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New Evidence reports on presentations given at EULAR 2009

New Evidence reports on presentations given at EULAR 2009. Factors Affecting the Efficacy and Safety of Rituximab Given at Varying Points in the Treatment of Rheumatoid Arthritis. Report on EULAR 2009 presentations.

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New Evidence reports on presentations given at EULAR 2009

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  1. New Evidence reports on presentations given at EULAR 2009 Factors Affecting the Efficacyand Safety of Rituximab Given at Varying Points in theTreatment of Rheumatoid Arthritis

  2. Report on EULAR 2009 presentations • Rituximab compared with further TNF inhibitor therapy in rheumatoid arthritis patients who had previously failed TNF inhibitor therapy(Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257) • Inhibition of joint damage and improved clinical outcomes with a combination of rituximab and methotrexate in patients with early active rheumatoid arthritis who are naïve to methotrexate: a randomized, active comparator placebo-controlled trial (IMAGE) (Tak P-P, et al. EULAR 2009: Abstract OP-0022) • Long-term safety of rituximab: follow-up of the rheumatoid arthritis clinical trials and re-treatment population (Van Vollenhoven R, et al. EULAR 2009: Abstract OP-0026) • Rate of serious infections in rituximab-treated patients with rheumatoid arthritis who subsequently received other biologic therapies(Genovese MC, et al. EULAR 2009: Abstract SAT0097) • Autoantibody-positive rheumatoid arthritis patients have enhanced clinical response when compared with seronegative patients (Isaacs J, et al. EULAR 2009: Abstract FRI0256) EULAR = European League Against Rheumatism TNF = tumour necrosis factor

  3. Rituximab compared with further TNF inhibitor therapy in rheumatoid arthritis patients who had previously failed TNF inhibitor therapy Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  4. Background • Results of the REFLEX study showed that rituximab is effective andwell tolerated in patients who have had an inadequate response to one or more TNF-Is.1 • At EULAR 2009, Gómez-Reino and colleagues presented the resultsof their prospective, observational study. • The study was designed to assess the efficacy of cycling to an alternative TNF-I, compared with receiving rituximab, in RA patients who had previously failed TNF-I therapy.2 EULAR = European League Against Rheumatism RA = rheumatoid arthritis TNF-I = tumour necrosis factor inhibitor 1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806. 2. Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  5. Study design • The study by Gómez-Reino and colleagues is an ongoing, multicentre, prospective, three-year observational study of a cohort of RA patients who received either rituximab or an alternative TNF-I, having previously failed a TNF-I. • Results are based on the first follow-up of patients at 3–6 months after treatment initiation. • Patients were included in the study if they had active RA that had been previously treated with a TNF-I which did not provide an adequate response, was contraindicated because of safety, or was discontinued. RA = rheumatoid arthritis TNF-I = tumour necrosis factor inhibitor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  6. Study design (cont’d) • Assessments were made at baseline, on treatment adjustment, every 4 months, and on premature discontinuation. • Assessments included: • DAS28 to evaluate inflammatory status and ESR • evaluation of 66 joints for swelling and 68 joints for tenderness • response assessment using EULAR criteria • HAQ-DI score • VAS patient assessment of disease activity DAS28 = 28-joint Disease Activity Score ESR = erythrocyte sedimentation rate EULAR = European League Against Rheumatism HAQ-DI = Health Assessment Questionnaire Disability Index VAS = Visual Analogue Scale Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  7. Key findings • At the time of this analysis, there were 226 evaluable patients: • 69 had received rituximab • 157 had received an alternative TNF-I • Compared with those receiving an alternative TNF-I, significantly more patients receiving rituximab: • had received at least DMARDs • reported toxicity with DMARDs • used concomitant glucocorticoids • reported morning stiffness • were older • had disease duration of >4 years • had higher DAS28, SJC, TJC, ESR, and HAQ-DI scores DAS28 = 28-joint Disease Activity Score DMARD = disease-modifying anti-rheumatic drug ESR = erythrocyte sedimentation rate HAQ-DI = Health Assessment Questionnaire Disability Index SJC = swollen joint count; TJC = tender joint count TNF-I = tumour necrosis factor inhibitor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  8. Key findings (cont’d) • The number of patients who were RF positive at baseline in each group was not given. • In the first 3–6 months, rituximab-treated patients had a greater mean change in DAS28 response of –1.54 (95% CI, –1.91 to –1.17) versus the TNF-I–treated patients, who had a change of –0.87 (95% CI, –1.11 to –0.64) (p = 0.002). • A significantly greater proportion of rituximab-treated patients had a decrease in DAS28 >1.2 than those receiving an alternative TNF-I (57.6% versus 37.9%, respectively; p = 0.012). • In a subgroup of patients with only one TNF-I failure, mean change from baseline in DAS28 was statistically significantly greater for those receiving rituximab (n = 30; mean change in DAS28 –1.6) compared with those receiving an alternative TNF-I (n = 107; mean change in DAS28 –0.8) (p = 0.008). CI = confidence interval DAS28 = 28-joint Disease Activity Score RF = rheumatoid factor TNF-I = tumour necrosis factor inhibitor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  9. Key findings (cont’d) • No statistically significant differences occurred in the mean change in DAS28 between rituximab (n = 29; mean change in DAS28 –1.50) andTNF-I (n = 17; mean change in DAS28 –0. 9) in a subgroup of patients with two or more previous TNF-I failures. • Statistically significantly more rituximab-treated patients achieved a moderate or good EULAR response compared with those receiving an alternative TNF-I. • Changes from baseline in all other disease activity and patient-reported outcome measures assessed were statistically significant in favour of rituximab-treated patients over those treated with an alternative TNF-I, with the exception of HAQ-DI. • Overall, both treatments were well tolerated. • In all, 28 AEs were reported (15 in the rituximab group and 13 in the TNF-I group), with some patients experiencing more than one AE. • A total of 8 infections were reported:3 infections in the rituximab group and 5 in the TNF-I group. AE = adverse event; DAS28 = 28-joint Disease Activity Score EULAR = European League Against Rheumatism HAQ-DI = Health Assessment Questionnaire Disability Index TNF-I = tumour necrosis factor inhibitor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  10. Figure 1. Proportion of patients who achieved a EULAR response at first follow-up (3–6 months) following treatment with rituximab or an alternative TNF-I EULAR = European League Against Rheumatism TNF-I = tumour necrosis factor inhibitor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  11. Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  12. Key conclusion • Rituximab provides an alternative therapeutic option to TNF cycling in RA patients who have failed previousTNF inhibitor therapy. RA = rheumatoid arthritis TNF = tumour necrosis factor Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.

