Jasvinder A. Singh

2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas. The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1). Table 1 Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations METHODS We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below. Systematic Literature Review – Sources, Databases and Domains Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3. The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included. For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System. We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia

DINESH KHANNA, JOHN D. FITZGERALD, PUJA P. KHANNA, SANGMEE BAE, MANJIT K. SINGH, TUHINA NEOGI, MICHAEL H. PILLINGER, JOAN MERILL, SUSAN LEE, SHRADDHA PRAKASH, MARIAN KALDAS, MANEESH GOGIA, FERNANDO PEREZ-RUIZ, WILL TAYLOR, FREDERIC LIOTE, HYON CHOI, JASVINDER A. SINGH, NICOLA DALBETH, SANFORD KAPLAN, VANDANA NIYYAR, DANIELLE JONES, STEVEN A. YAROWS, BLAKE ROESSLER, GAIL KERR, CHARLES KING, GERALD LEVY, DANIEL E. FURST, N. LAWRENCE EDWARDS, BRIAN MANDELL, H. RALPH SCHUMACHER, MARK ROBBINS, NEIL WENGER, AND ROBERT TERKELTAUB

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

2012 American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis

In response to a request for proposal from the American College of Rheumatology (ACR), our group was charged with developing non-pharmacologic and pharmacologic guidelines for treatments in gout that are safe and effective, i.e., with acceptable risk-benefit ratio. These guidelines for the management and anti-inflammatory prophylaxis of acute attacks of gouty arthritis complements our manuscript on guidelines to treat hyperuricemia in patients with evidence of gout (or gouty arthritis) (1). Gout is the most common cause of inflammatory arthritis in adults in the USA. Clinical manifestations in joints and bursa are superimposed on top of local deposition of monosodium urate crystals. Acute gout characteristically presents as self-limited, attack of synovitis (also called “gout flares”). Acute gout attacks account for a major component of the reported decreased health-related quality of life in patients with gout (2, 3). Acute gout attacks can be debilitating and are associated with decreased work productivity (4, 5). Urate lowering therapy (ULT) is a cornerstone in the management of gout, and, when effective in lowering serum urate (SUA), is associated with decreased risk of acute gouty attacks (6). However, during the initial phase of ULT, there is an early increase in acute gout attacks, which has been hypothesized due to remodeling of articular urate crystal deposits as a result of rapid and substantial lowering of ambient urate concentrations (7). Acute gout attacks attributable to the initiation of ULT may contribute to non-adherence in long-term gout treatment, as reported in recent studies (8). In order to systematically evaluate a broad spectrum of acute gouty arthritis, we generated multifaceted case scenarios to elucidate decision making based primarily on clinical and laboratory test-based data that can be obtained in a gout patient by both non-specialist and specialist health care providers in an office practice setting. This effort was not intended to create a novel classification system of gout, or new gout diagnostic criteria, as such endeavors are beyond the scope of this work. Prior gout recommendations and guidelines, at the independent (i.e, non pharmaceutical industry-sponsored) national or multinational rheumatology society level, have been published by EULAR (9, 10), the Dutch College of General Practitioners (11), and the British Society for Rheumatology (BSR)(12). The ACR requested new guidelines, in view of the increasing prevalence of gout (13), the clinical complexity of management of gouty arthritis imposed by co-morbidities common in gout patients (14), and increasing numbers of treatment options via clinical development of agents(15–17). The ACR charged us to develop these guidelines to be useful for both rheumatologists and other health care providers on an international level. As such, this process and resultant recommendations, involved a diverse and international panel of experts. In this manuscript, we concentrate on 2 of the 4 gout domains that the ACR requested for evaluation of pharmacologic and non-pharmacologic management approaches: (i) analgesic and anti-inflammatory management of acute attacks of gouty arthritis, and (ii) pharmacologic anti-inflammatory prophylaxis of acute attacks of gouty arthritis. Part I of the guidelines focused on systematic non-pharmacologic measures (patient education, diet and lifestyle choices, identification and management of co-morbidities) that impact on hyperuricemia, and made recommendations on pharmacologic ULT in a broad range of case scenarios of patients with disease activity manifested by acute and chronic forms of gouty arthritis, including chronic tophaceous gouty arthropathy(1). Each individual and specific statement is designated as a “recommendation”, in order to reflect the non-prescriptive nature of decision making for the hypothetical clinical scenarios. So that the voting panel could focus on gout treatment decisions, a number of key assumptions were made, as described in Part I of the guidelines (1). Importantly, each proposed recommendation assumed that correct diagnoses of gout and acute gouty arthritis attacks had been made for the voting scenario in question. For treatment purposes, it was also assumed that treating clinicians were competent, and considered underlying medical comorbidities (including diabetes, gastrointestinal disease, hypertension, and hepatic, cardiac, and renal disease), and potential drug toxicities and drug-drug interactions, when making both treatment choicesand dosing decisions on chosen pharmacologic interventions. The RAND/UCLA methodology used here emphasizes level of evidence, safety, and quality of therapy, and excludes analyses of societal cost of health care. As such, the ACR gout guidelines are designed to reflect best practice, supported either by level of evidence or consensus-based decision-making. These guidelines cannot substitute for individualized, direct assessment of the patient, coupled with clinical decision making by a competent health care practitioner. The motivation, financial circumstances, and preferences of the gout patient also need to be considered in clinical practice, and it is incumbent on the treating clinician to weigh the issues not addressed by this methodology, such as treatment costs, when making management decisions. Last, the guidelines for gout management presented herein were not designed to determine eligibility for health care cost coverage by third party payers.

A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis

Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.

