Orrin Troum

Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study

Objective: To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment. Methods: A randomised, open-label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events. Results: At week 16, 62% of infliximab-treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule-1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. Conclusions: In this exploratory, open-label trial (with single-blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis-generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.

Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study

Objective To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. Methods ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2. Results 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients. Conclusions Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.

Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

Objective To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. Methods ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. Results Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). Conclusions Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. Trial registration number NCT00810199.

The Young Adult With Hip Pain: Diagnosis and Medical Treatment, Circa 2004

Hip pain in young adults (18-35 years old) often is characterized by nonspecific symptoms, normal imaging studies, and vague findings from the history and physical examination. In younger patients, pain is more likely to be caused by congenital hip dysplasia, athletic injuries, trauma, spondyloarthropathy, and by conditions that first appear during this stage of life, such as rheumatoid arthritis, osteoarthritis, intravenous drug use, alcoholism, or corticosteroid use. The history and physical examination may narrow the diagnosis to intraarticular, extraarticular, or referred sources of pain. Plain radiography and magnetic resonance imaging are the preferred initial imaging procedures. Analyses of the blood, urine, and synovial fluid can be helpful in diagnosing inflammation, infection, and systematic rheumatic disease. Fractures, infection, and ischemic necrosis should be ruled out early because they require immediate treatment to prevent damage to the joint. Hip trauma at a young age increases the risk of osteoarthritis with advancing age, and, unlike most older adults, young adults receiving total hip replacement can expect revision surgery. Medical treatment often involves patient education, physical therapy, and pharmacotherapy. Acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids for pain and antibiotics for infection are the most often prescribed drugs for this population.

The effects of tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the ACT-RAY MRI substudy

Objective To examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI. Methods In a substudy of a randomised, double-blind, phase 3b study (ACT-RAY) of biologic-naïve patients with RA who were methotrexate (MTX)-inadequate responders, 63 patients were randomised to continue MTX or receive placebo (PBO), both in combination with TCZ 8 mg/kg every 4 weeks, with optional additional disease-modifying antirheumatic drugs at week 24 if Disease Activity Score of 28 joints < 3.2. The most symptomatic hand was imaged with 0.2 Tesla extremity MRI at weeks 0, 2, 12 and 52. MR images were scored using Outcome Measures in Rheumatology–Rheumatoid Arthritis Magnetic Resonance Imaging Score. Predictors of week 52 erosion progression were determined by logistic regression analysis. Results TCZ + PBO (n=32) demonstrated mean improvements in synovitis from baseline to weeks 2 (−0.92; p=0.0011), 12 (−1.86; p<0.0001) and 52 (−3.35; p<0.0001), while TCZ + MTX (n=31) had mean improvements in synovitis at week 12 (−0.88; p=0.0074), but not week 52 (−1.00; p=0.0711). TCZ+PBO demonstrated mean reductions in osteitis at weeks 12 (−5.10; p=0.0022) and 52 (−8.56; p=0.0006), while TCZ+MTX had mean reductions at weeks 2 (−0.21; p<0.05) and 12 (−3.63; p=0.0008), but not week 52 (−2.31; p=0.9749). Mean erosion scores did not worsen in either group. MRI erosion scores at weeks 12 and 52 correlated strongly with radiography erosion scores at week 52 (r>0.80). Baseline synovitis and worsening of osteitis predicted erosion progression. Conclusions Rapid suppression of synovitis and osteitis with reduction in structural joint damage progression occurred with TCZ, as monotherapy or in combination with MTX, through week 52.

Rheumatoid Arthritis Disease Activity and Disability Affect the Risk of Serious Infection Events in RADIUS 1

Objective. To determine whether disease activity and disability independently correlate with serious infection event (SIE) risk in a large rheumatoid arthritis (RA) cohort. Methods. The associations between SIE and Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in the Rheumatoid Arthritis Disease-Modifying Antirheumatic Drug Intervention and Utilization Study (RADIUS 1) cohort were evaluated using the Andersen-Gill model (a proportional HR model allowing > 1 event per patient). Results. Of 4084 patients with 347 SIE, 271 patients experienced ≥ 1 SIE. A 5-unit CDAI increase and 0.4-unit HAQ-DI increase corresponded to an increase in SIE risk with and without covariate adjustments. A 5-unit CDAI increase corresponded with a 7.7% increased SIE risk (adjusted HR 1.077, 95% CI 1.044–1.112, p < 0.0001) and a 0.4-unit HAQ-DI increase with a 30.1% increased risk (adjusted HR 1.301, 95% CI 1.225–1.381, p < 0.0001). Categorical analysis showed that more severe RA activity (even after controlling for disability) and disability were associated with an increased SIE risk. Conclusion. Increased RA disease activity and disability were each associated with a significantly increased SIE risk in the RADIUS 1 cohort, which could not be completely accounted for by disability.

Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials

Objective In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray. Methods Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses. Results Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively). Conclusions Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

Examining the validity of the rheumatoid arthritis magnetic resonance imaging score according to the OMERACT filter—a systematic literature review

Objective To examine whether the RA MRI score (RAMRIS) for RA of the wrist/hand meets the OMERACT filter criteria-truth (validity), discrimination and feasibility. Methods We conducted a systematic literature review in PubMed and Scopus, from 1970 through June 2014, focused on MRI measures of synovitis, osteitis/bone marrow oedema, erosions and/or joint space narrowing in RA randomized controlled trials and observational studies with cohort size ⩾10. Strength of evidence was assessed using the Cochrane Handbook criteria. Results Of 634 MRI titles/abstracts, 202 met the review criteria, with 92 providing at least 1 type of validity. Four articles provided criterion validity, and 26 articles utilized RAMRIS to assess 1.5 T MRI images. Histopathology data showed inflammation corresponding to MRI of synovitis and osteitis. MRI erosions corresponded to those identified with CT. Content and construct validity for RAMRIS synovitis, osteitis and erosions were documented by correlations with clinical, laboratory and/or radiographic data. Each measure was sensitive to change and responsive to therapy. RAMRIS synovitis and osteitis were able to discriminate between the efficacy of treatments vs placebo in 12-week studies, whereas RAMRIS erosions required studies of ⩾24 weeks. Conclusion RAMRIS synovitis, osteitis and erosions imaged with 1.5 T MRI are valid and useful for evaluating joint inflammation and damage for RA of the wrist/hand, according to the OMERACT filter.

Proceedings from the 7th Annual International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) conference

The International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) was founded in 2005 with the goal of discussing matters related to imaging in rheumatology, particularly, validation, education, and use in clinical practice and research. Because the field of musculoskeletal (MSK) imaging is rapidly evolving, continuous education in the field is imperative. ISEMIRs international faculty and world-renowned experts presented the newest information as it relates to the use of magnetic resonance imaging (MRI) and ultrasound (US) at the 7th annual ISEMIR meeting which took place on April 12-14, 2014 in Santa Monica, California. Presentations from the meeting can be viewed at www.isemir.org.

SAT0370 Association of renal dysfunction and development of tophi in subjects with chronic refractory gout and response to treatment with pegloticase

Background Many, but not all patients with chronic refractory gout develop tophi; and the factors that govern tophus formation are not known. To address this question, we assessed subjects enrolled in the pivotal trials of pegloticase, a mammalian recombinant uricase conjugated to polyethylene glycol that is approved for the treatment of gout refractory to conventional oral urate lowering therapy. Objectives To determine the factors associated with the presence of tophi in patients with chronic refractory gout. Methods This analysis used results from two pivotal randomised controlled trials (RCTs)1,2 to assess the clinical characteristics of subjects with chronic refractory gout and effects of treatment with pegloticase. Overall, 73% of the subjects in these trials had clinically apparent tophi at baseline and 27% did not. Demographic features of these subjects were assessed and renal function was evaluated by measurement of estimated glomerular filtration rate (eGFR). Subjects were treated with pegloticase, 8 mg every other week (q2w) in a 6 month RCT and then followed for up to 3 years in an open label extension (OLE). Results The analysis included subjects with chronic refractory gout, 154 with tophi at baseline and 57 without tophi. Chronic refractory gout subjects in the two groups were generally similar at baseline, but with a difference in disease duration: 16.3 years for tophaceous subjects vs 11.7 years for subjects without tophi (p=0.007). There were no significant differences in most comorbidities for the two groups. However, eGFR was significantly lower in the subjects with tophi (85.2 mL/min) vs those without tophi (116.5 mL/min) (p=0.001). The frequency of tophi increased in subjects with lower eGFR values (Table). Six months of treatment with pegloticase (8 mg q2w) in a subgroup of subjects resulted in complete or partial resolution of at least one tophus with no increase in others in 74% of subjects, but had no significant effect on renal function measured by eGFR (78.8 mL/min vs 84.2 mL/min, n=51, p=0.7). Continued treatment with pegloticase in the OLE further decreased the burden of tophi, but had no significant effect on renal function measured by eGFR (75.7 mL/min, p=0.6).Abstract SAT0370 – Table 1 Baseline eGFR(mL/min) Non-tophaceous(n=57) Tophaceous(n=154) ≥90 (n=97) 33 (34.0%) 64 (66.0%) 60 to<90 (n=54) 16 (29.6%) 38 (70.4%) 30 to<60 (n=43) 5 (11.6%) 38 (88.4%) 15 to<30 (n=17) 3 (17.6%) 14 (82.4%) p=0.0094, Cochran-Mantel-Haenszel chi square test Conclusions These results indicate that chronic refractory gout patients may present with or without clinically apparent tophi. A significant association was noted between the presence of renal dysfunction measured by eGFR and the frequency with which chronic refractory gout patients manifested tophi. Pegloticase treatment markedly decreased the tophus burden, but in this analysis did not improve renal function. These results suggest that renal failure may predispose patients to tophus formation, whereas the resolution of tophi in this analysis did not appear to improve renal function. References [1] Sundy JS, Baraf HS, Yood RA, et al. JAMA2011;306:711–720. [2] Baraf HS, Becker MA, Gutierrez-Urena SR, et al. Arthritis Res Ther2013;15:R137. Disclosure of Interest N. L. Edwards Consultant for: AstraZeneca, Horizon Pharma, Ironwood Pharmaceuticals, SOBI International, J. Singh: None declared, O. Troum Shareholder of: Theralogix, Grant/research support from: Abbvie, Amgen, CORONA, Novartis, Pfizer, R-Pharm, Consultant for: Abbvie, Amgen, BMS, Pfizer, Roche, Genentech, Speakers bureau: Abbvie, Amgen, BMS, Celgene, Novartis, Pfizer, Roche, Genentech, A. Yeo Consultant for: Horizon Pharma, P. Lipsky Consultant for: Horizon Pharma