David J. Chang

Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial

BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. METHODS 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494). FINDINGS 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups. INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. FUNDING Wyeth Research.

Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial

Objectives To evaluate the efficacy and safety of intravenous ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, active rheumatoid arthritis (RA) patients despite methotrexate treatment. Methods In this double-blind, placebo-controlled, phase III study, active RA patients on stable methotrexate were randomly assigned to one course of two infusions of ofatumumab 700 mg (n=130) or placebo (n=130), 2 weeks apart. The primary endpoint was the ACR20 response at week 24. Secondary endpoints included ACR50/70, EULAR response, disease activity score based on 28 joints using C-reactive protein, adverse events (AE) and immunogenicity. Results At week 24, a greater proportion of patients on ofatumumab compared with placebo achieved an ACR20 response (50% vs 27%, p<0.001) and a good or moderate EULAR response (67% vs 41%, p<0.001). All other key secondary efficacy endpoints were significantly improved on ofatumumab. Efficacy observed by 8 weeks was sustained throughout the study. The most common AE for ofatumumab versus placebo were rash (21% vs <1%) and urticaria (12% vs <1%), mostly occurring on the first infusion day. Overall, first-dose infusion reactions were 68% for ofatumumab and 6% for placebo, mostly mild to moderate; second-dose infusion reactions markedly declined (<1% and 0%). Serious AE were reported in 5% of ofatumumab versus 3% of placebo patients. Infection rates were 32% and 26% (serious infections <1% and 2%), respectively. One death (interstitial lung disease), unrelated to study drug, was reported on ofatumumab. No antidrug antibodies were detected in ofatumumab patients. Conclusions Ofatumumab significantly improved all clinical outcomes in biological-naive, active RA patients with no detectable immunogenicity at week 24. No unexpected safety findings were identified. Trial Registry clinical trials.gov registration number NCT00611455

Subcutaneously administered ofatumumab in rheumatoid arthritis: a phase I/II study of safety, tolerability, pharmacokinetics, and pharmacodynamics.

Objective. To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics. Methods. In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required. Results. Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30–100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg. Conclusion. Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868)

Epidemiology and Treatment of New-Onset and Established Rheumatoid Arthritis in an Insured US Population

To investigate the epidemiology and treatment of rheumatoid arthritis (RA) in a population broadly representative of employed adults in the US, using a retrospective cohort design.

Longitudinal Treatment Patterns and Associated Outcomes in Patients With Newly Diagnosed Systemic Lupus Erythematosus.

PURPOSE The treatment of systemic lupus erythematosus (SLE) is complex, with a wide range of drugs commonly prescribed. The aims of this study were to identify longitudinal treatment patterns in patients with incident SLE and to estimate the associations of treatment patterns with clinical and economic outcomes. METHODS This retrospective, observational cohort study used a US managed care claims database to identify patients with newly diagnosed SLE and 4-year treatment follow-up. Patients were aged ≥ 18 years, with continuous medical and pharmacy benefits for 12 months before and 48 months after the index date (first medical claim with a diagnosis of SLE). Longitudinal treatment patterns were grouped using a k-means cluster analysis. Therapies were included in the cluster analysis if the mean number of prescriptions in each year was ≥ 0.05. Clinical and economic outcomes were compared across clusters using multivariate regression analyses. FINDINGS Data from 1611 patients with incident SLE were analyzed (91.4% women; mean [SD] age, 44.5 [9.5] years; 56.2% managed primarily by a specialist). Hydroxychloroquine and corticosteroids were the most commonly prescribed therapies; methotrexate, azathioprine, and mycophenolate mofetil also met the criteria for inclusion in the cluster analysis. Ten treatment clusters were identified; the most common was minimally treated patients (42.8%). Hydroxychloroquine monotherapy, corticosteroid monotherapy, and corticosteroid/hydroxychloroquine combination therapy were received by 34.0%, 11.2%, and 7.8% of patients, respectively. Methotrexate or azathioprine with a corticosteroid/hydroxychloroquine were received by 4.2% of patients. Changes in therapy, except discontinuations, were rare. Compared with the minimally treated cluster, those that received corticosteroid monotherapy (mean dose, >12.0 mg/d) had poorer clinical and economic outcomes; the hydroxychloroquine-monotherapy cluster had similar or better outcomes; and patients who received a corticosteroid/hydroxychloroquine with or without methotrexate or azathioprine demonstrated outcomes that were poorer but that appeared better than those with corticosteroid monotherapy. SLE-related visits with a nonspecialist were common (~45%) and remained unchanged over time despite better clinical and economic outcomes associated with specialist visits. IMPLICATIONS This study utilized cluster analysis, an unsupervised machine-learning method, to systematically discern treatment patterns over 4 years and to estimate outcomes associated with the identified treatment patterns. The results suggest that minimal treatment is the most common approach in patients with newly diagnosed SLE. Clinical and economic outcomes are poorest with corticosteroid monotherapy but may improve with the addition of hydroxychloroquine and/or an immunosuppressive agent. A large proportion of SLE care is provided by nonspecialists despite the potential benefits of involving a specialist.

