification of Lupus Nephritis. Class I or II lupus nephritis does not require immunosuppressive therapy. Class III or IV is treated aggressively. Until recently, the cyclophosphamide combined with IV glucocorticoids has been the standard of care for induction therapy of class III and IV lupus nephritis. Cyclophosphamide is an alkylating agent that promotes DNA cross-linking and affects T and B cell proliferation and antibody production. It is usually dosed according to total body surface area and adjusted for decreased creatinine clearance. Cyclophosphamide toxicity includes hematologic, infectious, urologic, reproductive, and rare pulmonary complications and bladder, skin, myeloproliferative, and oropharyngeal cancers. To date, there is no definitive evidence from clinical trials to guide clinicians on the dose of glucocorticoids for induction therapy of lupus nephritis. Current ACR recommendations are based on expert opinion and consensus. Early open label and RCTs showed short-term efficacy of glucocorticoids for treatment of lupus nephritis. Subsequently, an RCT comparing cyclophosphamide to glucocorticoids showed superiority of cyclophosphamide for induction therapy of proliferative lupus nephritis. Non-response was more common in the group treated with IV glucocorticoids and the probability of achieving remission was higher in the glucocorticoid plus cyclophosphamide group (32). Long-term follow-up of the study participants indicated that an increase in creatinine by 50% or 100% was less common in patients receiving combination treatment (33). Over the past decade, several studies demonstrated efficacy of mycophenolate mofetil for induction therapy in lupus nephritis (34–36). The drug is metabolized to mycophenolic acid, an inhibitor of inosine 5-monophosphate dehydrogenase, which is required for de novo synthesis of guanosine nucleotides. Mycophenolate mofetil inhibits lymphocyte proliferation, induces apoptosis of activated T cells, and inhibits adhesion molecule expression and fibroblast proliferation. Gastrointestinal toxicity is common and may respond to dose reduction or enteric coated formulation. Hematologic toxicity is also common, ranging from mild cytopenias to red cell aplasia. Mycophenolate mofetil is contraindicated in pregnancy because of case reports suggesting teratogenicity (37). In a meta-analysis of 4 selected RCTs evaluating the efficacy of mycophenolate mofetil vs. cyclophosphamide for induction, when data on maintenance therapy were excluded, mycophenolate mofetil was not superior to cyclophosphamide for induction treatment of lupus nephritis (36). Recently updated guidelines recommend using either cyclophosphamide or mycophenolate mofetil combined with glucocorticoids for induction therapy of class III or IV proliferative lupus nephritis (38). Response to cyclophosphamide or mycophenolate mofetil may differ based on race. Asians and Europeans seem to respond better to cyclophosphamide than Hispanics and African Americans (38). Box: Histopathologic classification of lupus nephritis Class I: minimal mesangial Class II: mesangial proliferative Class III: focal proliferative Class IV: diffuse proliferative (with active, active and chronic, or chronic lesions) Class V: Membranous (with or without co-existing class III or IV lupus nephritis) Class VI: advanced sclerosing lupus nephritis with >90% globally sclerotic glomeruli
- #50 Maintenance therapy Current guidelines recommend either mycophenolate mofetil or azathioprine for maintenance therapy in lupus nephritis. Both are superior to cyclophosphamide for this purpose (39). Evidence from 2 studies of comparative efficacy of mycophenolate mofetil vs. azathioprine is conflicting (40,41). Treatment duration is guided by clinical experience. In a study of 227 patients with lupus nephritis class III, IV or V, who showed a clinical response to a 24-week induction with either cyclophosphamide or mycophenolate mofetil patients were randomly assigned to treatment with mycophenolate mofetil (2 gm/d) or azathioprine (2 mg/kg/d). After 3 years of follow up, mycophenolate mofetil was significantly superior to azathioprine with respect to time to treatment failure (primary end point), time to renal flare, and time to rescue therapy (40). In contrast, an open-label study demonstrated no significant difference in patients treated with mycophenolate mofetil vs. azathioprine for maintenance treatment of lupus nephritis over a period of 4 years. All patients in this study were initially treated with low-dose cyclophosphamide for induction therapy (41). Calcineurin inhibitors such as cyclosporine are also used for maintenance therapy. A multicenter, randomized, open pilot trial compared the efficacy of cyclosporine vs. azathioprine for maintenance therapy of lupus nephritis. Seventy five