Systemic Lupus Erythematosus

Systemic lupus erythematosus, SLE, SLE Nephritis, SLE management, SLE classification, ACR vs SLICC criteria, New Drugs in SLE.

1. SYSTEMIC LUPUS ERYTHEMATOSUS June 1& 8, 2015

2. Outline Introduction : Definition, epidemiology Pathogenesis : Etiology , Risk factors, pathology. Diagnosis : SLICC 2012 v/s ACR 1997. Autoantibodies in Lupus. Systemic Manifestations : overview and life threatening complications. Management : Therapies old and new, special conditions, monitoring disease activity, Flare definition and management, pipeline therapies.

3. Systemic Lupus Inflammatory multisystem disease. Women>Men- 9:1 ratio. 90 % cases are women of childbearing age. African Americans>Whites. Onset usually between ages 15 and 45 years, but can occur in childhood or later in life. Highly variable course and prognosis, ranges from mild to life threatening. Characterized by flares and remissions. Tissue-binding autoantibodies and immune complexes.

4. Systemic Lupus Incidence & Prevalence : increasing Improved survival, diagnosing milder cases. Geographical variability : African-Americans > Caucasians (3x) Asian-American and Hispanics > Caucasians Age at diagnosis: 16-55 years of age: 65% of cases < 16: 20% > 65: 15% US UK Japan Incidence (per 100000 per year) 5.1 3.8 2.9 Prevalence (per 100000) 52.2 26.2 28.4

5. Lupus : History Lupus means “wolf” in Latin. 10 th century- 1 st used medically in c ase reports. Described clinically in the 19 th century Butterfly rash in 1845 Arthritis in 1892 Nephritis in 1895 by Osler Serologic tests become available in the 20 th century LE cell in 1948 Lupus anticoagulant in 1952 ANA in 1954 1971- First set of classification criteria.

6. Pathogenesis Genetics Abnormal Immune response Environment

7. Genetic Factors

8. Environmental Triggers UV light (A2 and B component) Gender ( female > male, Estrogen ) EBV Vitamin D deficiency Other organic compounds. Silica dust, solvents, petroleum products, Smoking. Drugs Long list : Sulfonamide , Hydralazine, Isoniazid, d- Penicillamine , Antiarrhythmic drugs : Propafenone , procainamide, disopyramide… Interferons and TNF inhibitors.

9. Activation of innate immunity. Lowered activation thresholds and abnormal activation pathways. Ineffective regulation of CD4+ and CD8+ T cells, B cells and myeloid derived suppressor cells. Reduced clearance of immune complexes and apoptotic cells.

10. Development of Autoantibodies Formation of Antinuclear antibodies

11. Mechanisms of organ damage

12. Organ damage Cytokines involved in tissue injury / organ damage in lupus include : B cell maturation/survival cytokines B-Lymphocyte Stimulator ( BLyS /BAFF). Interlukin 6, 17, 18. Proinflammatory type 1 and 2 interferons (IFNs)

13. Autoantibodies in SLE Antibody Prevalence Antigen recognized ANA 98 % Multiple nuclear antigens Anti- dsDNA 70 Double stranded DNA Anti- Sm 25 Protein complexed to 6 species of nuclear U1 RNA Anti-RNP 40 Protein complexed to U1 RNA Anti-Ro (SS-A) 30 Protein complexed to hY RNA (60kDa and 52 kDa ) Anti-La (SS-B) 10 Protein complexed to hyRNA (47 – kDa ) Antihistone 70 Histone proteins associated with DNA. Antiphospholipid 50 β 2 G1, Phospholipids, prothrombin Antierytherocyte 60 RBC membrane Antiplatelet 30 Surface and altered cytoplasmic antigens on platlets Antineuronal 60 Neuronal and lymphocyte surface antigens Antiribosomal P 20 Ribosomal protein

14. Clinical relevance : Autoantibodies ANA High sensitivity, low specificity. Best screening test Repeated negative tests makes SLE unlikely Can be positive in upto 10-15% of normal individuals.   I mmunofluorescent technique (IF ) more reliable than ELISA and/or bead assays.

