Dinesh Khanna

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.

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Definitions and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥ 25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone.

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

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

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.

Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study

Objective Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. Methods In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. Results Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. Conclusions The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.

The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context

Introduction Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN. Methods and analysis SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500–2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions. Ethics and dissemination The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

Summary BACKGROUND Twelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC. METHODS Patients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed. RESULTS Between November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores. INTERPRETATION Treatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile. FUNDING National Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.

Distinctions between diagnostic and classification criteria

Rheumatologists face unique challenges in discriminating between rheumatologic and non-rheumatologic disorders with similar manifestations, and in discriminating among rheumatologic disorders with shared features. The majority of rheumatic diseases are multisystem disorders with poorly understood etiology; they tend to be heterogeneous in their presentation, course, and outcome, and do not have a single clinical, laboratory, pathological, or radiological feature that could serve as a “gold standard” in support of diagnosis and/or classification. Thus, the development of criteria for use in routine clinical care and in clinical research has been an important focus in rheumatology. Improved understanding of disease pathogenesis and new diagnostic tools have led to reexamination of existing classification and diagnostic criteria with updated classification criteria for some diseases being endorsed recently (1, 2). The American College of Rheumatology (ACR) Subcommittee on Classification and Response Criteria is responsible for guiding the development and validation of new classification and response criteria that are eventually considered for ACR endorsement. This includes review of proposals for the development of new criteria sets and providing the ACR leadership with recommendations for development and approval of new classification and response criteria sets (1, 3–5). The Subcommittee has previously published a guidance paper for the development of classification and response criteria (6). This prior work has provided details about the rationale for the ACR’s position on classification criteria, but clarification around the issue of diagnostic criteria was lacking. Indeed, the ACR endorsed preliminary diagnostic criteria for fibromyalgia (7) in 2010, which prompted discussions about whether the Subcommittee should also support the development and ACR endorsement of diagnostic criteria, in addition to that of classification and response criteria. The primary objectives of this current article, by former and current members of the Subcommittee on Classification and Response Criteria, are to compare diagnostic and classification criteria, using specific examples from the published literature, and to clarify the ACR’s position on both types of criteria.