  13. Inhibition of joint damage and improved clinical outcomes with a combination of rituximab and methotrexate in patients with early active rheumatoid arthritis who are naïve to methotrexate: a randomized active comparator placebo-controlled trial (IMAGE) Tak P-P,et al. EULAR 2009: Abstract OP-0022.

  14. Background • At EULAR 2009, Tak and colleagues presented data from the IMAGE (International Study in Methotrexate-nAïve Subjects InvestiGating Rituximab’s Efficacy) study. • The IMAGE study was designed to evaluate clinical and radiographic outcomes with a combination of rituximab and MTX versus MTX alone in patients with early RA not previously treated with MTX.1 EULAR = European League Against Rheumatism MTX = methotrexate; RA = rheumatoid arthritis 1. Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  15. Study design • The IMAGE study was a prospective, double-blind, phase III, randomized, controlled trial designed to assess the efficacy of rituximab in combination with MTX compared to MTX monotherapy in RA patients. • Patients included in the study: • had no prior exposure to MTX, with a disease duration of <4 years • had an SJC and TJC of ≥8 each • had a CRP concentration of ≥1.0 mg/dL • were RF positive or exhibited erosive damage • Patients were randomized to receive placebo plus MTX, rituximab (2 x 500 mg) plus MTX, or rituximab (2 x 1000 mg) plus MTX. • MTX was initiated in all groups at 7.5 mg/wk and titrated to 20 mg/wk by week 8. Rituximab was given by intravenous infusion on days 1 and 15. CRP = C-reactive protein; MTX = methotrexate RA = rheumatoid arthritis; RF = rheumatoid factor SJC = swollen joint count; TJC = tender joint count Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  16. Study design (cont’d) • At week 24, patients with DAS28 ≥2.6 received a second course of rituximab. • Patients with DAS28 <2.6 were re-treated if and when their DAS28 increased to ≥2.6. • Radiographs were taken at screening, and at weeks 24 and 52, and centrally read using mTSS. Readers were blinded to the sequence and treatment. • The primary endpoint was the change from screening in mTSS at week 52. • Secondary endpoints included ACR and EULAR responses, MCR (ACR70 maintained for at least 6 months), and change in DAS28. ACR = American College of Rheumatology DAS28 = 28-joint Disease Activity Score EULAR = European League Against Rheumatism MCR = major clinical response mTSS = Genant-modified sharp method Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  17. Key findings • A total of 755 patients were randomized, and 715 patients were radiographically evaluable at 52 weeks. • Groups were well matched at baseline, with a mean RA duration of 0.9 years and DAS28 >7. • At 52 weeks, the rituximab (2 x 1000 mg) plus MTX group had a significantly lower change in mTSS (p = 0.0003) compared with the placebo plus MTX group. • This comparison was not significant for the rituximab (2 x 500 mg) plus MTX group versus the placebo plus MTX group. • At 52 weeks, the rituximab (2 x 1000 mg) plus MTX group had a significantly higher proportion of patients with no joint progression (p <0.05) compared with the placebo plus MTX group. • This comparison was not significant for the rituximab (2 x 500 mg) plus MTX group versus the placebo plus MTX group. DAS28 = 28-joint Disease Activity Score mTSS = Genant-modified sharp method MTX = methotrexate; RA = rheumatoid arthritis Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  18. Figure 1. Mean change in mTSS scoreafter 52 weeks of treatment mTSS = Genant-modified sharp method Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  19. Figure 2. Percentage of patients with an mTSS score ≤0 after 52 weeks of treatment mTSS = Genant-modified sharp method Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  20. Key findings (cont’d) • At 52 weeks, both doses of rituximab plus MTX improved ACR and EULAR responses, compared with MTX monotherapy. • The proportion of patients with an MCR after 52 weeks was: • 18.4% in the rituximab (2 x 1000 mg) plus MTX group (n = 250; p = 0.0006 versus MTX) • 17.3% in the rituximab (2 x 500 mg) plus MTX group (n = 249; p = 0.0019 versus MTX) • 8% in the placebo plus MTX group (n = 249) • The mean change in DAS28-ESR score was: • –3.21 in the rituximab (2 x 1000 mg) plus MTX group (n = 248) • –3.05 in the rituximab (2 x 500 mg) plus MTX group (n = 247) • –2.06 in the placebo plus MTX group (n = 244) (p <0.0001 for all comparisons with MTX) ACR = American College of Rheumatology DAS28 = 28-joint Disease Activity Score; ESR = erythrocyte sedimentation rate EULAR = European League Against Rheumatism; MCR = major clinical response mTSS = Genant-modified sharp method; MTX = methotrexate Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  21. Figure 3. ACR response after 52 weeks of treatment ACR = American College of Rheumatology Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  22. Figure 4. EULAR response after 52 weeks of treatment EULAR = European League Against Rheumatism Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  23. Key findings (cont’d) • Serious adverse events occurred in: • 10% of patients in the placebo plus MTX group • 9% of patients in the rituximab (2 x 500 mg) plus MTX group • 10% of patients in the rituximab (2 x 1000 mg) plus MTX group • The rate of serious infections (events per 100 patient-years) was: • 6.09 events in the placebo plus MTX group • 4.61 events in the rituximab (2 x 500 mg) plus MTX group • 3.73 events in the rituximab (2 x 1000 mg) plus MTX group • Three deaths occurred: two from pneumonia and one from cerebral infarction. • All deaths were in the placebo plus MTX group. MTX = methotrexate Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  24. Key conclusions • Using rituximab earlier in the treatment algorithm as a first-line biologic aids in the prevention of joint damage in rheumatoid arthritis. • Both higher (2 x 1000 mg) and lower (2 x 500 mg) doses of rituximab plus MTX improved clinical outcomes, as compared with MTX alone, after 52 weeks of treatment. • After 52 weeks of treatment in patients with early active rheumatoid arthritis, only rituximab (2 x 1000 mg) plus MTX significantly improved radiographic outcomes and inhibited joint damage. MTX = methotrexate Tak P-P, et al. EULAR 2009: Abstract OP-0022.

  25. Long-term safety of rituximab: follow-up of the rheumatoid arthritis clinical trials and re-treatment population Van Vollenhoven RF, et al.EULAR 2009: Abstract OP-0026.