15. Clinical relevance : Autoantibodies Anti dsDNA High titers : Specific 60% sensitivity. In some, Correlates with disease activity (Nephritis, vasculitis ) Anti- Sm Specific to SLE. More common in Blacks and Asians. No definite clinical correlation.

16. Clinical relevance : Autoantibodies Antiphospholipid Antibodies Ig G Anticardiolipin : High titres(>40 IU), Increased risk for clotting Anti β 2 glycoprotein. Lupus anticoagulant (By DRVVT ) Anti Ro/SS-A Non Specific Associated with : Sicca syndrome, Neonatal Lupus, Subacute cutaneous lupus Decreased risk for nephritis Women with childbearing potential and SLE should be screened for both Antiphospholipid and anti-Ro antibodies

17. Clinical relevance : Autoantibodies Anti RNP Non Specific, association with RA ( Rhupus ), black > white. Anti La/SS-B Decreased risk for nephritis, associated with anti Ro. Anti histone Drug induced lupus. Antierythrocyte Measured by DCT Antiplatelet N ot useful clinically Antineuronal Positivity in CSF : Active CNS Lupus Antiribosomal P Positivity in Serum : Depression, Psychosis in Lupus.

18. Diagnosis : SLE American Rheumatism Association (ARA) in 1982 (revised in 1997) proposed “criteria for classification "and not for diagnosis. Pitfalls of ACR 1997. Overly biased and weighted toward cutaneous lupus, with four cutaneous criteria. Omission of Hypocomplementemia . O nly psychosis and seizure were included. Biopsy-proven nephritis compatible with SLE was not included

19. Systemic Lupus International Collaborating Clinics (SLICC) classification 11 clinical and 6 immunological criteria The patient should satisfies atleast four of the criteria including at least one clinical criterion and one immunologic criterion. Biopsy-proven nephritis compatible with SLE in the presence of ANA or anti- dsDNA antibodies in the absence of other lupus features is regarded as sufficient for a patient to be diagnosed as having lupus.

20. Acute Cutaneous Lupus OR Subacute Cutaneous Lupus Acute cutaneous lupus:  lupus malar rash, bullous lupus, TENvariant of SLE, maculopapular lupus rash, photosensitive lupus rash (in the absence of dermatomyositis ). Subacute cutaneous lupus:  nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring.

21. Malar Rash Photosensitive lupus rash

22. Chronic Cutaneous Lupus Classic discoid rash localized (above the neck) or generalized (above and below the neck ) Hypertrophic ( verrucous ) lupus lupus panniculitis ( profundus ) M ucosal lupus lupus erythematosus tumidus chilblains lupus discoid lupus/lichen planus overlap

23. Classic Discoid Rash

24. Hypertrophic ( verrucous ) lupus Hypertrophic ( verrucous ) lupus

25. Lupus profundus Lupus affecting the fat underlying skin aka ‘lupus panniculitis ’. Dented scar and Nodule.

26. lupus erythematosus tumidus T umidus dermal form of lupus. C haracteristically photosensitive R ed , swollen, urticaria -like bumps and patches Ring-shaped (Annular)

27. Oral OR Nasal Ulcers Oral: palate, buccal , tongue Nasal ulcers In the absence of vasculitis , Behcet’s disease, infection ( herpesvirus ), inflammatory bowel disease, reactive arthritis, and acidic foods.

28. Nonscarring alopecia Diffuse thinning or hair fragility with visible broken hairs. Synovitis involving 2 or more joints Characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness

29. Serositis Typical pleurisy for > 1 day OR pleural effusions OR pleural rub Typical pericardial pain (pain with recumbency improved by sitting forward) for > 1 day OR pericardial effusion OR pericardial rub OR pericarditis by electrocardiography. Renal Urine PCR (or 24-hour urine protein) > 500 mg protein/24 hours OR RBC casts.

30. Neurologic Seizures, psychosis, mononeuritis multiplex. M yelitis , peripheral or cranial neuropathy. A cute confusional state.

