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SLE Incurable Multisystemic autoimmune disease Predominantly women 1:9

Median age of disease onset Afro-carribean: 26yrs Asian: 33yrs Caucasian: 33yrs

Mortality 10 year survival rate

SLE- Emerging therapies Mycophenolate mofitil Anti-CD20 CTLA4Ig Anti-IL6R Anti-BlyS Abetimus (LJP-394)

SLE Commonest CTD after Rheumatoid

Prevalence of SLE in South London Afro-Caribbeans 1.7 / 1,000 (CI 1.3-2.2) West African 1.1 / 1,000 (CI 0.58-1.6) Caucasians 0.35 / 1,000 (CI 0.26-0.4) Molokhia M et al. Systemic lupus erythematosus in migrants from west Africa compared with Afro-Caribbean people in the UK. Lancet. 2001 May 5;357(9266):1414-5.

What is Lupus? Multisystemic autoimmune disease Markedly Heterogeneous No definition American College of Rheumatology The 1982 revised criteria for the classification of systemic lupus erythematosus

Classification criteria (  4 of 11) Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurological disorder American College of Rheumatology The 1982 revised criteria for classification of systemic lupus erythematosus

Classification criteria (  4 of 11) 9. Haematological 10. ANA positivity 11. Immunological American College of Rheumatology The 1982 revised criteria for classification of systemic lupus erythematosus

Classification criteria (  4 of 11) Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurological disorder

Classification criteria (  4 of 11) Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurological disorder Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions

Classification criteria (  4 of 11) Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurological disorder Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

Lupus Nephritis Detected in clinic by: Urinalysis -blood, protein Blood pressure Microscopy

Glomerulonephritis Class I Normal Class II Mesangioproliferative Class III Focal Proliferative Class IV Diffuse Proliferative Class V Membraneous Class VI Sclerosing nephropathy

Neurological manifestations Fits Psychosis

Neurological manifestations Headache Chorea Cerebrovascular disease Cognitive dysfunction Transverse myelitis, optic neuritis Sensorineural hearing loss Coma

Classification criteria (  4 of 11) 9. Haematological Haem.  Hb  WBC,lymphos  Plts 10. ANA positivity 11. Immunological Anti-DNA, anti-Sm Anti-phospholipid

Haematological Autoimmune cytopenias Lymphopenia Autoimmune haemolytic anaemia Immune thrombocytopenia

Classification criteria (  4 of 11) 9. Haematological Haem.  Hb  WBC,lymphos  plts 10. ANA positivity 11. Immunological Anti-DNA, anti-Sm Anti-cardiolipin

Classification criteria (  4 of 11) 9. Haematological Haem.  Hb  WBC,lymphos  plts 10. ANA positivity 11. Immunological Anti-DNA, anti-Sm Anti-cardiolipin Lupus anticoagulant

Anti-Double stranded DNA Highly specific for SLE Occurs in up to 80% of patients Particularly associated with renal disease Titres correlate with activity

Anti-Smith (Anti-Sm) Highly specific for SLE Only occurs in 10-30% cases Strong association with renal disease Levels stable, no correlation to disease activity

Anti-cardiolipin and Lupus anticoagulant Strongly associated with anti-phospholipid syndrome May occur in the absence of SLE False positive VDRL

General features Fever LN Weight loss Myalgia (rarely myositis) Fatigue (common, acute, chronic)

Laboratory features ESR/CRP CRP>30-40=infection IgG/autoab (ANA) Anti-dsDNA Complement C3,C4

Extractable nuclear antigens -ENA Smith - Sm Ro La Ribonuclear protein - RNP

Management No drug is licensed for SLE Proliferative Glomerulonephritis -Class III/IV

Management Sunblock, education NSAID Antimalarials Hydroxychloroquine, mepacrine Thalidomide Corticosteroids Topical, low dose, or high dose (oral/im/iv)

Hydroxychoroquine No double blind prospective trials Double blind prospective withdrawal study 47patients-25 continued, 24 stopped 24 wks Risk of flare X2.5 higher placebo (95% CI 1.08-5.58) Risk of severe flare X6.1 higher (95% CI , 0.72-52.44) The Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991 Jan 17;324(3):150-4.