patients with lupus nephritis IV, Vc or Vd, initially treated with IV glucocorticoids (1 mg/kg/3 d) followed by oral cyclophosphamide and prednisone for a median of 90 days, were randomized to treatment with azathioprine or cyclosporine for 2 (core study) and 4 years. Azathioprine and cyclosporine were equally effective in preventing disease flares, the primary outcome of the study. Proteinuria, a secondary end point, decreased significantly with both treatments. Blood pressure and creatinine clearance did not change significantly with either treatment; extrarenal manifestations and clinical activity decreased with both treatments (42). Data from this study indicate that cyclosporine and azathioprine are equally effective for maintenance treatment of lupus nephritis and have similar effects on blood pressure and renal function. Tacrolimus, also a calcineurin inhibitor, may be used to treat diffuse proliferative or membranous lupus nephritis. Meta analysis of data from open-label trials, case-control studies, and RCTs showed that tacrolimus may be effective as induction and maintenance therapy for lupus nephritis or in treatment of refractory lupus nephritis with persistent proteinuria (43). Rituximab is a monoclonal antibody directed against CD20, a membrane protein expressed on B-cells. Rituximab depletes B cells from the peripheral blood. Open-label trials indicated improvement of lupus nephritis after B-cell depletion; however RCTs did not show statistically significant response compared with placebo (44-46). Current ACR guidelines propose mycophenolate mofetil or azathioprine as preferred maintenance therapy for proliferative lupus nephritis. Calcineurin inhibitors or rituximab combined with glucocorticoids may be used for patients with inadequate response to cyclophosphamide or mycophenolate mofetil (38). To date, no RCT has directly compared calcineurin inhibitors to mycophenolate mofetil for maintenance treatment of class III or IV lupus nephritis.
- #51 Treatment of serious neuropsychiatric SLE manifestations is relatively empirical and includes IV glucocorticoids, immunoglobulin and cyclophosphamide. An RCT comparing cyclophosphamide to glucocorticoids after 3 days of IV immunoglobulin for treatment of transverse myelitis in lupus showed that relapse was more common in the steroid group. (51). Case reports and small, uncontrolled studies suggest beneficial effect of rituximab in treatment of neuropsychiatric lupus; however, the relapse rate seems to be high.
- #52 Pleuritis responds to treatment with NSAIDs and low to moderate doses of glucocorticoids. Immunosuppressive treatment is reserved for refractory cases. Diffuse alveolar hemorrhage presents abruptly, carries poor prognosis, and requires treatment with IV glucocorticoids and immunosupressants. Plasmapheresis may also be considered. Pulmonary hypertension is rare in SLE (0.5–17%) and may be secondary to vasculopathy, interstitial pulmonary fibrosis, or in situ thrombosis (52). SLE patients with pulmonary hypertension are at high risk for cardiac failure and early death. Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and prostacyclin analogs with or without immunosuppressive medications may be used to treat pulmonary hypertension in lupus. An RCT showed efficacy of cyclophosphamide in mild and moderate pulmonary hypertension in patients with SLE by reducing pulmonary artery systolic pressure and improving the New York Heart Association functional class (53). A retrospective study suggests that patients with SLE and mild to moderate pulmonary hypertension may respond to treatment with cyclophosphamide and glucocorticoids while patients with more severe disease may require combination of vasodilators with immunosuppressants (54). A small study indicated that interstitial lung disease treated with glucocorticoids for at least 1 week resulted in indolent progression or stabilization over time (55). Larger clinical trials have not been done, and treatment decisions are based on clinical experience. Azathioprine or cyclophosphamide is frequently recommended for patients who have not responded to glucocorticoids (56). Acute lupus pneumonitis requires treatment with high doses of glucocorticoids and cyclophosphamide.
- #53 Depending on the severity of the ocular involvement and the activity of the systemic disease, treatment may include antimalarial agtents, NSAIDs, or oral or IV glucocorticoids. Scleral or retinal involvement may require concomitant use of pulse glucocorticoids, followed by 1 mg/kg of prednisone equivalent, combined with immunosuppressive therapy (57). Retinal vasculitis and arterial or venous retinal occlusion in the presence of antiphospholipid antibodies may require concomitant use of immunosuppressive medications and antiplatelet agents or anticoagulation.