31. Hemolytic anemia . Leukopenia (<4000/mm3) OR Lymphopenia (< 1000/mm3). Thrombocytopenia (<100,000/mm3 ).

32. IMMUNOLOGIC CRITERIA ANA > reference negative value. Anti-ds DNA Anti- Sm Anti phospholipid Low serum complement Positive direct Coomb’s test

33. SLICC : What's new Non scarring alopecia added as new entity. Old Hematological divided into 3. Inclusion of mononeuritis multiplex, myelitis , and acute confusional state in CNS manifestation. Biopsy proven lupus nephritis Addition of Low complement levels in immune criteria. Antiphospholipid antibodies.

34. Performance of the SLICC as compared to old ACR criteria SLICC : Sensitivity and specificity were 94% and 93%. ACR 1997: Sensitivity and specificity were 86% 93%. The new criteria retain the specificity while being more sensitive . The new criteria retains the goal of simplicity of use, yet reflects current knowledge of SLE obtained in 29 years since the initial ACR criteria.

35. Systemic Manifestations : Overview Prevalence, % Manifestations

36. Musculoskeletal I ntermittent polyarthritis soft tissue swelling and tenderness in joints and/or tendons (hand, wrist, knee) Joint deformities develop in only 10 % I ndividuals having rheumatoid-like arthritis with erosions who fulfill criteria for both RA and SLE (" rhupus ") may be coded as having both diseases.

37. Renal Manifestations One of most serious manifestation. Classification of Lupus Nephritis is purely histologic. Renal biopsy indicated in every SLE patient with evidence of nephritis. UPCR >0.5, RBC casts. Nephrotic Syndrome ESRD

38. ISN/RPS classification of lupus nephritis Class I Minimal mesangial lupus nephritis (Light microscopy : Normal glomeruli) Class II Mesangial proliferative LN (few isolated subepithelial /endothelial deposits visible by IF or electron microscopy) Class III Focal lupus nephritis (<50% glomerulli , sub endothelial deposits ) III A Active lesions III A/C Active and Chronic Lesions III C Chronic Lesions Class IV Diffuse lupus nephritis ( >50% glomeruli involved, Segmental and Global lesions) IV – S (A) Active lesions - Diffuse segmental proliferative lupus nephritis IV – G (A) Active lesions - Diffuse global proliferative lupus nephritis IV – S (A/C) Active & chronic lesions - Diffuse segmental proliferative & sclerosing lupus nephritis IV – G (A/C) Active & chronic lesions - Diffuse global proliferative & sclerosing lupus nephritis IV – S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis IV – G (C) Chronic inactive lesions with scars - Diffuse segmental global lupus nephritis Class V Membranous lupus nephritis Class VI Advanced sclerosing lupus nephritis

39. Neurological Manifestations C ognitive dysfunction D ifficulty with memory and reasoning Headaches, when excruciating, often indicates SLE flare Psychosis : must be distinguished from glucocorticoid induced psychosis. Disabling myelopathy. Stroke, TIAs Aseptic meningitis.

40. Cutaneous Photosensitivity Malar rash Oral Ulcers Alopecia Discoid Rash Vasculitis rash Urticaria

41. Cardiopulmonary Pleuritic Chest pain, pleural effusion. Pericarditis, pericardial effusion, tamponade . Myocarditis Coronary artery disease. Lupus pneumonitis. Interstitial fibrosis. Pulmonary HTN Alveolar hemorrhage , ARDS.

42. Gastrointestinal Nausea, vomiting, diarrohea , pain abdomen. Transaminitis . Mesenteric Vasculitis pancreatitis

43. Hematologic Anemia (chronic disease) Leukopenia Lymphopenia Thrombocytopenia Lymphadenopathy Splenomegaly Auto Immune Haemolytic anemia

44. Life threatening complications Cutaneous Digital Gangrene Cutaneous Necrosis Thrombocytopenia Autoimmune Hemolytic Anemia Catastrophic Antiphospholipid Syndrome. Pericardial Tamponade Myocarditis Pulmonary Alveolar Hemorrhage Myelitis Mesenteric Vasculitis

45. Management : SLE No cure. Complete sustained remission, rare. Mainstay : Supress symptoms and prevent organ damage. Depends on severity of disease. Prevention of complications of disease and its treatment.