  26. Background • At EULAR 2009, Van Vollenhoven and colleagues presented data from their study examining the long-term safety of rituximab in combination with MTX in patients with RA.1 EULAR = European League Against Rheumatism MTX = methotrexate; RA = rheumatoid arthritis 1. Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  27. Study design • The study by Van Vollenhoven and colleagues was a pooled analysis of safety data from RA patients treated with rituximab in combination with MTX in a global clinical trial program. • All patients were offered repeat treatment with rituximab, as determined by clinical need. • Data were collected on AEs, including infusion reactions, infections, and malignancies. • Serious infusion reaction events were defined as evidence of pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema, throat irritation, cough, bronchospasm, hypotension,or hypertension. AE = adverse event; MTX = methotrexate RA = rheumatoid arthritis Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  28. Key findings • The analysis (as of April 2008) was based on 5,964 patient-years of rituximab exposure. • A total of 2,579 patients with RA received multiple courses of rituximab: 1,926; 1,228; 794; and 282 patients received ≥2, ≥3, ≥4, and ≥5 courses, respectively. • A total of 2,417 patients were followed for >1 year, 1,198 for >2 years, 743 for >3 years, 564 for >4 years, and 109 for >5 years from start of treatment. • Withdrawals from the trial due to AEs occurred in 138 patients (5%). • The most frequent AEs were infusion-related reactions. There were 15 serious infusion-related events in 14 patients (0.5%), with 10, 4, 0, 1, and 0 events in C1 to C5, respectively. • Twenty-five percent (25%) of patients reported infusion reactions for the first infusion of the first course, and the percentage decreased for subsequent infusions. AE = adverse event; C = course RA = rheumatoid arthritis Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  29. Key findings (cont’d) • Rates of AEs, serious AEs, and infections remained stable following each course. • The overall serious infection event rate was 4.26/100 patient-years (95% CI, 3.77–4.82). • Rates of infection and serious infection remained stable over time. • One case of progressive, multifocal leukoencephalopathy was reported in a patient who also received cancer chemotherapy. • There were no cases of tuberculosis. • The malignancy rate was comparable to malignancy rates in the general RA population. AE = adverse event; CI = confidence interval MTX = methotrexate; RA = rheumatoid arthritis Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  30. Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  31. Figure 1. Serious infection event rates by rituximab treatment course Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  32. Key conclusions • Overall rates of adverse events, serious adverse events, and infections remained stable over time and by treatment course. • No cases of tuberculosis were reported. • In long-term re-treatment trials, rituximab has remained well tolerated with administration of up to five courses, with a stable safety profile. Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.