- #54 Laboratory testing should include a complete blood count, basic metabolic panel, and urinalysis on routine follow-up visits. These tests allow the clinician to evaluate for hematologic, renal, and other target-organ manifestations. Many clinicians also routinely test for double-stranded DNA antibodies and complement C3 and C4 levels; however, this practice is controversial for clinically stable patients. Although a prospective RCT showed that 4-week treatment with prednisone of clinically stable but serologically active patients averts a severe flare (61), C3 and C4 and double-stranded DNA antibodies are more useful in assessing SLE activity in symptomatic patients or in assessing response to treatment. Other monitoring should be tailored to individual disease manifestations (Table 3). Consideration should be given to laboratory monitoring for immunosuppressive medication toxicity and ophthalmologic evaluation of patients treated with hydroxychloroquine, particularly those older than 40 years who have been treated for a long period. Clinicians should be alert to osteoporosis prevention and prescribe treatment when appropriate. Clinicians should also consider periodic lipid testing and order lipid-lowering agents, as needed.
- #55 All patients with SLE should receive influenza and pneumococcal vaccinations. In addition, a recent study showed that the quadrivalent human papillomavirus vaccine is well tolerated and reasonably effective in patients with stable SLE and does not induce an increase in lupus activity or flares (62). Patients receiving immunosuppressive therapy or on daily prednisone >20 mg, should not receive live attenuated vaccines, including herpes zoster (shingles), Flumist, measles-mumps-rubella, and smallpox. Tuberculin skin testing is recommended for SLE patients requiring prolonged treatment with glucocorticoids or immunosuppressive therapy.
- #56 Fertility is not significantly affected in SLE; however, SLE flares at a higher rate during pregnancy and the immediate post-partum period. The presence of anti-SSA antibodies may predict adverse pregnancy outcomes, as may other factors, including antiphopsholipid antibodies, renal disease, thrombocytopenia, hypertension, and the use of prednisone. Becoming pregnant during clinical remission correlates with lower frequency and severity of lupus exacerbations. The initial presentation of SLE with hematologic or renal manifestations during pregnancy is not uncommon. Clinicians should also consider pregnancy-related hematologic, vascular and renal abnormalities that mimic SLE manifestations, including eclampsia and the HELLP syndrome (a group of symptoms that occur in pregnant women with hemolysis, elevated liver enzymes, and low platelet count). Antimalarials can be used safely in pregnant SLE patients (63). Active lupus manifestations in pregnancy are usually treated with hydroxychloroquine and prednisone. It is advisable to continue hydroxychloroquine in pregnancy because discontinuation is associated with increased risk for flares and pregnancy is associated with risk for increased disease activity. Hydroxychloroquine may also offer protection against cardiac manifestations of neonatal lupus (65). For severe manifestions, IV glucocorticoids and azathioprine may be considered because azathioprine has not been identified as a human teratogen (64). Mycophenolate mofetil, cyclophosphamide or methotrexate are contraindicated due to potential teratogenicity.
- #57 Patients with serious complications should be hospitalized. Indications include severe thrombocytopenia, severe or rapidly progressive renal disease, suspected lupus pneumonitis or pulmonary hemorrhage, and severe cardiovascular or CNS manifestations. A major cause of death in SLE is infection, including infection from opportunistic pathogens. SLE patients with unexplained fever should be hospitalized for evaluation and initiation of treatment with antibiotics. Empirical coverage should include Staphyloccocus aureus, Pseudomonas species, Klebsiella species, Escherichia coli, and Acinetobacter species. Chest pain in lupus patients could be due to coronary artery disease, serositis, pulmonary embolism, or esophageal disease. Lupus increases the risk for endothelial dysfunction, and long-term treatment with steroids increases traditional risk factors for coronary artery disease (65). Neurologic symptoms in lupus patients may be due to neuropsychiatric lupus, infection, the antiphospholipid syndrome, or hypertension. All lupus patients with acute neurologic manifestations should be admitted and rapidly evaluated with appropriate imaging, cerebrovascular fluid analysis, echocardiogram, and laboratory studies.