46. Management : Algorithm

47. Management : Algorithm

48. Management : SLE Non life- or organ –threatening. Non Pharmacological conservative, Risk factor modification. Addition of Low dose Corticosteroids, belimumab . Life- or organ –threatening. Nephritis, Myelitis, vasculitis . High dose iv steroids + Immunosuppressant. Special conditions Pregnancy, Dermatitis, Thrombotic crisis.

49. Therapies Available Glucocorticoids. Antimalarials . NSAIDs ( Asprin ) Biologicals . Cyclophosphamide Mycophenolate mofetil Azathioprine Methotrexate Tacrolimus Lefunomide IV Ig FDA approved. “Off label” but standard of care “Borrowed drugs”

50. Nonpharmacological management S unscreens, SPF atleast 30, prefered ≥ 55. Smoking cessation. Weight loss. Exercise. Optimal Blood pressure control. Supplemental Vit D. Avoid High-dose oestrogen therapy, Oral contraceptive * Avoids culprit meds : Sulphonamides. Avoid pregnancy

51. Nonpharmacological management S unscreens, SPF atleast 30, prefered ≥ 55. Smoking cessation. Weight loss. Exercise. Optimal Blood pressure control. Supplemental Vit D. Avoid High-dose oestrogen therapy, Oral contraceptive * Avoids culprit meds : Sulphonamides. Avoid pregnancy

52. Pharmacological therapies

53. NSAIDs For minor symptoms. A rthralgia , musculoskeletal, fever, headaches and mild serositis . S hort periods only. Adverse effects : Aseptic meningitis, Transaminitis , Decreased renal function, GI bleed, Vasculitis . (NSAID) All esp. COX 2 inhibitors : increase risk of MI

54. Glucocorticoids Rapidly reduce inflammation. M odulate innate and adaptive immune response. Dosages : depend on severity. Low dose prednisone (0.1–0.2 mg/kg) Mild SLE cutaneous and musculoskeletal symptoms Medium dose prednisone (0.5 mg/kg) Moderate SLE Pleuropericarditis or Hematological manifestsations High dose oral prednisone (1.0–1.5 mg/kg) or IV methylprednisolone (1 g or 15 mg/kg) Severe disease renal or neuropsychiatric manifestations or vasculitis

55. Glucocorticoids ( Contd …) long-term adverse effects Infections, HTN, Hyperglycemia , Acne, Asptic necrosis of bones, Cushings syndrome, CHF, Fragile Skin, Insomnia, Menstrual irregularities, osteoporosis, psychosis… Add calcium (1,500 mg / day ) & vitamin D (800 IU/day), If prednisone or equivalent ≥ 5 mg / day.

56. Antimalarial agents MOA : Inhibit endosome function ? Disrupt class II MHC Decreasing antigen presentation. Activates endosomal TLR: decrease IFN α . Use : constitutional, musculoskeletal, skin and mild pleuritic symptoms. Dose : 200-400 mg daily. Adverse effects :Retinal damage, agranulocytosis, aplastic anemia , cardiomyopathy, myopathy, peripheral neuropathy, pigmentation of skin, Quinacrine : diffuse yellow skin.

57. Cyclophosphamide A lkylating agent, Cross-links DNA and suppress DNA synthesis, Prevents division of cells. For lupus nephritis, neuropsychiatric lupus, severe systemic vasculitis . D osing Protocols. NIH : I/V CPM (0.5–1.0 g/m 2 bsa ) once / month X 6  months, f/b once / 3 months for 2  years . Euro Lupus : I/V CPM 500 mg / 2 weeks X 3  months, f/b AZA or NIH regimen as maintenance.

58. Cyclophosphamide In comparative study no significant difference between NIH and Euro Lupus. Adverse reactions : Severe infections, alopecia, lymphomas and bladder Ca and infertility. I/V mesna decrease risk of bladder Ca. Gonadotropin releasing hormone use prevents premature ovarian failure.

59. Azathioprine Purine analogue, inhibits synthesis of xanthylic and adenylic acids, supress DNA synthesis. Use : systemic features of lupus, & maintenance dose for Lupus Nephritis, ISN class III & IV. Option as induction agent in patients with LN, concerned with risk of infertility with CPM.