Hydroxychoroquine-Toxicity Alopecia Deposition in the cornea Diarrhoea Rash Myopathy Liver and haematological toxicity

Hydroxychoroquine- Retinal toxicity Increase risk Doses over 6.5mg/kg Cumulative dose over 800g Increased age Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. 1997 Aug;40(8):1482-6. 1 patient with definite toxicity (1 of 1,207; 0.08%) other patients with indeterminate but probable toxicity (5 of 1,207; 0.4%).

Hydroxychoroquine Rare instances of congenital defects in malarial prophylaxis doses Sensorineural hearing loss and cleft plate Reduce dose in renal impairment Caution hepatic disease Mepacrine negligible retinal toxicity

Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Petri et al. Am J Med. 1994 Mar;96(3):254-9. longitudinal cohort study of 264 patients 3,027 patient visits Regression analysis

HCQ 200+ 400mg associated with lower serum cholesterol (8.9 +/- 3.44 SE mg%). A change in prednisone dose of 10 mg was associated with a change in cholesterol of 7.5 +/- 1.46 (SE) mg% A 10-mg change in prednisone dose led to a change in mean arterial blood pressure of 1.1 mm Hg

Immunosuppressants Cyclophosphamide Azathioprine Methotrexate Mycophenolate Mofetil

Cyclophosphamide NIH trials Superiority in Prolif Nephritis High dose iv cyclopho VS steroid alone For induction Austin et al NEJM 1986 Maintenance Boumpas et al Lancet 1992

Cyclophosphamide Side effects High dose 0.5-1g/m2 Monthly thence quarterly Estimates of infertility 23-41% Infection Bladder cancer -Mesna

Randomized study of maintenance Rx Cyclo, azathioprine and MMF Contreras, G. et al. N Engl J Med 2004;350:971-980

Randomized study of maintenance Rx Cyclo, azathioprine and MMF Contreras, G. et al. N Engl J Med 2004;350:971-980 Kaplan-Meier Estimates of Relapse-free Survival

Induction therapy: Mycophenolate Mofetil Vs Cyclophosphamide Chan, T. M. et al. N Engl J Med 2000;343:1156-1162 Outcome of Treatment Chan, T. M. et al. N Engl J Med 2000;343:1156-1162

Chan, T. M. et al. N Engl J Med 2000;343:1156-1162 Mean ({+/-}SD) Serum Albumin Concentration and Urinary Protein Excretion in Patients with Diffuse Proliferative Lupus Nephritis Who Were Treated with Mycophenolate Mofetil and Prednisolone (Group 1) or with Cyclophosphamide and Prednisolone Followed by Azathioprine and Prednisolone (Group 2)

Long-Term Study of Mycophenolate Mofetil as Continuous Induction and Maintenance Treatment for Diffuse Proliferative Lupus Nephritis. Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK. J Am Soc Nephrol. 2005 Feb 23 Cyclo + azathioprine 31pts Mycophenolate 33pts All class IV 63 month median F/U

Long-Term Study of Mycophenolate Mofetil as Continuous Induction and Maintenance Treatment for Diffuse Proliferative Lupus Nephritis. Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK. J Am Soc Nephrol. 2005 Feb 23 No difference in outcomes ESRF or death 4 vs 0 (NS P=0.062) Significantly less infections (p = 0.013) infections requiring hospitalisation (p=0.014 )

Mycophenolate Mofetil Hydrolysed to Mycophenolic acid Inhibits inosine monophosphate dehydrogenase Blocks de novo synthesis guanosine nucleosides Suppresses lymphocyte proliferation Suppresses glycosylation of adhesion molecules

Mycophenolate Mofetil Side effects Diarrhoea Lymphopenia Infection Increasingly used in non-renal lupus

Azathioprine Maintenance therapy, steroid sparing, Class II LN Bone marrow suppression- neutropenia Hepatitic liver toxicity Thiopurine methyl transferase (TPMT)

Anti-CD20 therapy Rituximab Chimeric mouse/human antibody IgG1/ κ Anti-CD20 Depletes pre-B - mature B-lymphocytes Spares lymphoid precursors and plasma cells.

