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  • Figure 3. Kaplan-Meier Estimates of Relapse-free Survival.
  • Table 3. Outcome of Treatment.
  • Figure 2. 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). The mean serum albumin concentration was significantly higher than the base-line value after two weeks of therapy in group 2 and after four weeks of therapy in group 1, and it remained significantly higher at each subsequent evaluation (P<0.05 for the comparisons in each group). Urinary protein excretion was significantly lower than the base-line value after two weeks of therapy in group 1 and after four weeks of therapy in group 2, and it remained significantly lower at each subsequent evaluation (P<0.05 for the comparisons in each group). The numbers below the panels are numbers of patients for whom data were available.
  • S Lecture

    1. 1. Systemic Lupus Erythematosus
    2. 2. SLE <ul><li>Incurable Multisystemic autoimmune disease </li></ul><ul><li>Predominantly women 1:9 </li></ul>
    3. 3. Median age of disease onset <ul><li>Afro-carribean: 26yrs </li></ul><ul><li>Asian: 33yrs </li></ul><ul><li>Caucasian: 33yrs </li></ul>
    4. 4. Mortality 10 year survival rate
    5. 5. SLE- Emerging therapies <ul><li>Mycophenolate mofitil </li></ul><ul><li>Anti-CD20 </li></ul><ul><li>CTLA4Ig </li></ul><ul><li>Anti-IL6R </li></ul><ul><li>Anti-BlyS </li></ul><ul><li>Abetimus (LJP-394) </li></ul>
    6. 6. SLE <ul><li>Commonest CTD after Rheumatoid </li></ul>
    7. 7. Prevalence of SLE in South London <ul><ul><li>Afro-Caribbeans 1.7 / 1,000 (CI 1.3-2.2) </li></ul></ul><ul><li>West African 1.1 / 1,000 (CI 0.58-1.6) </li></ul><ul><li>Caucasians 0.35 / 1,000 (CI 0.26-0.4) </li></ul><ul><ul><ul><li>Molokhia M et al. Systemic lupus erythematosus in migrants from west Africa compared with Afro-Caribbean people in the UK. </li></ul></ul></ul><ul><li>Lancet. 2001 May 5;357(9266):1414-5. </li></ul>
    8. 8. What is Lupus? <ul><li>Multisystemic autoimmune disease </li></ul><ul><li>Markedly Heterogeneous </li></ul><ul><li>No definition </li></ul><ul><li>American College of Rheumatology </li></ul><ul><li>The 1982 revised criteria for the classification of systemic lupus erythematosus </li></ul>
    9. 9. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>American College of Rheumatology The 1982 revised criteria for classification of systemic lupus erythematosus
    10. 10. Classification criteria (  4 of 11) <ul><li>9. Haematological </li></ul><ul><li>10. ANA positivity </li></ul><ul><li>11. Immunological </li></ul>American College of Rheumatology The 1982 revised criteria for classification of systemic lupus erythematosus
    11. 11. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    12. 12. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    13. 13. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
    14. 14. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    15. 15. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    16. 16. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
    17. 17. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    18. 18. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    19. 19. Lupus Nephritis <ul><li>Detected in clinic by: </li></ul><ul><li>Urinalysis -blood, protein </li></ul><ul><li>Blood pressure </li></ul><ul><li>Microscopy </li></ul>
    20. 20. Glomerulonephritis <ul><li>Class I Normal </li></ul><ul><li>Class II Mesangioproliferative </li></ul><ul><li>Class III Focal Proliferative </li></ul><ul><li>Class IV Diffuse Proliferative </li></ul><ul><li>Class V Membraneous </li></ul><ul><li>Class VI Sclerosing nephropathy </li></ul>