60. Azathioprine Dosage : For Induction : 2 - 3 mg/kg/day PO; For maintenance : 1 -2 mg/kg/day; If CrCI < 50 ml/min, decrease frequency. Adverse effects : BM suppression, GI intolerance, hypersensitivity and hepatotoxicity. induction therapy for selected

61. Mycophenolate M ofetil M onophosphate dehydrogenase Inhibitor, blocks synthesis of guanosine nucleotides and proliferation of T and B cells. Use : I nduction and maintenance therapy in lupus nephritis & moderate to severe SLE. NB : M ore effective in Hispanic, African- A mericans and non- A sians, non white races with lupus nephritis, compared to CPM.

62. Mycophenolate M ofetil Dosages : MMF For Induction : 2-3 g/d PO. For maintenance : 1 -2 g/d. Adverse Effects : Nausea, abdominal pain, diarrhoea, myelosuppression and infections.

63. Methotrexate F olate antimetabolite, inhibits DNA synthesis. Use : for musculoskeletal manifestations, also good for serositis and to some extent for skin manifestations. Dosage : 10-25 mg/week PO or SC along with folic acid. Requires dose modification renal impairment. Adverse Effects : stomatitis , bone marrow suppression , hepatitis, alopecia and pneumonitis, pulmonary fibrosis.

64. Biologicals

65. B elimumab F ully human monoclonal antibody against B lymphocyte stimulator ( BLyS ), important for survival of B cells. FDA approved. Use : reduce disease activity in SLE patients with mild–moderate disease , without severe renal or central nervous system. (FDA approved)

66. B elimumab Dose : 10 mg/kg IV wks 0, 2 and 4, then monthly. Generally, well tolerated, not associated with a high rate of adverse events.

67. Rituximab C himeric mouse/human monoclonal antibody specific for human CD20. Selectively Depletes CD20+ mature B cells from circulation. Use : For non responders to above therapy.

68. Rituximab Currently, not approved for SLE. Only in patients with refractory disease esp. cytopenia , nephritis or neuropsychiatric lupus. Dose : 375 mg/m 2 / wk x 4 or 1g/2 wks x 2, along with corticosteroids and other immunosuppressive agents. Infection (including PML), infusion reactions, headache, arrhythmias, allergic responses.

69. IV Immunoglobulin Off -label use in catastrophic antiphospholipid syndrome. M echanism of action of IVIG in SLE t/t not clear. Small clinical trials, have reported variable efficacy of IVIG. Off label : in patients with refractory SLE, concomitant infection.

70. Therapy for specific SLE manifestations

71. M ainstay of treatment for any inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids. P ulse, 1 g of methylprednisolone IV daily for 3 days followed by high dose (0.5- 1 mg/kg/day) prednisone or equivalent.

72. Lupus Nephritis In Mild disease : Start with hydroxychloroquine, RAAS blockers, manage proteinuria and hypertension. Treatment with hydroxychloroquine have higher rates of renal response, fewer relapses, and reduced accrual of renal damage.

73. Lupus Nephritis Patients with ISN grade III or IV disease, treatment with GCs and CPM reduce progression to ESRD and death. For Induction : GCs + CPM or MMF Both CPM and MMF were found to be equally effictive . MMF preferred in Hispanic, African-Americans and non-Asians, non white races .

74. Lupus Nephritis Azathioprine (AZA) may be effective for induction but is slower to influence response and associated with more flares. For Maintenance : either MMF or AZA can be used, in some studies MMF was found more efficacious. For Refractory cases : consider rituximab / alternate therapy.

75. Crescentic Lupus Nephritis Crescents in glomeruli have got worse prognosis. Currently only High dose CPM with High-Dose GC, in induction phase is recommended.

76. Membranous Lupus Nephritis Classified as ISN class V, have proliferative changes. In pure Membranous variant, immunosuppression is not recommended unless proteinuria in nephrotic range. ACE inhibitors and ARB’s are recommended. Alternate day GC’s plus CPM/ MMF / Cyclosporine all effective in reducing proteinuria.