  33. Rate of serious infectionsin rituximab-treated patients withrheumatoid arthritis who subsequentlyreceived other biologic therapies Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  34. Background • An increase in the number of treatment options for RA has meant that patients may switch therapies a number of times during the course of their disease. • After using rituximab, other biologic DMARDs may be given during a period of B-cell depletion. • The safety implications, particularly those concerning infection, of switching from rituximab to other biologic therapies have not been examined.1 • At EULAR 2009, Genovese and colleagues presented data from their study examining the rate of serious infection events in RA patients previously treated with rituximab and subsequently receiving a biologic DMARD while peripherally B-cell (CD20+) depleted.1 DMARD = disease-modifying anti-rheumatic drug EULAR = European League Against Rheumatism RA = rheumatoid arthritis 1. Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  35. Study design • Eligible patients were those with active RA who had received at least one course of rituximab (either 2 x 500 mg or 2 x 1000 mg infusions given 2 weeks apart) during participation in one of seven clinical trials (SERENE, SUNRISE, MIRROR, SIERRA, REFLEX III, DANCER IIa, and DANCER IIb) and 2 open-label extension trials (DANCER and REFLEX). • Patients who completed the trial or withdrew from receiving further courses of rituximab were required to enter a safety follow-up period consisting of periodic visits approximately every 12 weeks for at least one year, during which additional biologic DMARD RA therapies were permitted. • Patients were examined based on the biologic DMARD therapy received during the follow-up. DMARD = disease-modifying anti-rheumatic drug RA = rheumatoid arthritis Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  36. Study design (cont’d) • All patients receiving biologic DMARD therapy in addition to concomitant weekly MTX were assessed as 2 groups: • all patients receiving biologic DMARDs, including TNF-Is • patients receiving a TNF-I • Patients receiving a TNF-I in addition to or subsequent to receiving a different biologic DMARD were included in the TNF-I sub-population. • Serious infection events (SIEs), peripheral CD19+ counts (a surrogate marker for CD20+ B cells), and concomitant medications were collected. • Due to limited data (cut-off date was April, 2008), only exploratory descriptive analysis was performed, with no formal statistical testing. • The SIE rates (events per 100 patient-years) while on rituximab but before initiation of a biologic DMARD were calculated and compared to rates after initiating a biologic DMARD. DMARD = disease-modifying anti-rheumatic drug MTX = methotrexate; RA = rheumatoid arthritis TNF-I = tumour necrosis factor inhibitor Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  37. Key findings • To date, 2,579 patients have received rituximab treatment in the global clinical trial program, representing 5,964.3 patient-years. • Of the rituximab-treated patients, 216 (8%) have switched to another biologic DMARD following rituximab treatment: • 178 patients (82%) received TNF-Is: 52 (25%) received etanercept, 54 (25%) received infliximab, and 69 (32%) received adalimumab as their first biologic DMARD after rituximab • 31 patients (14%) received abatacept, and 9 patients (4%) received anakinra (included 2 patients who subsequently received a TNF-I) • Approximately 35% of the 216 patients received their biologic within6 months of their last rituximab infusion. • Median and mean time from the last dose of rituximab to the first biologic DMARD was 8 months (range: 0.5–37 months) and 9 (±6) months, respectively. • Median and mean follow-up time after receipt of the subsequent biologic was 11 months (range: 0–45 months) and 12 (±9) months, respectively. DMARD = disease-modifying anti-rheumatic drug TNF-I = tumour necrosis factor inhibitor Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  38. Key findings (cont’d) • At the time of receiving further RA treatment, the majority (86.1%) of patients had peripheral B-cell depletion, with CD19+ levels below the LLN (<80 cells/μL). • The mean CD19+ B-cell count was 34.7 (±64.7) cells/μL (range: 0–459 cells/μL). • The overall SIE rate in the all-exposure safety population was 4.26/100 patient-years (95% CI, 3.77–4.82). • Of the 216 patients who withdrew and received another biologic DMARD, a total of 13 SIEs in 12 patients were reported during treatment with rituximab and prior to receipt of another DMARD (5.73/100 patient-years). • Following the initiation of the biologic DMARD, 12 SIEs in 12 patients were reported (5.36/100 patient-years). CI = confidence interval DMARD = disease-modifying anti-rheumatic drug LLN = lower limit of normal; RA = rheumatoid arthritis SIE = serious infection event Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  39. Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  40. Key findings (cont’d) • The median and mean time to the SIE after initiating another biologic DMARD was 6 months (range: 0–23 months) and 9 (±8) months, respectively. • The time to the specific SIE was highly variable and did not show any specific temporal pattern. • Of the 12 patients reporting SIEs following another biologic DMARD, 10 patients had mean peripheral B-cell counts below the LLN at the time of receiving the biologic DMARD and at the last measurement prior to the SIE, with a mean of 23.6 (±26.9) cells/μL and a median of 10 cells/μL (range: 1–69 cells/μL). • Of these 10 patients, one patient had an IgG level below the LLN (5.2 g/L) prior to the SIE. • This patient experienced a UTI while on adalimumab and subsequently had an IgG level above the LLN 18 days following the onset of infection. DMARD = disease-modifying anti-rheumatic drug LLN = lower limit of normal; SIE = serious infection event; UTI = urinary tract infection Genovese MC, et al. EULAR 2009: Abstract SAT0097.

  41. Key findings (cont’d) • Three (3) patients experienced more than one SIE: • One patient had two cases of pneumonia (before and after starting anakinra) • A second patient had pneumonia before starting adalimumab and a UTI after starting adalimumab • A third patient experienced one case of bronchitis and one case of UTI before starting etanercept • In the 31 patients receiving abatacept and 9 patients receiving anakinra, there was one SIE before and one SIE after receiving each of these biologics. • All but five of the patients with SIEs were also taking concomitant glucocorticoids. • There were no opportunistic or fatal infections. Genovese MC, et al. EULAR 2009: Abstract SAT0097. SIE = serious infection event; UTI = urinary tract infection

  42. Key conclusions • In this updated exploratory analysis, the use of other biologic therapies in RA patients previously treated with rituximab was not associated with an increase in the rate of serious infections. • Overall, the infections were variable and typical for RA patients. Genovese MC, et al. EULAR 2009: Abstract SAT0097. RA = rheumatoid arthritis

