Jeffrey R. Curtis

Association Between the Initiation of Anti–Tumor Necrosis Factor Therapy and the Risk of Herpes Zoster

IMPORTANCE Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk. OBJECTIVES To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk. DESIGN, SETTING, AND PATIENTS We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use. MAIN OUTCOME MEASURES Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy. RESULTS Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36). CONCLUSION AND RELEVANCE Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens.

Vitamin D Status and Its Associations with Disease Activity and Severity in African Americans with Recent-onset Rheumatoid Arthritis

Objective. To examine the prevalence of vitamin D insufficiency and the associations of vitamin D concentration with disease status in African Americans with rheumatoid arthritis (RA). Methods. Study participants (n = 266) were enrolled in the Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) Registry. The vitamin 25(OH)-D was measured on baseline plasma, and associations of 25(OH)-D with disease status (baseline and at 3 years’ disease duration) were examined using univariate and multivariate regression. Results. The prevalence of 25(OH)-D insufficiency (≤ 37.5 nmol/l or 15 ng/ml) was 50%, with the highest prevalence in winter. In unadjusted analyses, vitamin D concentrations were inversely associated with baseline pain (p = 0.04), swollen joints (p = 0.04), and Disease Activity Score (DAS28, p = 0.05) but not with measures at 3 years’ disease duration. There were no multivariate associations of 25(OH)-D with any disease measures at baseline or at 3 years, with the exception of a positive borderline association with rheumatoid factor positivity at enrollment (p = 0.05). Conclusion. Vitamin D insufficiency is common in African Americans with recent-onset RA. Unadjusted associations of circulating vitamin D with baseline pain, swollen joints, and DAS28 were explained by differences in season, age, and gender and were not significant in multivariate analyses. In contrast to reports of Northern Europeans with early inflammatory arthritis, there are not strong associations of 25(OH)-D concentration with symptoms or disease severity in African Americans with RA.

Timing and Magnitude of Initial Change in Disease Activity Score 28 Predicts the Likelihood of Achieving Low Disease Activity at 1 Year in Rheumatoid Arthritis Patients Treated with Certolizumab Pegol: A Post-hoc Analysis of the RAPID 1 Trial

Objective. To determine the relationship between timing and magnitude of Disease Activity Score [DAS28(ESR)] nonresponse (DAS28 improvement thresholds not reached) during the first 12 weeks of treatment with certolizumab pegol (CZP) plus methotrexate, and the likelihood of achieving low disease activity (LDA) at 1 year in patients with rheumatoid arthritis. Methods. In a post-hoc analysis of the RAPID 1 study, patients achieving LDA [DAS28(ESR) ≤ 3.2] at Year 1 were assessed according to DAS28 nonresponse at various timepoints within the first 12 weeks. Results. Seven-hundred eighty-three patients were included (CZP 200 mg, n = 393; CZP 400 mg, n = 390). A total of 86.9% of patients in the CZP 200 mg group had a DAS28 improvement of ≥ 1.2 by Week 12. Of the 13.1% of patients with DAS28 improvement < 1.2 by Week 12, only 2.0% had LDA at Year 1. Failure to achieve LDA at Year 1 depended on timing of nonresponse — 22.3%, 8.4%, and 2.0% of patients with DAS28 improvement < 1.2 by Weeks 1, 6, and 12, respectively, had LDA at Year 1 — and magnitude of initial lack of DAS28 improvement; for example, compared with the patients with DAS28 < 1.2 improvement, fewer patients with DAS28 < 0.6 had LDA at Year 1 (17.4%, 2.4%, and 0.0% at Weeks 1, 6, and 12, respectively). Conclusion. Failure to achieve improvement in DAS28 within the first 12 weeks of therapy was predictive of a low probability of achieving LDA at Year 1. Moreover, the accuracy of the prediction was found to be strongly dependent on the magnitude and timing of the lack of the response. (Clinical Trial Registration Nos. NCT00152386 and NCT00175877).

Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis

Objective. To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA. Methods. Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches: (i) treatment to target (TT): patients assessed 24 weeks after each course and retreated if not in remission [DAS in 28 joints based on ESR (DAS-28-ESR) ≥ 2.6]; (ii) treatment as needed (PRN): patients retreated at the physician’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses, if both swollen and tender joint counts were ≥8. All courses consisted of i.v. rituximab 2 × 1000 mg 2 weeks apart plus MTX. Observed data were analysed according to treatment strategy. Results. Multiple courses of rituximab maintained or improved responses irrespective of regimen. TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN. TT resulted in significantly more patients achieving major clinical response. PRN resulted in recurrence of disease symptoms between courses, with TT significantly reducing the incidence of RA flares. Despite more frequent retreatment with TT compared with PRN, the rates of serious adverse events and serious infections were comparable between regimens. Conclusions. Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile. TT may be the preferable rituximab treatment regimen for patients with RA.

Rapid Improvement in the Signs and Symptoms of Rheumatoid Arthritis Following Certolizumab Pegol Treatment Predicts Better Longterm Outcomes: Post-hoc Analysis of a Randomized Controlled Trial

Objective. To assess the kinetics of response to certolizumab pegol (CZP), and association between rapid response and longterm outcomes, in patients with active rheumatoid arthritis (RA). Methods. This was a post-hoc analysis of the randomized, double-blind RAPID 1 study in patients who received methotrexate (MTX) and either CZP 200 mg subcutaneously or placebo every 2 weeks for 52 weeks. Clinical and radiographic outcomes at Week 52 were evaluated based on the Disease Activity Score 28 (DAS28) ≥ 1.2 and American College of Rheumatology 20% (ACR20) responses at Week 6 and Week 12. Results. Clinical responses [European League Against Rheumatism (EULAR), DAS28 ≥ 1.2, and ACR20 responses] were rapid in CZP-treated patients. Week 12 DAS28 ≥ 1.2 responders had better clinical and radiographic outcomes at Week 52 compared with nonresponders. Among Week 12 responders, incremental benefit of earlier response was observed: Week 6 DAS28 ≥ 1.2 responders and ACR20 responders had significantly higher ACR response rates and were more likely to achieve remission at Week 52 than Week 12 responders. Patients with a clinical response at Week 6 had faster, more meaningful sustained improvements in patient-derived outcomes than those responding by Week 12 only. Conclusion. Rapid attainment of clinical response in patients with RA is associated with improved longterm outcomes. Analysis of the kinetics of response to CZP during the first 12 weeks of therapy potentially permits informed prediction of clinical success or need to alter treatment. In patients not achieving a clinical response at Week 12 treatment adjustment should be considered. Trial registration NCT00152386.

Validity of Claims-Based Stroke Algorithms in Contemporary Medicare Data Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study Linked With Medicare Claims

Background—The accuracy of stroke diagnosis in administrative claims for a contemporary population of Medicare enrollees has not been studied. We assessed the validity of diagnostic coding algorithms for identifying stroke in the Medicare population by linking data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study to Medicare claims. Methods and Results—The REGARDS Study enrolled 30 239 participants ≥45 years in the United States between 2003 and 2007. Stroke experts adjudicated suspected strokes, using retrieved medical records. We linked data for participants enrolled in fee-for-service Medicare to claims files from 2003 through 2009. Using adjudicated strokes as the gold standard, we calculated accuracy measures for algorithms to identify incident and recurrent strokes. We linked data for 15 089 participants, among whom 422 participants had adjudicated strokes during follow-up. An algorithm using primary discharge diagnosis codes for acute ischemic or hemorrhagic stroke (International Classification of Diseases, Ninth Revision, Clinical Modification codes: 430, 431, 433.x1, 434.x1, 436) had a positive predictive value of 92.6% (95% confidence interval, 88.8%–96.4%), a specificity of 99.8% (99.6%–99.9%), and a sensitivity of 59.5% (53.8%–65.1%). An algorithm using only acute ischemic stroke codes (433.x1, 434.x1, 436) had a positive predictive value of 91.1% (95% confidence interval, 86.6%–95.5%), a specificity of 99.8% (99.7%–99.9%), and a sensitivity of 58.6% (52.4%–64.7%). Conclusions—Claims-based algorithms to identify stroke in a contemporary Medicare cohort had high positive predictive value and specificity, supporting their use as outcomes for etiologic and comparative effectiveness studies in similar populations. These inpatient algorithms are unsuitable for estimating stroke incidence because of low sensitivity.

Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis.

IntroductionAdministrative claims data have not commonly been used to study the clinical effectiveness of medications for rheumatoid arthritis (RA) because of the lack of a validated algorithm for this outcome. We created and tested a claims-based algorithm to serve as a proxy for the clinical effectiveness of RA medications.MethodsWe linked Veterans Health Administration (VHA) medical and pharmacy claims for RA patients participating in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA). Among individuals for whom treatment with a new biologic agent or nonbiologic disease-modifying agent in rheumatic disease (DMARD) was being initiated and with registry follow-up at 1 year, VARA and administrative data were used to create a gold standard for the claims-based effectiveness algorithm. The gold standard outcome was low disease activity (LDA) (Disease Activity Score using 28 joint counts (DAS28) ≤ 3.2) or improvement in DAS28 by > 1.2 units at 12 ± 2 months, with high adherence to therapy. The claims-based effectiveness algorithm incorporated biologic dose escalation or switching, addition of new disease-modifying agents, increase in oral glucocorticoid use and dose as well as parenteral glucocorticoid injections.ResultsAmong 1,397 patients, we identified 305 eligible biologic or DMARD treatment episodes in 269 unique individuals. The patients were primarily men (94%) with a mean (± SD) age of 62 ± 10 years. At 1 year, 27% of treatment episodes achieved the effectiveness gold standard. The performance characteristics of the effectiveness algorithm were as follows: positive predictive value, 76% (95% confidence interval (95% CI) = 71% to 81%); negative predictive value, 90% (95% CI = 88% to 92%); sensitivity, 72% (95% CI = 67% to 77%); and specificity, 91% (95% CI = 89% to 93%).ConclusionsAdministrative claims data may be useful in evaluating the effectiveness of medications for RA. Further validation of this effectiveness algorithm will be useful in assessing its generalizability and performance in other populations.

Consistency of Knee Pain and Risk of Knee Replacement: The Multicenter Osteoarthritis Study

Objective. To examine whether the consistency or persistence of knee pain, in addition to its severity, predicts incident total knee replacement (TKR). Methods. The Multicenter Osteoarthritis Study (MOST) is a longitudinal study of persons aged 50 to 79 years with symptomatic knee osteoarthritis or at high risk of disease. Subjects were queried about the presence of knee pain on most days of the previous 30 days (i.e., frequent knee pain; FKP) at 2 timepoints: a telephone screen followed by a clinic visit (median separation 4 weeks). We defined a knee as having “consistent pain” if the subject answered positively to the FKP question at both timepoints, “inconsistent pain” if FKP was positive at only one timepoint, or as “no FKP” if negative at both. We examined the association between consistent FKP and risk of TKR using multiple binomial regression with generalized estimating equations. Results. In 3026 persons (mean age 63 yrs, mean body mass index 30.4), 2979 knees (50%) had no FKP at baseline, 1279 knees (21.5%) had inconsistent FKP, and 1696 knees (28.5%) had consistent FKP. Risk of TKR over 30 months was 0.8%, 2.6%, and 8.8% for knees with no, inconsistent, and consistent FKP, respectively. Relative risks of TKR over 30 months were 1.2 (95% CI 0.6–2.3) and 2.3 (95% CI 1.2–4.4) for knees with inconsistent and consistent FKP, compared with those without FKP. This association was consistent across each level of pain severity on the Western Ontario and McMaster Universities Osteoarthritis Index. Conclusion. Consistency of frequent knee pain is associated with an increased risk of TKR independently of knee pain severity.

Validation of ICD‐9‐CM codes to identify gastrointestinal perforation events in administrative claims data among hospitalized rheumatoid arthritis patients

To validate, using physician review of abstracted medical chart data as a gold standard, a claims‐based algorithm developed to identify gastrointestinal (GI) perforation cases among rheumatoid arthritis (RA) patients.

Predicting Hip and Major Osteoporotic Fractures Using Administrative Data

T he Fracture Risk Assessment tool (FRAX) was released in 2008 by the World Health Organization (WHO). The FRAX algorithm uses bone mineral density (BMD) and 11 additional clinical and physiological risk factors to estimate a person’s 10-year probability of hip and other major osteoporotic fracture. The latter is defined by the WHO as a hip, clinical vertebral, distal forearm, or humerus fracture. Ensrud et al, using risk prediction models that included only age and BMD or age and fracture history, concluded that these few risk factors predicted 10-year risk of hip and other major osteoporotic fractures as well as FRAX-based models. We performed a similar evaluation using administrative claims data, which do not include information on BMD. We derived and examined several fracture risk prediction models to determine if demographics, history of fracture, and comorbidities—all identifiable within administrative claims data—could be used to predict hip fracture and major osteoporotic fractures, as well as models with additional clinical information or models de-