Samuel L Whittle

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.

Active foot synovitis in patients with rheumatoid arthritis: applying clinical criteria for disease activity and remission may result in underestimation of foot joint involvement.

OBJECTIVE To determine whether application of criteria for remission in rheumatoid arthritis (RA) may result in underestimation of foot joint involvement among patients in a clinic setting. METHODS RA patients (n = 123) were assessed at baseline and 6 months after commencement of a response-driven combination disease-modifying antirheumatic drug (DMARD) protocol. Remission was assessed using disease activity measures (the 28-joint Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index [CDAI]) as well as Boolean-based criteria for remission (the 1981 American College of Rheumatology [ACR] preliminary criteria and the 2011 ACR/European League Against Rheumatism [EULAR] provisional criteria). The prevalence of foot synovitis and the mean swollen/tender foot joint count in RA patients meeting any of these remission criteria were estimated by hurdle (mixed distribution) regression. RESULTS In patients who received 6 months of combination DMARD treatment, application of the 1981 ACR criteria and the newly proposed 2011 ACR/EULAR criteria, each utilizing full joint counts (which includes assessment of the feet), classified the least number of patients as being in remission (8-10%), and evidence of foot synovitis was minimal among these patients. In contrast, ongoing foot synovitis was present in a substantial proportion of patients (>20%) meeting the 28-joint count criteria for remission, including the DAS28-ESR, SDAI, CDAI, and 2011 ACR/EULAR criteria (clinical practice setting or clinical trials). Furthermore, applying the 2011 ACR/EULAR composite remission criterion of a SDAI score ≤3.3 to define remission did not adequately capture the resolution of foot synovitis (i.e., residual foot involvement was still detected in a substantial proportion of patients classified as being in remission by this definition). CONCLUSION Although the DAS28-ESR, CDAI, and SDAI have been validated for assessment of remission in RA, this study shows that the performance of these 3 disease activity measures, which do not provide a direct assessment of the foot, in detecting foot synovitis is poor, in contrast to that of the 1981 ACR and 2011 ACR/EULAR remission criteria utilizing full joint counts. Thus, patients may be at risk of ongoing damage if treatment decisions are made solely on the basis of criteria that omit foot joint assessment.

Tumour necrosis factor inhibitors and risk of serious infection in rheumatoid arthritis.

Tumour necrosis factor inhibitors have demonstrated significant clinical and radiological benefits in rheumatoid arthritis (RA). However, they have important adverse effects including an association with infection. Results from current studies, including meta‐analyses of randomized controlled trials and observational studies, are conflicting regarding the risk of serious infection in RA patients treated with TNF inhibitors. The majority of data suggest an increased risk, in particular of respiratory, skin and soft tissue infections, including tuberculosis. This increased risk of tuberculosis is of particular concern in the APLAR region. However, adverse event analysis remains a difficult area to study and decisions regarding initiation of TNF inhibitors must be made on a case‐by‐case basis after carefully considering the risks and benefits.

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.

Australian and New Zealand recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e Initiative

To develop evidence‐based recommendations for the diagnosis and management of gout in Australia and New Zealand as part of the multi‐national 3e Initiative.

In the clinic. Rotator cuff disease.