    21. 21. Classification criteria (  4 of 11) <ul><ul><li>Malar rash </li></ul></ul><ul><ul><li>Discoid rash </li></ul></ul><ul><ul><li>Photosensitivity </li></ul></ul><ul><ul><li>Oral ulcers </li></ul></ul><ul><ul><li>Arthritis </li></ul></ul><ul><ul><li>Serositis </li></ul></ul><ul><ul><li>Renal disorder </li></ul></ul><ul><ul><li>Neurological disorder </li></ul></ul>
    22. 22. Neurological manifestations <ul><li>Fits </li></ul><ul><li>Psychosis </li></ul>
    23. 23. Neurological manifestations <ul><li>Headache </li></ul><ul><li>Chorea </li></ul><ul><li>Cerebrovascular disease </li></ul><ul><li>Cognitive dysfunction </li></ul><ul><li>Transverse myelitis, optic neuritis </li></ul><ul><li>Sensorineural hearing loss </li></ul><ul><li>Coma </li></ul>
    24. 24. Classification criteria (  4 of 11) <ul><li>9. Haematological </li></ul><ul><ul><ul><ul><li>Haem.  Hb </li></ul></ul></ul></ul><ul><ul><ul><ul><li> WBC,lymphos </li></ul></ul></ul></ul><ul><ul><ul><ul><li> Plts </li></ul></ul></ul></ul><ul><li>10. ANA positivity </li></ul><ul><li>11. Immunological </li></ul><ul><ul><ul><ul><li>Anti-DNA, anti-Sm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Anti-phospholipid </li></ul></ul></ul></ul>
    25. 25. Haematological <ul><li>Autoimmune cytopenias </li></ul><ul><li>Lymphopenia </li></ul><ul><li>Autoimmune haemolytic anaemia </li></ul><ul><li>Immune thrombocytopenia </li></ul>
    26. 26. Classification criteria (  4 of 11) <ul><li>9. Haematological </li></ul><ul><ul><ul><ul><li>Haem.  Hb </li></ul></ul></ul></ul><ul><ul><ul><ul><li> WBC,lymphos </li></ul></ul></ul></ul><ul><ul><ul><ul><li> plts </li></ul></ul></ul></ul><ul><li>10. ANA positivity </li></ul><ul><li>11. Immunological </li></ul><ul><ul><ul><ul><li>Anti-DNA, anti-Sm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Anti-cardiolipin </li></ul></ul></ul></ul>
    27. 27. Classification criteria (  4 of 11) <ul><li>9. Haematological </li></ul><ul><ul><ul><ul><li>Haem.  Hb </li></ul></ul></ul></ul><ul><ul><ul><ul><li> WBC,lymphos </li></ul></ul></ul></ul><ul><ul><ul><ul><li> plts </li></ul></ul></ul></ul><ul><li>10. ANA positivity </li></ul><ul><li>11. Immunological </li></ul><ul><ul><ul><ul><li>Anti-DNA, anti-Sm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Anti-cardiolipin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lupus anticoagulant </li></ul></ul></ul></ul>
    28. 28. Anti-Double stranded DNA <ul><li>Highly specific for SLE </li></ul><ul><li>Occurs in up to 80% of patients </li></ul><ul><li>Particularly associated with renal disease </li></ul><ul><li>Titres correlate with activity </li></ul>
    29. 29. Anti-Smith (Anti-Sm) <ul><li>Highly specific for SLE </li></ul><ul><li>Only occurs in 10-30% cases </li></ul><ul><li>Strong association with renal disease </li></ul><ul><li>Levels stable, no correlation to disease activity </li></ul>
    30. 30. Anti-cardiolipin and Lupus anticoagulant <ul><li>Strongly associated with anti-phospholipid syndrome </li></ul><ul><li>May occur in the absence of SLE </li></ul><ul><li>False positive VDRL </li></ul>
    31. 31. General features <ul><li>Fever </li></ul><ul><li>LN </li></ul><ul><li>Weight loss </li></ul><ul><li>Myalgia (rarely myositis) </li></ul><ul><li>Fatigue (common, acute, chronic) </li></ul>
    32. 32. Laboratory features <ul><li>ESR/CRP </li></ul><ul><ul><ul><li>CRP>30-40=infection </li></ul></ul></ul><ul><li>IgG/autoab (ANA) </li></ul><ul><li>Anti-dsDNA </li></ul><ul><li>Complement </li></ul><ul><ul><ul><li>C3,C4 </li></ul></ul></ul>
    33. 33. Extractable nuclear antigens -ENA <ul><li>Smith - Sm </li></ul><ul><li>Ro </li></ul><ul><li>La </li></ul><ul><li>Ribonuclear protein - RNP </li></ul>
