Kaleb Michaud

American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials

OBJECTIVE Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

A Comparison of Patient Characteristics and Outcomes in Selected European and U.S. Rheumatoid Arthritis Registries

PURPOSE Randomized controlled trials (RCTs) have demonstrated the efficacy of biologic agents in the treatment of rheumatic diseases. However, results from RCTs may not be generalizable to clinical practice because of their strict inclusion and exclusion criteria. Assessment of safety using RCT data also is limited by short duration of follow-up and relatively small sample sizes, which generally preclude analysis of longer term outcomes and rare adverse events. In rheumatology, various observational cohorts and registries have been created to complement information obtained from RCTs, some with the primary purpose of monitoring effectiveness and safety of biologic agents. Most registries are either drug based or disease based. These registries include patients with a variety of rheumatic diseases including RA. METHODS To provide a qualitative comparison of selected U.S. and European rheumatoid arthritis (RA) biologics registries and cohorts including ARTIS, BIOBADASER, BSRBR, BRASS, CLEAR, CORRONA, NDB, RABBIT, SCQM, and VARA. RESULTS A careful comparison of these registries, as provided in this article, can provide a basis for understanding the many similarities and differences inherent in their design, as well as societal context and content, all of which can significantly impact their results and comparisons across registers. SUMMARY The increasing use of biologic agents for treatment of rheumatic diseases has raised important questions about cost, safety, and effectiveness of these agents. The unique and variable features of patient populations and registry designs in Europe and the U.S. provide valuable and complementary data on comparative effectiveness and safety of biologic agents to what can be derived from RCTs.

Biologic drugs for rheumatoid arthritis in the Medicare program: a cost-effectiveness analysis.

OBJECTIVE Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered infliximab. We undertook to develop a model to compare the costs and quality-adjusted life years (QALYs) generated by each of the 4 biologic agents. METHODS Data were drawn from meta-analysis of randomized controlled trials and from a large longitudinal outcomes databank. Uncertainty was addressed using probabilistic and one-way sensitivity analyses. A lifetime horizon and Medicare viewpoint were adopted. RESULTS In the base case analysis, anakinra was the least effective and least costly strategy. Etanercept, adalimumab, and infliximab were similar in terms of effectiveness, but infliximab was more costly. If decision makers are willing to pay a maximum of

Rheumatoid arthritis treatment and the risk of severe interstitial lung disease

50,000/QALY, the probability that infliximab is cost-effective is <1%. Findings were robust to a range of sensitivity analyses. Only if the dose of infliximab remains constant over time is this likely to be a cost-effective strategy. CONCLUSION Infliximab is unlikely to be cost-effective in the Medicare population compared with either etanercept or adalimumab. Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor alpha inhibitors.

Increased incidence of herpes zoster among patients with systemic lupus erythematosus.

Objectives: Interstitial lung disease (ILD) is an important complication of rheumatoid arthritis (RA) or its treatment, and is associated with substantially increased mortality. Reports have suggested that infliximab with or without azathioprine might lead to rapidly progressive or fatal ILD. We used an RA data bank to assess the associations of treatments for RA and severe ILD. Methods: ILD was identified in hospitalisations and death records in 100 of 17 598 RA patients and studied in relation to RA therapy with Cox regression analyses. Results: The incidence of hospitalisation for ILD (HILD) was 260 per 100 000 patient years. Among those hospitalised for ILD, 27.0% died. In multivariable models of current and past RA treatment, the only current treatment associated with HILD was prednisone: hazard ratio (HR) 2.5 [95% confidence interval (CI) 1.5–4.1]. Among past therapies, prednisone (HR 3.0, 95% CI 1.0–8.9), infliximab (HR 2.1, 95% CI 1.1–3.8), etanercept (HR 1.7, 95% CI 1.0–3.0), and cyclophosphamide (HR 3.7, 95% CI 0.9–15.5) were associated with HILD. Pre‐existing lung problems were identified in 67% of HILD. Only one case of HILD in the 100 hospitalisations suggested a possible temporal relationship between infliximab and HILD. Conclusions: Associations between RA treatment and HILD are confounded by the prescription of treatments for ILD such as prednisone, infliximab, etanercept, and cyclophosphamide. There is no clear pattern of causal association of treatment and ILD, and there is no clear evidence to support a causal relationship between infliximab, azathioprine, and HILD.

Treatment and nontreatment predictors of health assessment questionnaire disability progression in rheumatoid arthritis: A longitudinal study of 18,485 patients

Herpes zoster (HZ) is the painful reactivation of latent varicella zoster virus infection. The incidence of HZ may be increased in some autoimmune diseases, including systemic lupus erythematosus (SLE). We examined the incidence and risk factors for HZ in a prospective cohort of patients with physician-diagnosed SLE compared to those diagnosed with non-inflammatory musculoskeletal conditions (MSK). After excluding participants with a history of prior HZ at enrollment, we followed 1485 SLE patients and 2775 MSK with semi-annual mailed questionnaires for incident HZ between 2001 and 2010. Age-adjusted incidences were calculated for each group and Cox proportional hazard models were used to identify predictors of HZ. Zostavax® vaccination rates were compared between groups. Participants had a mean age of 60 years at enrollment, with 13.9 years of disease. SLE patients had more HZ at all ages, with an age-adjusted incidence of 12.0/1000 person-years compared to MSK (8.7/1000 person-years) and a hazard ratio of 1.7 (95% CI 1.08–2.71) for SLE. Increasing age and reduced functional status were independent predictors of HZ. In SLE, prednisone and mycophenolate mofetil use conferred additional risk. SLE had the lowest HZ vaccination rates among age-eligible subjects.

Converting modified health assessment questionnaire (HAQ), multidimensional HAQ, and HAQII scores into original HAQ scores using models developed with a large cohort of rheumatoid arthritis patients

To examine predictors of progression of disability in rheumatoid arthritis (RA), as measured by the Health Assessment Questionnaire disability index (HAQ), and to determine rates of progression during biologic treatment.

Patient Perception of the Burden of Weight Gain and Blood Pressure Increase among RA Patients Using Celecoxib, Rofecoxib, and Non-specific NSAIDs

The Stanford Health Assessment Questionnaire Disability Index (HAQ) is the gold standard functional status questionnaire in rheumatology, but it is lengthy. Three shorter versions, the modified HAQ (MHAQ), the Multidimensional HAQ (MDHAQ), and the HAQII are often used in outcomes research as HAQ substitutes. We developed conversion formulas between these modified versions and the original HAQ.

Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: Associations with prednisone, disease-modifying antirheumatic drugs, and anti–tumor necrosis factor therapy

Nonsteroidal anti-inflammatory medications (NSAIDs) may be accompanied by clinically important renal side effects. We compared the rate of reported side effects from celecoxib, rofecoxib, and nonspecific (NS) NSAIDs and their burden in RA patients. Patients on rofecoxib were more likely to report a problem with weight gain (P < 0.05) and an increase in blood pressure (P < 0.001). In addition, rofecoxib users were 28% more likely to be in a more severe category for being bothered by unintentional weight gain (OR = 1.28, P < 0.05) and 53% more likely to state that they were in a more severe category for blood pressure increase (OR = 1.53, P < 0.000), compared with patients receiving celecoxib. Weight gain and blood pressure were also increased by coexisting cardiovascular disease. Clinicians should be aware that patient-reported weight gain and increases in blood pressure can occur with all NSAIDs, and may be particularly increased with rofecoxib. Existing cardiovascular disease is also an independent predictor of weight gain and increased blood pressure.