Clinical Slide Set. Rotator Cuff Disease Shoulder pain is a common musculoskeletal disorder and has a substantial negative effect on quality of life. Its monthly prevalence in the general population is reported to be between 18% and 31%, whereas lifetime prevalence ranges between 6.7% and 66.7% (1). Shoulder pain is the third most frequent musculoskeletal reason to present to primary care (2) and accounts for up to 10% of all referrals to physical therapists (3). Although the natural history of shoulder pain varies and is often self-limiting, up to half of persons who present for care, particularly the elderly, might continue to have pain and/or functional disturbance for up to 2 years after presentation (4). The rotator cuff (RC) comprises the supraspinatus, infraspinatus, subscapularis, and teres minor muscles, which envelop the shoulder joint and facilitate both movement and dynamic stabilization of the joint throughout its large range of motion. Disorders of the RC are the most common cause of shoulder pain in primary care: In 1 primary care study of shoulder pain presentations, a clinical diagnosis of RC tendinopathy was made in 85% of cases (5). Numerous descriptive terms for pathology affecting the RC and related anatomical structures have been used in clinical practice and the literature. This is often confusing for patients and clinicians alike. The use of “rotator cuff disease” as an umbrella term allows a simpler categorization of all symptomatic disorders of the RC, regardless of mechanism (inflammatory, degenerative, or acute injury) or precise anatomical location (e.g., supraspinatus tendon versus subacromial bursa) (6). Although anatomical descriptions of the RC muscles often imply that they are independent structures, in practice the entire RC acts as an integrated functional unit. RC disease includes diagnostic terms, such as rotator cuff tendinopathy or tendinitis, tears of the cuff muscles, the impingement syndrome, calcific tendinitis, and subacromial bursitis, but excludes adhesive capsulitis (“frozen shoulder”) and other disorders of the glenohumeral joint. The prevalence of RC tears increases with age. In a cross-sectional study in the general population, the prevalence of sonographically defined, full-thickness RC tears was 22.1% and increased with each decade of life from 10.7% for persons in their 50s to 36.6% for persons 80 years or older, and two thirds of tears were asymptomatic (7). The prevalence of partial-thickness tears and altered tendon morphology in the general population is likely to be even greater. Full-thickness RC tears may be detected in as many as 1 in 6 asymptomatic adults in the general population (8), although 1 study reported that up to 50% of older individuals (mean age 70 years, range 52 to 85) with asymptomatic tears develop pain within 5 years (9). Calcific tendinitis is an uncommon form of RC disease (10). The exact pathophysiologic relevance of calcium deposits in the RC tendons is unclear. While calcium deposition may be seen in as many as 6.8% of patients with shoulder pain, prevalence estimates for calcium deposition in the RC of asymptomatic shoulders range from 2% to 20% (11). Prevention What are the risk factors for rotator cuff disease? Risk factors for RC disease are those that affect the structural resilience of the RC and/or place excessive biomechanical demand on the RC. The most important risk factor is age. Age-related changes in collagen composition in the tendons of the RC are seen even in macroscopically normal tendons and are believed to predispose the tendon to the inflammation and failure seen in RC disease. Other intrinsic risk factors include obesity, smoking, diabetes mellitus, genetics, and various anatomical factors, particularly those that reduce the supraspinatus outlet area in the subacromial space (11). The most important extrinsic risk factors are occupational and sporting activities. Although the pathology underlying RC disease is likely to be multifactorial, it is believed that repeated abduction of the shoulder may damage the supraspinatus tendon by impinging on the inferior surface of the acromion. The anatomy of the acromion and development of fatigue or imbalance of muscular strength in the RC muscles may also predispose to subacromial impingement (12). There is evidence that manual work is a predisposing factor for RC disease. In 1 study at a shipyard, the prevalence of supraspinatus tendinitis was higher in welders than in age-matched office workers (13). In a study of manual workers, a higher frequency of exposure to forceful upper-limb tasks that required high hand grip strength was a risk factor for RC tendinitis (14). A more recent study showed that manual labor involving repetitive use of the arms above shoulder level that is perceived by the worker as heavy physical labor is a risk factor for RC disease (odds ratio [OR], 3.3; 95% CI, 1.3 to 8.4), although age is a stronger risk factor in a working population (OR, 4.7; CI, 2.2 to 10.0 for men aged 45 to 49 vs. men younger than 40). Other occupational risk factors also seem to be important, including lack of social support from coworkers (15). Professional and recreational athletes who engage in sports with frequent overhead activity (such as tennis, swimming, gymnastics, and volleyball) and particularly sports that involve throwing (such as baseball, cricket, and water polo) are at increased risk for RC disease due to persistent and often severe biomechanical load on the muscles of the RC in an abducted and externally rotated position (16). Injury to the RC may occur even in adolescent athletes. Other professionals that place unusual biomechanical demands on the shoulder, such as orchestral musicians, may also be at increased risk for RC disease. Are there measures that can prevent rotator cuff disease or its recurrence? Interventions in the workplace to reduce excessive overhead activity or loading of the shoulder in the abducted position may help to reduce the risk for RC disease. If overhead activities cannot be avoided or modified, exercises designed to improve the flexibility of the RC and strengthen the muscles of the cuff and the scapular stabilizing muscles may help to prevent RC disease (Figure). Whereas workplace-based interventions and strength training may be effective in reducing nonspecific upper-limb pain in workers, there are no controlled trials that allow for definitive recommendations regarding the prevention of RC pathology for specific occupations (17). Figure. Scapular stabilizing, isometric, and supraspinatus strengthening exercises. There is a consensus that exercise and stretching programs directed at the muscles of the shoulder girdle are worthwhile measures toward minimizing risk for shoulder injury in at-risk athletes; however, no controlled trials have specifically demonstrated the efficacy of this approach. In athletes, training directed at specific shoulder movements (e.g., throwing) may result in unbalanced strength development in the RC muscles, which may interfere with the role of the cuff in centering the humeral head in the glenoid fossa during abduction and predispose to subacromial impingement. Because the infraspinatus is the primary muscle that counteracts the tendency of the deltoid muscle to pull the humeral head superiorly during abduction, preventive exercise regimens in athletes often focus on isolating and preserving the relative strength of the infraspinatus with external rotation exercises (18). Clinical Bottom Line: Prevention RC disease is the most common cause of shoulder pain in primary care. Disorders of the RC increase in prevalence with age, but are frequently asymptomatic or self-limiting. Occupational or sporting activities that require repetitive overhead use of the arms increase the risk for RC disease. Shoulder-strengthening exercises and workplace interventions might help to reduce this risk. Diagnosis What symptoms are suggestive of rotator cuff disease? A complete and accurate history remains fundamental to diagnosis, proper understanding of the personal and occupational impact of the symptoms on the individual patient, and tailoring the management plan. RC disease is common in middle-aged and older persons and usually has a nontraumatic onset, except in the case of acute traumatic RC tears. Patients typically describe pain in the upper arm near the deltoid insertion that is exacerbated by overhead activity or is worse at night, particularly when lying on the affected side (19). Patients may also describe weakness or loss of function, and the symptoms may have important emotional and financial consequences. While history-taking remains the cornerstone of the complete clinical encounter, there is little evidence that allows quantification of the diagnostic utility of individual findings in the history in patients with suspected RC disease. A recent systematic review identified only 2 studies, both of low methodological quality, that investigated the diagnostic accuracy of history-taking for RC disease (20). Neither pain during sleep nor pain with motion was found to be helpful in identifying patients with RC tears. However, there are few data regarding the diagnostic accuracy of individual symptoms in RC disease without tears, and interpretation of existing observational studies is hampered by the diversity of classification systems and descriptions of shoulder disorders (6, 19). What physical examination findings and maneuvers during the examination are helpful? The physical examination plays an important role in the diagnosis of RC disease. Pain in the shoulder may arise from structures including the glenohumeral joint, the glenoid labrum, the joint capsule, the RC, and the acromioclavicular (AC) joint. Referred pain from the viscera and cervical radicular pain should be specifically considered in the history and examination. A standard shoulder examination should include adequate exposure of the shoul

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.

Prolonged remission of chronic reactive arthritis treated with three infusions of infliximab.

Reactive arthritis is generally self-remitting but can be chronic. Predictors of chronicity include HLA B27 positivity and triggering infections with Yersinia, Salmonella, Shigella, or Chlamydia. Nonsteroidal antiinflammatory drugs and local steroids are the mainstays, with some evidence for disease modifying antirheumatic drugs. Limited evidence suggests effectiveness of tumor necrosis factor antagonists. We report the case of reactive arthritis following a Chlamydia urinary tract infection progressing to a chronic course, treated with a short course of high dose tumor necrosis factor antagonist, followed up for over 2 years with prolonged remission, allowing discontinuation of disease modifying antirheumatic drug therapy.