    34. 34. Management <ul><li>No drug is licensed for SLE </li></ul><ul><li>Proliferative Glomerulonephritis </li></ul><ul><li>-Class III/IV </li></ul>
    35. 35. Management <ul><li>Sunblock, education </li></ul><ul><li>NSAID </li></ul><ul><li>Antimalarials </li></ul><ul><ul><ul><li>Hydroxychloroquine, mepacrine </li></ul></ul></ul><ul><li>Thalidomide </li></ul><ul><li>Corticosteroids </li></ul><ul><ul><ul><li>Topical, low dose, or high dose (oral/im/iv) </li></ul></ul></ul>
    36. 36. Hydroxychoroquine <ul><li>No double blind prospective trials </li></ul><ul><li>Double blind prospective withdrawal study </li></ul><ul><li>47patients-25 continued, 24 stopped </li></ul><ul><li>24 wks </li></ul><ul><li>Risk of flare X2.5 higher placebo (95% CI 1.08-5.58) </li></ul><ul><li>Risk of severe flare X6.1 higher (95% CI , 0.72-52.44) </li></ul><ul><ul><li>The Canadian Hydroxychloroquine Study Group. </li></ul></ul><ul><li>N Engl J Med. 1991 Jan 17;324(3):150-4. </li></ul>
    37. 37. Hydroxychoroquine-Toxicity <ul><li>Alopecia </li></ul><ul><li>Deposition in the cornea </li></ul><ul><li>Diarrhoea </li></ul><ul><li>Rash </li></ul><ul><li>Myopathy </li></ul><ul><li>Liver and haematological toxicity </li></ul>
    38. 38. Hydroxychoroquine- Retinal toxicity <ul><li>Increase risk </li></ul><ul><li>Doses over 6.5mg/kg </li></ul><ul><li>Cumulative dose over 800g </li></ul><ul><li>Increased age </li></ul><ul><ul><li>Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. </li></ul></ul><ul><ul><li>1997 Aug;40(8):1482-6. </li></ul></ul><ul><ul><ul><li>1 patient with definite toxicity (1 of 1,207; 0.08%) </li></ul></ul></ul><ul><ul><ul><li>other patients with indeterminate but probable toxicity (5 of 1,207; 0.4%). </li></ul></ul></ul>
    39. 39. Hydroxychoroquine <ul><li>Rare instances of congenital defects in malarial prophylaxis doses </li></ul><ul><li>Sensorineural hearing loss and cleft plate </li></ul><ul><li>Reduce dose in renal impairment </li></ul><ul><li>Caution hepatic disease </li></ul><ul><li>Mepacrine negligible retinal toxicity </li></ul>
    40. 40. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. <ul><li>Petri et al. Am J Med. 1994 Mar;96(3):254-9. </li></ul><ul><ul><li>longitudinal cohort study of 264 patients </li></ul></ul><ul><ul><li>3,027 patient visits </li></ul></ul><ul><ul><li>Regression analysis </li></ul></ul>
    41. 41. <ul><ul><li>HCQ 200+ 400mg associated with lower serum cholesterol </li></ul></ul><ul><ul><li>(8.9 +/- 3.44 SE mg%). </li></ul></ul><ul><ul><ul><li>A change in prednisone dose of 10 mg was associated with a change in cholesterol of 7.5 +/- 1.46 (SE) mg% </li></ul></ul></ul><ul><ul><ul><li>A 10-mg change in prednisone dose led to a change in mean arterial blood pressure of 1.1 mm Hg </li></ul></ul></ul>
    42. 42. Immunosuppressants <ul><li>Cyclophosphamide </li></ul><ul><li>Azathioprine </li></ul><ul><li>Methotrexate </li></ul><ul><li>Mycophenolate Mofetil </li></ul>
    43. 43. Cyclophosphamide <ul><li>NIH trials </li></ul><ul><li>Superiority in Prolif Nephritis </li></ul><ul><li>High dose iv cyclopho VS steroid alone </li></ul><ul><li>For induction </li></ul><ul><li>Austin et al NEJM 1986 </li></ul><ul><li>Maintenance </li></ul><ul><li>Boumpas et al Lancet 1992 </li></ul>
    44. 44. Cyclophosphamide Side effects <ul><li>High dose 0.5-1g/m2 </li></ul><ul><li>Monthly thence quarterly </li></ul><ul><li>Estimates of infertility 23-41% </li></ul><ul><li>Infection </li></ul><ul><li>Bladder cancer -Mesna </li></ul>
    45. 45. Randomized study of maintenance Rx Cyclo, azathioprine and MMF Contreras, G. et al. N Engl J Med 2004;350:971-980
    46. 46. 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
    47. 47. 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