  43. Autoantibody-positive rheumatoid arthritispatients have enhanced clinical response when compared with seronegative patients Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  44. Background • Previous studies using rituximab in patients with an inadequate response to TNF-Is have suggested that seropositivity for either or both of the autoantibodies RF and anti-CCP is associated with improved clinical benefit compared with seronegative patients.1 • At EULAR 2009, Isaacs and colleagues presented data from a pooled non-placebo controlled patient cohort from the MIRROR2 and SERENE3 trials, designed to examine the effect of patient seropositivity on the efficacy of rituximab.1 CCP = cyclic citrullinated peptide EULAR = European League Against Rheumatism RA = rheumatoid arthritis; RF = rheumatoid factor TNF-I = tumour necrosis factor inhibitor 1. Isaacs JD, et al. EULAR 2009: Abstract FRI0256. 2. Rubbert-Roth A, et al. ACR 2008: Abstract 363. 3. Emery P, et al. ACR 2008: Abstract 364.

  45. Study design • The study by Isaacs and colleagues was designed to examine whether baseline seropositivity (RF and/or anti-CPP) enriches clinical responses versus patients seronegative for both autoantibodies in a population of RA patients from the MIRROR and SERENE trials. • The MIRROR and SERENE trials were randomized, double-blind, placebo-controlled, phase III trials designed to evaluate the safety and efficacy of various regimens of rituximab in combination with MTX in patients who had had a previous inadequate response to MTX. • Both studies had the following inclusion criteria: • RA for at least 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of RA • SJC ≥8 (66 joint count) and TJC ≥8 (68 joint count) at screening and baseline • either CRP ≥0.6 mg/dL or ESR ≥28 mm/hour • background MTX 10–25 mg/week at a stable dose ACR = American College of Rheumatology CCP = cyclic citrullinated peptide; CRP = C-reactive protein ESR = erythrocyte sedimentation rate; MTX = methotrexate RA = rheumatoid arthritis; RF = rheumatoid factor SJC = swollen joint count; TJC = tender joint count Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  46. Study design (cont’d) • Patients received rituximab by intravenous infusion on days 1 and 15 at doses of 2 x 500 mg or 2 x 1000 mg. • At week 24, further courses of rituximab were permitted according to individual study criteria. • All infusions of rituximab were preceded by 100 mg intravenous methylprednisone. • Patients from low-dose rituximab (2 x 500 mg, 2 x 500 mg) and high-dose rituximab (2 x 1000 mg, 2 x 1000 mg) groups were included from both studies. • The first course of the dose escalation arm from the MIRROR study (2 x 500 mg) was also included in the analysis, although second-course data (2 x 1000 mg) were excluded to ensure alignment with other treatment groups. • Clinical outcomes determined at weeks 24 and 48 included ACR and EULAR responses, change from baseline in DAS28, low disease activity (DAS28 <3.2), and remission (DAS28 ≤2.6). ACR = American College of Rheumatology DAS28 = 28-joint Disease Activity Score EULAR = European League Against Rheumatism Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  47. Study design Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  48. Study design (cont’d) • Serological status for RF (positive: >20 IU/mL) and anti-CCP (positive: >5 U/mL, DiastatTM, AxisShield, Dundee, Scotland) were determined at baseline. • Patients positive for either or both autoantibodies were compared to those who were seronegative for both. • The analyses were carried out in patients who completed 48 weeks in their respective studies without imputation for missing values. • Association of serotype with clinical outcomes was assessed by logistic regression analysis or by analysis of variance (ANOVA) as appropriate at weeks 24 and 48. • A significance level of p <0.05 was adopted throughout. CCP = cyclic citrullinated peptide RF = rheumatoid factor Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  49. Key findings • A total of 670 patients were included (554 seropositive,116 seronegative). • Across all analyses, patients positive for only one autoantibody showed a comparable response to patients positive for both autoantibodies. • As single-positive patients comprised a relatively small component of the total seropositive population, all results are represented as a pooled seropositive population. • Following the first and second courses of rituximab, both seronegative and seropositive patients showed a decrease in DAS28-ESR. • Seropositive patients responded with a significantly greater decrease than the seronegative patients at all time points. • After adjusting for initial change in DAS28 at week 24, there was statistical evidence that seropositive patients showed a further enhanced reduction of DAS28 at week 48 compared with seronegative patients (p <0.05). DAS28 = 28-joint Disease Activity Score ESR = erythrocyte sedimentation rate Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

  50. Figure 1. Change from baseline in DAS28-ESR by serotype in pooled samples from MIRROR and SERENE DAS28 = 28-joint Disease Activity Score ESR = erythrocyte sedimentation rate Isaacs JD, et al. EULAR 2009: Abstract FRI0256.

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