77. Pregnancy and Lupus Lupus does not affects fertility. Rate of fetal loss increased. Demise is higher in mothers with high disease activity SLE nephritis APLA Women with AntiRo SSA need additional monitoring, high risk for neonatal Lupus. APLA with SLE treated with heparin and low dose Asprin .

78. Pregnancy and Lupus Glucocorticoids are Category A Cyclosporin , Tacrolimus Rituximab in Category C AZA, HCQs, MMF, CPM as category D (benefits outweighs risk) MTX is Cat X (risk outweighs benefits) Mgx : HCQs and if required prednisone at lowest dose for short time. AZA may be added. Breast feeding should be avoided ( glucocorticoids and immunosuppressants get into breast milk).

79. Neonatal Lupus Rare condition Not true lupus, passively transferred autoimmune disease Transplacental transfer of IgG anti SSA or SSB antibodies 5-7% transient rash, resolves by 6-8 months 2% cardiac complications, congenital heart block .

80. Neonatal Lupus Trans-placental fluorinated corticosteroids, dexamethasone and betamethasone . Hydroxychloroquine during pregnancy associated with reduced rates of NLS. IVIg was reported to prevent recurrence of CHB in one study , but two large RCTs failed to show any beneficial effect.

81. Drug Induced Lupus Appears during therapy. Fever, malaise, arthritis, intense arthralgia, myalgia, serositis , and or rash (less common). ANA positivity very high. Differs from SLE White predominance, less female predilection, rare involvement of kidneys or brain. Commonly antihistone antibody positive, Anti dsDNA and RNP rare Management: Withdraw offending drug Low doses of systemic corticosteroids if severe disease.

82. Microvascular Thrombotic Crisis Hemolysis , thrombocytopenia, and microvascular thrombosis in kidneys, brain and other tissues. High mortility . LAB : PS shows schistocytes , LDH is elevated, Antibodies to ADAMS13. Management : Plasma exchange, along with GC therapy.

83. Lupus and a ntiphospholipid syndrome Repeated fetal losses, venous or arterial clotting, with atleast 2 positive tests for APLA( 12 weeks apart) . Target INR B etween 2.0 – 2.5 (One episode of venous clotting). Between 3.0 – 3.5 (recurring clots or arterial clotting) Heparin and Warfarin. S tatins, hydroxychloroquine , and rituximab might be useful.

84. Disease Activity Assessment WHY IMPORTANT..?? For quantification of lupus disease activity primarily to check effectiveness of a new drug. N ot used in routine medical practice.

85. Disease Activity Assessment Most commonly used disease activity instruments SLEDAI SLEDAI, SLEDAI-2000, SRI-50 SELENA-SLEDAI BILAG Classic and BILAG 2004 Composite indices SRI BICLA

86. SLEDAI 24 lupus manifestations Parameters scored only if present ( ie active lupus) 1 6 Clinical, 8 lab parameters. Manifestation items are weighted with scores 1 to 8. Total score is sum Mild : 0-5 Moderate : 6-12 Severe: 13-20 Score reduction requires complete resolution. 3 to 7 point reduction = clinically meaningful improvement.

87. SLEDAI Limitations Cannot measure partial improvement of individual parameter. Cannot measure worsening of an existing abnormality Some items are “unfairly” scored ( eg thrombocytopenia)

88. SELENA-SLEDAI S eizures that are due to past irreversible central nervous system damage are excluded. Some other descriptors were modified like “cerebrovascular accident” was modified to exclude hypertensive cause. Detects less severe items than SLEDAI 2K. Easy to use.

89. BILAG Measures improvement/ worsening in disease activity by organ system domain. Individual parameters grouped into 9 organ domains and scored: 0,1,2,3,4 meaning “not present”, “improving” , “same” , “worse” and “new” respectively. made with intention to treat. Scores A to E, A = severe disease activity; E = no activity.

90. Composite Responder Indices For assessing disease activity in response to therapy. Identify both improvement and worsening in same and different organ system.

91. Take home message SLE : Multifactorial disease. No cure, but disease activity can be limited if detected early and remissions can be reached. Management : requires both lifestyle modification and pharmacotherapy. Severe disease : managed by GC’s and Immunosuppressants . Disease activity assessment : For future prospects.