Rituximab Licensed for use in B-cell NHL Not associated with increased risk of infection.

B-Cell Characteristics Express surface immunoglobulin Antigen uptake via surface immunoglobulin for processing and presentation Provides cognitive help for T-cells Produces cytokines e.g. IL-4 and IL-10 Constitutive production of antibodies by plasma cells

Rituximab in SLE No control clinical trials in SLE Several case series suggesting benefit Leandro et al 21 patients Looney et al 17 patients Van Vollenhoven et al 15 patients Sfikakis et al 10 patients Albert et al 8 patients Tanaka et al 7 patients Ryan et al 4 patients

Leandro et al ACR 2004 Abs1126 21 patients with active SLE Treated Day 1 Methylpred 750mg Rituximab 1g Day 2 Cyclophosphamide 750mg Day 14 Rpt day 1 Day 15 Rpt day 2

Leandro et al ACR 2004 Abs1126 20/21 successfully B-cell depleted (<5 CD19+ B cells/ μ l). Time to repopulation 3-8/12, 1pt >3yrs Mean serum Ig levels decreased within Normal range

Leandro et al ACR 2004 Abs1126 Follow up 3-46 months (mean 19) Response in all patients with B-cell depletion 9 pts - no other I/S therapy at 12-46/12

Leandro et al ACR 2004 Abs1126 Response seen in all aspects of the BILAG Particularly: Fatigue arthralgia/arthritis serositis nephritis thrombocytopenia and haemolytic anaemia

Leandro et al ACR 2004 Abs1126 1 serious infusion reaction No serious or opportunistic infections 1 patient HACA on retreatment

First 7 patients dsDNA reduced by 53% (0-93%) at 6/12 dsDNA, histone signif reduced(p<0.005) at 12/12 Cambridge et al. ACR 2004 abs1723

ENA behaved differently in different patients RNP, SSA NS Significant rise in Sm at 6 months (p<0.05) PCP, TT no change Cambridge et al. ACR 2004 abs1723

Looney et al Arthritis Rheum. 2004;50:2580-9 A phase I/II dose-escalation trial Rituximab single infusion of 100 mg/m 2 (low dose) single infusion of 375 mg/m 2 (intermediate dose) 4 infusions(1 wk apart) of 375 mg/m 2 (high dose).

Looney et al Arthritis Rheum. 2004;50:2580-9 11/17 had profound B cell depletion (<5 CD19+ B cells/ μ l). Low dose 4/6 Intermediate 4/7 High dose 3/4

Looney et al Arthritis Rheum. 2004;50:2580-9 B-cell depleters SLAM score improved at 2/12 and 3/12 P = 0.0016 and P = 0.002, paired t-test Improvement persisted for 12 months Arthritis, rashes, mucositis and alopecia.

Looney et al Arthritis Rheum. 2004;50:2580-9 Absence of a significant change in anti-double-stranded DNA antibody and complement levels Six patients developed human antichimeric antibodies (HACAs) at a level > / =100 ng/ml

Cyclophosphamide and Rituximab Leandro et al 20/21 cyclo Van Vollenhoven et al 15/15 cyclo Looney et al 11/17 Sfikakis et al 8/10 Albert et al 6/8 Tanaka et al 7/7 Ryan et al 4/4 71/82 = 85%

Cyclophosphamide and Rituximab Cyclophos 35/36 97% No Cyclophos 36/46 78% p=0.019 Exclude dose escalating trial No Cyclophos 25/29 86% p=0.164

Rituximab Preliminary data promising in SLE Role of cyclophosphamide unclear Remission up to 3 years HACA 1% Lymphoma 4% RA 8% SLE

Rituximab Needs double blind controlled clinical trial

Sponsored by Arthritis Research Campaign SEcond Line Agents in Myositis

TRIAL DESIGN: A double-blind, randomised, placebo controlled trial comparing: steroids alone, steroids plus methotrexate, steroids plus ciclosporin, steroids plus methotrexate plus ciclosporin .

INCLUSION CRITERIA Polymyositis or Dermatomyositis Myositis secondary to other CTD Receiving prednisolone Active disease and muscle weakness

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