External Validation of the Lupus Impact Tracker in a Southeastern US Longitudinal Cohort With Systemic Lupus Erythematosus

To examine the external validity of the Lupus Impact Tracker (LIT), a systemic lupus erythematosus (SLE)‐specific, health‐related quality of life (HRQoL) tool in a population‐based cohort of patients with SLE in Atlanta, Georgia. We modeled the association of LIT scores with patient‐reported measures of SLE activity (Systemic Lupus Activity Questionnaire [SLAQ]) and organ damage (self‐administered Brief Index of Lupus Damage [SA‐BILD]). We investigated the association of LIT scores with general HRQoL using the Short Form 12 (SF‐12).

External validation of the Lupus Impact Tracker in a longitudinal cohort with systemic lupus erythematosus from the Southeastern United States.

To examine the external validity of the Lupus Impact Tracker (LIT), a systemic lupus erythematosus (SLE)‐specific, health‐related quality of life (HRQoL) tool in a population‐based cohort of patients with SLE in Atlanta, Georgia. We modeled the association of LIT scores with patient‐reported measures of SLE activity (Systemic Lupus Activity Questionnaire [SLAQ]) and organ damage (self‐administered Brief Index of Lupus Damage [SA‐BILD]). We investigated the association of LIT scores with general HRQoL using the Short Form 12 (SF‐12).

FRI0339 Development of a Novel Patient Reported Outcome (PRO) Measure: The Systemic Lupus Erythematosus (SLE) Steroid Questionnaire (SSQ)

Background Many SLE patients receive oral glucocorticoids (steroids) as part of their treatment regimen. While providing symptom relief, most patients experience short- and long-term side effects associated with steroid use. Objectives To develop a PRO to assess benefits, side effects, and impact associated with steroid use in SLE patients. Methods Following IRB approval, 6 US rheumatology practices enrolled SLE patients with current or recent (past year) steroid use to participate in concept elicitation (CE) interviews about their steroid experience. A draft SSQ was developed, cognitively debriefed (CD) with SLE subjects, and finalized based on patient feedback, clinical input and a translatability assessment (an evaluation to assure words can be easily translated into other languages). Results 33 subjects (95% female, 55% Caucasian, 25% African American, mean age 47 years, 52% moderate/severe SLE) completed CE interviews. Subjects reported symptom improvement and increased energy. Common side effects included weight gain (67%), swelling/moon face (36%), and mood swings/feelings of rage (21%). Most subjects (67%) would be happier if steroids were discontinued. During CD interviews (n=13), the SSQ was found to be comprehensive, clear, and relevant. Minor revisions were made to improve clarity. Key results from CE interviews and a summary of the final SSQ content are provided below. Concepts mentioned during CE interview % Reporting (n=33) Potential side effects discussed prior to receiving steroids 71% Expectations about side effects match experience once starting steroids? 50% Side effects: weight gain, swelling/moon face, mood swings/feelings of rage 67%/36%/21% Stopped or changing dose without consulting physician 30% Overall satisfied with steroids 75% Concepts in Final Questionnaire† Number of Items (50) Steroid dose/duration 4 Impact of steroids (in general) 19 Benefits of steroids 7 Work/productivity 3 Side effects 10 Emotions 6 Overall satisfaction 1 †Most subjects reported side effects were worse than expected. ‡Most items use a 7-day recall period. Conclusions The SSQ is the first comprehensive PRO, developed with significant patient and clinical input, to assess SLE patient experience of oral steroid use. Its measurement properties will be evaluated in the future. Acknowledgements The research presented in this abstract was funded by GlaxoSmithKline, USA. Disclosure of Interest S. D. Mathias Consultant for: GlaxoSmithKline, P. Berry Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, J. deVries Shareholder of: GlaxoSmithKline, A. Askanase Consultant for: GlaxoSmithKline, K. Pascoe Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, H. Colwell Consultant for: GlaxoSmithKline, D. Chang Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline