Bethan L. Richards

Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative

Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA). Methods. A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008–09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice. Results. A total of 49 242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice. Conclusions. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.

Epidemiology of large-vessel vasculidities

The systemic vasculitides are multisystem disorders characterised by the inflammation of blood vessels and tissue necrosis. Classified by the size of the vessels affected, the large vessel vasculitides include giant cell arteritis (GCA) and Takayasus arteritis (TA). These are anatomically, epidemiologically and clinically distinct conditions. They are often associated with considerable morbidity and mortality. The classification of vasculitis has been an area of controversy for many years and current classification criteria remain suboptimal. Although intensive efforts are under way to improve them, a further understanding of the aetiology and pathogenesis of these diseases is required to develop more sensitive and specific diagnostic tests. These efforts, however, have been hampered by the low prevalence of these diseases. The establishment of national and international registries is encouraged to enhance valuable data collection. These are anatomically, epidemiologically and clinically distinct conditions. This article summarises the current classification systems for systemic vasculitis and their limitations. We also review the presently known epidemiology, risk factors and morbidity and mortality associated with GCA and TA.

Effect of leflunomide on the peripheral nerves in rheumatoid arthritis

Background: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis.

The efficacy and safety of antidepressants in inflammatory arthritis: a Cochrane systematic review.

Objectives. To determine the efficacy and safety of antidepressants in pain management in patients with inflammatory arthritis (IA). Methods. We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any antidepressants (administered via any route) to another analgesic intervention or placebo. We also searched the 2008–2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief ≥ 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. A risk of bias assessment was performed using methods recommended by the Cochrane Collaboration. Results. Eight trials (652 participants) in patients with rheumatoid arthritis (RA) and 1 trial in patients with ankylosing spondylitis (100 participants) were included in this review. The majority of studies were published in the late 1980s in patients with active disease receiving minimal disease-modifying antirheumatic drug therapy. All trials evaluated tricyclic antidepressants (TCA) and 2 studies included a selective serotonin uptake inhibitor. Seven of the 9 trials had high risk of bias, 2 were unclear, and metaanalysis was not performed due to trial heterogeneity. RA trials with short-term outcome (< 1 week) found no significant benefit of amitriptyline 25 mg in combination with dextropropoxyphene (DXP) 65 mg over placebo, and inferiority of amitriptyline + DXP versus DXP 130 mg [mean difference (MD) 10.0, 95% CI 0.4 to 19.6]. There was conflicting evidence regarding medium (1–6 wks) or longer-term (> 6 wks) benefits on pain. One trial in depressed patients with RA showed no significant difference between amitriptyline and paroxetine given for 8 weeks (65% vs 56% much or very much improved; RR 1.2, 95% CI 0.9 to 1.5). One trial found that amitriptyline was no better than placebo in reducing pain in patients with active AS over 2 weeks (MD −0.2, 95% CI −1.2 to 0.8). From 5 trials, withdrawals due to adverse events were not significantly different from placebo. However, there were significantly more minor adverse events in patients receiving TCA compared with those receiving a placebo (RR 2.3, 95% CI 1.2 to 4.4). These included somnolence, dizziness, dry mouth, and nausea. Conclusion. Based upon 9 trials of high or unclear risk of bias, it is not possible to draw firm conclusions about the efficacy of TCA as analgesics for patients with IA. The use of these agents may be associated with adverse events that are generally mild and do not lead to cessation of treatment. High-quality trials are needed in this area.

The OMERACT Ultrasound Working Group 10 Years On: Update at OMERACT 12

Musculoskeletal ultrasound (US) now thrives as an established imaging modality for the investigation and management of chronic inflammatory arthritis. We summarize here results of the Outcome Measures in Rheumatology (OMERACT) US working group (WG) projects of the last 2 years. These results were reported at the OMERACT 12 meeting at the plenary session and discussed during breakout sessions. Topics included standardization of US use in rheumatic disease over the last decade and its contribution to understanding musculoskeletal diseases. This is the first update report of WG activities in validating US as an outcome measure in musculoskeletal inflammatory and degenerative diseases, including pediatric arthritis, since the OMERACT 11 meeting.

An OMERACT reliability exercise of inflammatory and structural abnormalities in patients with knee osteoarthritis using ultrasound assessment

Objective To assess whether ultrasonography (US) is reliable for the evaluation of inflammatory and structural abnormalities in patients with knee osteoarthritis (OA). Methods Thirteen patients with early knee OA were examined by 11 experienced sonographers during 2 days. Dichotomous and semiquantitative scoring was performed on synovitis characteristics in various aspects of the knee joint. Semiquantitative scoring was done of osteophytes at the medial and lateral femorotibial joint space or cartilage damage of the trochlea and on medial meniscal damage bilaterally. Intra- and interobserver reliability were computed by use of unweighted and weighted κ coefficients. Results Intra- and interobserver reliability scores were moderate to good for synovitis (mean κ 0.67 and 0.52, respectively) as well as moderate to good for the global synovitis (0.70 and 0.50, respectively). Mean intra- and interobserver reliability κ for cartilage damage, medial meniscal damage and osteophytes ranged from fair to good (0.55 and 0.34, 0.75 and 0.56, 0.73 and 0.60, respectively). Conclusions Using a standardised protocol, dichotomous and semiquantitative US scoring of pathological changes in knee OA can be reliable.

Outcome Domains and Measures in Total Joint Replacement Clinical Trials: Can We Harmonize Them? An OMERACT Collaborative Initiative

Objective. To develop a plan for harmonizing outcomes for people undergoing total joint replacement (TJR), to achieve consensus regarding TJR outcome research. Methods. The TJR working group met during the 2014 Outcome Measures in Rheumatology (OMERACT) 12 meeting in Budapest, Hungary. Multiple conference calls preceded the face-to-face meeting. Brief presentations were made during a 1.5-h meeting, which included an overview of published systematic reviews of TJR trials and the results of a recent systematic review of TJR clinical trial outcome domains and measures. This was followed by discussion of potential core set areas/domains for TJR clinical trials (as per OMERACT Filter 2.0) as well as the challenges associated with the measurement of these domains. Results. Working group participants discussed which TJR clinical trial outcome domains/areas map to the inner versus outer core for core domain set. Several challenges were identified with TJR outcomes including how to best measure function after TJR, elucidating the source of the pre- and post-TJR joint pain being measured, joint-specific versus generic quality of life instruments and the importance of patient satisfaction and revision surgery as outcomes. A preliminary core domain set for TJR clinical trials was proposed and included pain, function, patient satisfaction, revision, adverse events, and death. This core domain set will be further vetted with a broader audience. Conclusion. An international effort with active collaboration with the orthopedic community to standardize key outcome domains and measures is under way with the TJR working group. This effort will be further developed with new collaborations.

Opioid analgesics for rheumatoid arthritis pain.

CLINICAL QUESTION Do the benefits of opioid analgesics outweigh the risks in patients with persistent pain due to rheumatoid arthritis? BOTTOM LINE Weak opioids (such as codeine, dextropropoxyphene, and tramadol) may be effective in the short-term management of rheumatoid arthritis pain, but adverse effects are common and may outweigh the benefits; alternative analgesics should be considered first.

Efficacy and safety of neuromodulators in inflammatory arthritis: a Cochrane systematic review

Objective. To determine the efficacy and safety of neuromodulators for pain management in patients with inflammatory arthritis. Methods. A Cochrane systematic review was performed as part of the 3e Initiative on pain management in inflammatory arthritis. We searched Medline, Embase, and Cochrane Central for studies to November 2010, and American College of Rheumatology/European League Against Rheumatism meeting abstracts published in 2008–2009. Studies were included if they were randomized or quasirandomized controlled trials that compared any neuromodulator (excluding cannabis) to another therapy (active or placebo, including nonpharmacological therapies) for pain in patients with RA, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis. Primary outcomes of interest were patient-reported pain relief of 30% or greater and withdrawals due to adverse events. Two authors independently extracted data and assessed methodological quality. A risk of bias assessment was performed using the methods recommended by the Cochrane Collaboration. Results. Three trials, all in RA and all at high risk of bias, were included in this review. Two placebo-controlled trials evaluated nefopam (52 participants) and one placebo-controlled trial evaluated topical capsaicin 0.025% (31 participants). Pooled analysis showed a significant reduction in pain levels favoring nefopam over placebo after 2 weeks [weighted mean difference −21.2, 95% CI −35.6 to −6.7; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5]. However, nefopam was associated with significantly more adverse events (RR 4.1, 95% CI 1.6 to 10.7; number needed to harm 9, 95% CI 2 to 367), predominantly nausea and sweating. In one trial, capsaicin reduced pain more than placebo at 1 and 2 weeks (MD −23.8, 95% CI −44.8 to −2.8; NNT 3, 95% CI 2–47, and −34.4, 95% CI −54.7 to −14.14; NNT 2, 95% CI 1.4 to 6, respectively). Of those who received capsaicin, 44% developed burning at the site of application and 2% withdrew as a result. Conclusion. Based on 3 small trials, which were all at high risk of bias, there is weak evidence that nefopam and capsaicin are superior to placebo in reducing pain in patients with RA, but both are associated with a significant side effect profile. There are no available data for other types of IA or for newer agents such as gabapentin or pregabalin.

The Efficacy and Safety of Opioids in Inflammatory Arthritis: A Cochrane Systematic Review

Objective. To determine the efficacy and safety of opioid analgesics in inflammatory arthritis (IA). Methods. We searched Medline, Embase, and Central to May 2010. Randomized controlled trials in adults with IA that compared opioids (administered via any route) to another intervention or placebo were included. Studies in the immediate postoperative setting were excluded. Two authors independently extracted data and assessed risk of bias. Primary endpoints were pain and adverse events (AE). Categorical data were pooled using RevMan5 and reported as relative risks (RR) or odds ratios (OR) with 95% confidence intervals (95% CI). Results. Eleven studies were included, all in patients with RA. The risk of bias of all studies was high. No study was longer than 6 weeks in duration and 4 studies used single doses of study drugs. Seven studies were between 1 and 6 weeks in duration and assessed 6 different oral opioids. Only 1 study investigated a strong opioid. Data could be pooled from 4 studies comparing weak opioids to placebo: there was no difference in withdrawals due to inadequate analgesia (RR 0.82, 95% CI 0.34, 2.01), but patient-reported global impression of change was superior with opioids (RR 1.44, 95% CI 1.03, 2.03). Opioids were more likely than placebo to cause AE (OR 3.90, 95% CI 2.31, 6.56). There was no difference between opioids and placebo in net efficacy after adjustment for AE. Conclusion. Based on 11 heterogeneous studies of short duration and high risk of bias, there is weak evidence that opioids are effective analgesics in RA. AE are common and may offset the benefits. The relative risks and benefits of opioids in IA beyond 6 weeks are unknown.