A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview

Background: We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis. Methods: In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics. Results: Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62–4.29) and a number needed to treat for benefit of 4 (95% CI 4–6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13–1.71), with a number needed to treat for harm of 52 (95% CI 29–152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21–0.99) and etanercept (OR 0.34, 95% CI 0.14–0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18–3.04; anakinra OR 2.05, 95% CI 1.27–3.29; and infliximab OR 2.70, 95% CI 1.43–5.26). Interpretation: Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis: ACR RA Treatment Recommendations

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

Anakinra for rheumatoid arthritis: a systematic review.

Objective. To perform a systematic review of clinical effectiveness and safety of anakinra in rheumatoid arthritis (RA). Methods. We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and the reference lists of included articles for randomized controlled trials comparing anakinra to placebo in adults with RA. Results. Five trials involving 2846 patients, 781 randomized to placebo and 2065 to anakinra, were included. There was a significant improvement in the number of participants achieving American College of Rheumatology (ACR)20 (38% vs 23%) treated with anakinra 50–150 mg daily versus placebo after 24 weeks. ACR50 (18% vs 7%), ACR70 (7% vs 2%), Health Assessment Questionnaire, visual analog scale for pain, Larsen radiographic scores, and erythrocyte sedimentation rate all demonstrated significant improvement with anakinra versus placebo as well. There were no statistically significant differences noted in the number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). An increase in incidence of serious infections in anakinra versus the placebo group (1.8% vs 0.6%) was noted that may be clinically significant. Injection site reactions were significantly increased, occurring in 71% of anakinra versus 28% of placebo group. Conclusion. Anakinra is a relatively safe and modestly efficacious biologic therapy for RA. More studies are needed to evaluate safety and efficacy, especially in comparison to other therapies, and adverse event data for the longterm use of anakinra have yet to be assessed.

Gout is associated with more comorbidities, poorer health-related quality of life and higher healthcare utilisation in US veterans

Objective: To better understand the impact of gout on functional status, health-related quality of life (HRQoL), mortality and healthcare utilisation in US veterans. Methods: All veterans seen in Veterans Integrated Service Network-13 from 1 October 1996 to 31 March 1998 received mailed surveys asking about demographic characteristics; performance of activities of daily living and HRQoL by Short Form-36 (SF-36) for Veterans. Administrative data included demographics; inpatient/outpatient healthcare utilisation; ICD-9 codes for gout, medical comorbidities and arthritis excluding gout—“arthritic comorbidity” and 1-year mortality. Multivariable estimates compared results between veterans with/without gout using least means squared. Results: Subjects with gout were significantly older, retired, not married, current non-smokers, with more comorbidities. Multivariable-adjusted bodily pain was somewhat worse (49.7 vs 47.1, p<0.01) and mental health (66.7 vs 68.6, p<0.01) domain scores somewhat better in patients with gout, both differences significant but not clinically meaningful (less than threshold of 5–10 points); other SF-36 domain and summary scores and functional limitations were similar. Medical or arthritic comorbidities predicted clinically/statistically lower adjusted scores in all SF-36 domains and physical domains (physical component summary), respectively. Patients with gout had significantly more annual primary care visits (3.5 vs 2.7, p<0.001) and admissions to hospital (18.3% vs 15.1%, p<0.01), fewer mental health visits (10.1% vs 13.7%, p<0.01) and similar mortality (2.6% vs 2.2%, p = 0.23). Conclusions: Gout is independently associated with higher medical and arthritic comorbidity, primary care and inpatient utilisation. Poorer HRQoL, functional limitation and higher mortality noted in univariate analyses in patients with gout were attributable to higher comorbidity and sociodemographic characteristics.

Periprosthetic infections after total shoulder arthroplasty: a 33-year perspective.

BACKGROUND To examine the rates and predictors of deep periprosthetic infections after primary total shoulder arthroplasty (TSA). METHODS We used prospectively collected data on all primary TSA patients from 1976-2008 at Mayo Clinic Medical Center. We estimated survival free of deep periprosthetic infections after primary TSA using Kaplan-Meier survival. Univariate and multivariable Cox regression was used to assess the association of patient-related factors (age, gender, body mass index), comorbidity (Deyo-Charlson index), American Society of Anesthesiologists class, implant fixation, and underlying diagnosis with risk of infection. RESULTS A total of 2,207 patients, with a mean age of 65 years (SD, 12 years), 53% of whom were women, underwent 2,588 primary TSAs. Mean follow-up was 7 years (SD, 6 years), and the mean body mass index was 30 kg/m(2) (SD, 6 kg/m(2)). The American Society of Anesthesiologists class was 1 or 2 in 61% of cases. Thirty-two confirmed deep periprosthetic infections occurred during follow-up. In earlier years, Staphylococcus predominated; in recent years, Propionibacterium acnes was almost as common. The 5-, 10-, and 20-year prosthetic infection-free rates were 99.3% (95% confidence interval [CI], 98.9-99.6), 98.5% (95% CI, 97.8-99.1), and 97.2% (95% CI, 96.0-98.4), respectively. On multivariable analysis, a male patient had a significantly higher risk of deep periprosthetic infection (hazard ratio, 2.67 [95% CI, 1.22-5.87]; P = .01) and older age was associated with lower risk (hazard ratio, 0.97 [95% CI, 0.95-1.00] per year; P = .05). CONCLUSIONS The periprosthetic infection rate was low at 20-year follow-up. Male gender and younger age were significant risk factors for deep periprosthetic infections after TSA. Future studies should investigate whether differences in bone morphology, medical comorbidity, or other factors are underlying these associations.