    48. 48. 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)
    49. 49. 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 <ul><li>Cyclo + azathioprine 31pts </li></ul><ul><li>Mycophenolate 33pts </li></ul><ul><li>All class IV </li></ul><ul><li>63 month median F/U </li></ul>
    50. 50. 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 <ul><li>No difference in outcomes </li></ul><ul><li>ESRF or death 4 vs 0 (NS P=0.062) </li></ul><ul><li>Significantly less </li></ul><ul><li>infections (p = 0.013) </li></ul><ul><li>infections requiring hospitalisation (p=0.014 ) </li></ul>
    51. 51. Mycophenolate Mofetil <ul><li>Hydrolysed to Mycophenolic acid </li></ul><ul><li>Inhibits inosine monophosphate dehydrogenase </li></ul><ul><li>Blocks de novo synthesis guanosine nucleosides </li></ul><ul><li>Suppresses lymphocyte proliferation </li></ul><ul><li>Suppresses glycosylation of adhesion molecules </li></ul>
    52. 52. Mycophenolate Mofetil <ul><li>Side effects </li></ul><ul><li>Diarrhoea </li></ul><ul><li>Lymphopenia </li></ul><ul><li>Infection </li></ul><ul><li>Increasingly used in non-renal lupus </li></ul>
    53. 53. Azathioprine <ul><li>Maintenance therapy, steroid sparing, Class II LN </li></ul><ul><li>Bone marrow suppression- neutropenia </li></ul><ul><li>Hepatitic liver toxicity </li></ul><ul><li>Thiopurine methyl transferase (TPMT) </li></ul>
    54. 54. Anti-CD20 therapy Rituximab <ul><li>Chimeric mouse/human antibody </li></ul><ul><li>IgG1/ κ </li></ul><ul><li>Anti-CD20 </li></ul><ul><li>Depletes pre-B - mature B-lymphocytes </li></ul><ul><li>Spares lymphoid precursors and plasma cells. </li></ul>
    55. 55. Rituximab <ul><li>Licensed for use in B-cell NHL </li></ul><ul><li>Not associated with increased risk of infection. </li></ul>
    56. 57. B-Cell Characteristics <ul><li>Express surface immunoglobulin </li></ul><ul><li>Antigen uptake via surface immunoglobulin for processing and presentation </li></ul><ul><li>Provides cognitive help for T-cells </li></ul><ul><li>Produces cytokines e.g. IL-4 and IL-10 </li></ul><ul><li>Constitutive production of antibodies by plasma cells </li></ul>
    57. 58. Rituximab in SLE <ul><li>No control clinical trials in SLE </li></ul><ul><li>Several case series suggesting benefit </li></ul><ul><li>Leandro et al 21 patients </li></ul><ul><li>Looney et al 17 patients </li></ul><ul><li>Van Vollenhoven et al 15 patients </li></ul><ul><li>Sfikakis et al 10 patients </li></ul><ul><li>Albert et al 8 patients </li></ul><ul><li>Tanaka et al 7 patients </li></ul><ul><li>Ryan et al 4 patients </li></ul>
    58. 59. Leandro et al ACR 2004 Abs1126 <ul><li>21 patients with active SLE </li></ul><ul><li>Treated </li></ul><ul><li>Day 1 Methylpred 750mg </li></ul><ul><li> Rituximab 1g </li></ul><ul><li>Day 2 Cyclophosphamide 750mg </li></ul><ul><li>Day 14 Rpt day 1 </li></ul><ul><li>Day 15 Rpt day 2 </li></ul>
    59. 60. Leandro et al ACR 2004 Abs1126 <ul><li>20/21 successfully B-cell depleted </li></ul><ul><li>(<5 CD19+ B cells/ μ l). </li></ul><ul><li>Time to repopulation 3-8/12, 1pt >3yrs </li></ul><ul><li>Mean serum Ig levels decreased within Normal range </li></ul>
    60. 61. Leandro et al ACR 2004 Abs1126 <ul><li>Follow up 3-46 months (mean 19) </li></ul><ul><li>Response in all patients with B-cell depletion </li></ul><ul><li>9 pts - no other I/S therapy at 12-46/12 </li></ul>
    61. 62. Leandro et al ACR 2004 Abs1126 <ul><li>Response seen in all aspects of the BILAG </li></ul><ul><li>Particularly: </li></ul><ul><li>Fatigue </li></ul><ul><li>arthralgia/arthritis </li></ul><ul><li>serositis </li></ul><ul><li>nephritis </li></ul><ul><li>thrombocytopenia and haemolytic anaemia </li></ul>
    62. 63. Leandro et al ACR 2004 Abs1126 <ul><li>1 serious infusion reaction </li></ul><ul><li>No serious or opportunistic infections </li></ul><ul><li>1 patient HACA on retreatment </li></ul>
    63. 64. <ul><li>First 7 patients </li></ul><ul><li>dsDNA reduced by 53% (0-93%) at 6/12 </li></ul><ul><li>dsDNA, histone </li></ul><ul><li>signif reduced(p<0.005) at 12/12 </li></ul><ul><li>Cambridge et al. ACR 2004 abs1723 </li></ul>
    64. 65. <ul><li>ENA behaved differently in different patients </li></ul><ul><li>RNP, SSA NS </li></ul><ul><li>Significant rise in Sm at 6 months (p<0.05) </li></ul><ul><li>PCP, TT no change </li></ul><ul><li>Cambridge et al. ACR 2004 abs1723 </li></ul>
    65. 66. Looney et al Arthritis Rheum. 2004;50:2580-9 <ul><ul><li>A phase I/II dose-escalation trial </li></ul></ul><ul><ul><li>Rituximab </li></ul></ul><ul><ul><li>single infusion of 100 mg/m 2 (low dose) </li></ul></ul><ul><ul><li>single infusion of 375 mg/m 2 (intermediate dose) </li></ul></ul><ul><ul><li>4 infusions(1 wk apart) of 375 mg/m 2 (high dose). </li></ul></ul>
    66. 67. Looney et al Arthritis Rheum. 2004;50:2580-9 <ul><ul><li>11/17 had profound B cell depletion (<5 CD19+ </li></ul></ul><ul><ul><li>B cells/ μ l). </li></ul></ul><ul><ul><li>Low dose 4/6 </li></ul></ul><ul><ul><li>Intermediate 4/7 </li></ul></ul><ul><ul><li>High dose 3/4 </li></ul></ul>
    67. 68. Looney et al Arthritis Rheum. 2004;50:2580-9 <ul><ul><li>B-cell depleters </li></ul></ul><ul><ul><li>SLAM score improved at 2/12 and 3/12 </li></ul></ul><ul><ul><li>P = 0.0016 and P = 0.002, paired t-test </li></ul></ul><ul><ul><li>Improvement persisted for 12 months </li></ul></ul><ul><ul><li>Arthritis, rashes, mucositis and alopecia. </li></ul></ul>
    68. 69. Looney et al Arthritis Rheum. 2004;50:2580-9 <ul><ul><ul><li>Absence of a significant change in anti-double-stranded DNA antibody and complement levels </li></ul></ul></ul><ul><ul><li>Six patients developed human antichimeric antibodies (HACAs) at a level > / =100 ng/ml </li></ul></ul>
    69. 70. Cyclophosphamide and Rituximab <ul><li>Leandro et al 20/21 cyclo </li></ul><ul><li>Van Vollenhoven et al 15/15 cyclo </li></ul><ul><li>Looney et al 11/17 </li></ul><ul><li>Sfikakis et al 8/10 </li></ul><ul><li>Albert et al 6/8 </li></ul><ul><li>Tanaka et al 7/7 </li></ul><ul><li>Ryan et al 4/4 </li></ul><ul><li>71/82 = 85% </li></ul>
    70. 71. Cyclophosphamide and Rituximab <ul><li>Cyclophos 35/36 97% </li></ul><ul><li>No Cyclophos 36/46 78% p=0.019 </li></ul><ul><li>Exclude dose escalating trial </li></ul><ul><li>No Cyclophos 25/29 86% p=0.164 </li></ul>
    71. 72. Rituximab <ul><li>Preliminary data promising in SLE </li></ul><ul><li>Role of cyclophosphamide unclear </li></ul><ul><li>Remission up to 3 years </li></ul><ul><li>HACA 1% Lymphoma </li></ul><ul><ul><ul><ul><li>4% RA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>8% SLE </li></ul></ul></ul></ul>
    72. 73. Rituximab <ul><li>Needs double blind controlled clinical </li></ul><ul><li>trial </li></ul>
    73. 74. Sponsored by Arthritis Research Campaign SEcond Line Agents in Myositis
    74. 75. TRIAL DESIGN: <ul><li>A double-blind, randomised, placebo controlled trial comparing: </li></ul><ul><ul><li>steroids alone, </li></ul></ul><ul><ul><li>steroids plus methotrexate, </li></ul></ul><ul><ul><li>steroids plus ciclosporin, </li></ul></ul><ul><ul><li>steroids plus methotrexate plus ciclosporin . </li></ul></ul>
    75. 76. INCLUSION CRITERIA <ul><li>Polymyositis or Dermatomyositis </li></ul><ul><li>Myositis secondary to other CTD </li></ul><ul><li>Receiving prednisolone </li></ul><ul><li>Active disease and muscle weakness </li></ul>

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