Elizaveta Vaysbrot

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).

Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis

Knee osteoarthritis (OA) is a common and progressive joint disease affecting more than 250 million people worldwide (1). It has significant effects on function (2) and considerable societal costs in terms of work loss (3), early retirement, and joint replacement (4). Osteoarthritis is a leading indication for use of prescription drugs, which costs about

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

3000 per year per patient (5). In the absence of effective disease-modifying medical treatments, a range of symptomatic treatments is available. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medicines for OA yet have significant toxicity, especially among the demographic groups in which the disorder is most prevalent (6). Intra-articular (IA) treatments are widely used, although their efficacy and safety remain in question. More knowledge about the comparative efficacy and toxicity of these compounds, which would be helpful for patients, physicians, payers, and policymakers, is needed to formulate rational treatment algorithms for OA. The relative effectiveness of OA treatments is difficult to discern from the literature, in part because few head-to-head comparison studies are available and traditional pairwise meta-analysis cannot integrate all of the evidence from several comparators. Therefore, our goal was to comprehensively review the literature and determine the relative efficacy of the primary knee OA treatments using a network meta-analysis design. Methods Data Sources and Searches We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Central Register of Controlled Trials from inception to 15 August 2014 (Supplement Table 1). All searches were limited to randomized, controlled trials in humans. No limits were applied for language, publication date, or publication status, and foreign-language papers were translated. We also hand-searched the reference lists of all retrieved studies and conference proceedings of the American Association of Orthopedic Surgeons, American College of Rheumatology, British Society for Rheumatology, European League Against Rheumatism, International League of Associations of Rheumatology, and Osteoarthritis Research Society International. The conference proceedings were searched from January 1990 to August 2014. We attempted to identify unpublished data by searching the Food and Drug Administration registry, ClinicalTrials.gov, product inserts, and pharmaceutical company Web sites, and by contacting experts, study authors, manufacturers, and primary authors of abstracts with incomplete data. Supplement. Data Supplement Study Selection We included all randomized, controlled trials involving adult human participants with clinical or radiologic diagnosis of symptomatic primary knee OA that compared at least 2 interventions of interest and reported extractable data for at least 1 measure of pain, function, or stiffness. On the basis of the treatment recommendations from the latest clinical practice guidelines for knee OA (7, 8) and the current prescription patterns worldwide (6), we included the following interventions and comparators: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, IA corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. We did not include nonrandomized studies because they generally lacked the high quality of the randomized evidence; without individual-participant data, we could not properly adjust effect estimates for potential confounders. Two reviewers independently screened all titles and abstracts identified by the searches. Full manuscripts of studies screened as potentially relevant by either reviewer were obtained and assessed by 2 independent reviewers according to the aforementioned criteria. Any discrepancies were resolved by consensus. Data Extraction and Quality Assessment After developing a data extraction form, we tested it on 10 randomly selected, included studies and refined accordingly. After completing an a priori training exercise, 2 reviewers independently extracted data from each study. The data were reviewed for consistency between the 2 extractors, and any disagreements were resolved by consensus. For each study, data extraction details included design, selection criteria, population characteristics, treatments, outcome measures, length of follow-up, and results. The outcome measures of interest were change from baseline in pain, function, and stiffness scores reported at 3-month follow-up. If 3-month data were not available, we used data from 2 to 6 months (the data point closest to 3 months was given preference). Intention-to-treat analysis data were used whenever available. When an article provided data on more than 1 outcome scale or a different outcome from the same construct, we extracted data from the scale that was highest on the hierarchy of suggested outcomes for meta-analysis of knee OA trials (9). Two independent reviewers assessed individual study quality using the Cochrane risk-of-bias tool, with any discrepancies resolved by consensus (10). We investigated the effect of study quality on results in the sensitivity analysis. Data Synthesis and Analysis Because the studies used different outcome measures, the change from baseline Western Ontario and McMaster Universities OA Index (WOMAC), visual analogue scale (VAS), and Likert scale scores in each study was translated into Hedges g effect sizes (11). Hedges g is defined as the difference in change from baseline between 2 interventions divided by the pooled SD of the differences, with corrections for small sample sizes. To assess potential heterogeneity among the studies, we calculated the between-study variance and examined baseline characteristics of participants, interventions, outcomes, and study quality. Network Meta-analysis A network meta-analysis synthesizes all available evidence within a consistent framework, thereby fully preserving the randomization within each trial (12). It accounts for multiple comparisons within a trial when there are more than 2 treatment groups (1315). This method considers all trials simultaneously and enables integration of direct evidence from head-to-head trials (when they exist) with indirect evidence (obtained from comparisons of treatments through their common reference) (16). To account for the expected clinical and methodological heterogeneity, we used Bayesian hierarchical random-effects models for mixed multiple-treatment comparisons with noninformative prior distributions (Supplement [Data Synthesis and Analysis]) (17, 18). The model contained parameters that described the relative treatment effect of each intervention compared with a common comparator (oral placebo). Other treatment comparisons were derived as differences between model parameters. We assumed a normal likelihood distribution for the effect size. The main assumption behind the validity of network meta-analysis is transitivity (13). This assumption requires that a valid synthesis of studies indirectly comparing 2 treatments (for example, A with C) by way of 2 direct comparisons (for example, A with B and B with C) must include studies that are sufficiently similar in important clinical and methodological characteristics (potential effect modifiers) (19). The populations within the included studies were similar and could be eligible for any of the treatments considered here based on the distributions of effect modifiers (mean age, percentage of women, baseline disease severity, baseline pain scores, duration of disease, and study quality) and inclusion and exclusion criteria of the studies. Another key assumption in a network meta-analysis is consistencythe notion that the direct and indirect estimates of the treatment effects are the same (20). Consistency was assessed using the node-splitting method (Supplement [Data Synthesis and Analysis]) (21). The results were presented graphically to visually assess the agreement between direct and indirect estimates. A value near 0 indicated that the comparisons in the network were consistent. Results were presented as median effect sizes for pain, function, and stiffness along with 95% central credible intervals (CrIs). For improving the clinical interpretability, they were converted back to the natural units of the most commonly used scale (WOMAC VAS, 0 to 100) (22). On the basis of the Osteoarthritis Research Society InternationalOutcome Measures in Rheumatology responder criteria, we prespecified an absolute change of 20 points on a scale of 0 to 100 as clinically significant improvement (23). We performed several sensitivity analyses on the primary outcome of pain to explore potential causes for heterogeneity. Multiple-treatment meta-regression analysis and subgroup analyses were done to assess the effect of study quality, sample size, and type of outcome scale used (WOMAC vs. other) (24). To examine the potential effect of reporting bias, we analyzed pain outcomes in trials reporting only pain; those reporting both pain and function; and those reporting pain, function, and stiffness. We also compared the baseline characteristics and study quality measures of these subsets of trials. The Supplement (Data Synthesis and Analysis) provides additional details of the statistical methods used. Role of the Funding Source The Agency for Healthcare Research and Quality had no role in study design, data collection, analysis or interpretation, preparation, review, or approval of the manuscript. The funding agency had no access to the data and did not perform any of the study analyses. Results Of the 4122 citations identified through our literature search, 3625 were excluded through title and abstract screening. Among the 497 full-text reports, 137 studies met inclusion criteria for the network meta-analysis (Appendix Figure). Figure 1 shows the network of all treatment comparisons analyzed for pain; the networks for function and stiffness are shown in the Supplement. Thirteen trials had 3 study group

Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: A systematic review and meta-analysis

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

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

OBJECTIVE To assess the relative efficacy of intra-articular hyaluronic acid (IAHA) in comparison with non-steroidal anti-inflammatory drugs (NSAIDs) for knee osteoarthritis (OA). METHODS We searched Medline, EMBASE, Google Scholar, ISI Web of Science, and Cochrane Database from inception until February 2013. Randomized controlled trials comparing HA with NSAIDs for knee OA were included if they reported at least one pain outcome. Two reviewers abstracted data and determined quality. Outcomes included pain, function, and stiffness. Random-effects meta-analyses were performed. RESULTS Five trials (712 participants) contributed to the pain analysis. Both groups showed improvement from baseline. The analysis found an effect size (ES) of -0.07 (95% CI: -0.24 to 0.10) at trial end, favoring neither treatment. There were no statistically significant differences between the groups at 4 and 12 weeks in function [ES = -0.08 (95% CI: -0.39 to 0.23)] or stiffness [ES = 0.03 (95% CI: -0.27 to 0.34)] analyses based on two trials. Injection site pain was the most common adverse event reported in the HA group, and gastrointestinal adverse events were more common in the NSAIDs group. CONCLUSION This meta-analysis suggests that IAHA is not significantly different from continuous oral NSAIDs at 4 and 12 weeks. Our study detected no safety concerns; however, the included trials had only a short follow-up duration. Given the favorable safety profile of IAHA over NSAIDs, this result suggests that IAHA might be a viable alternative to NSAIDs for knee OA, especially for older patients at greater risk for systemic adverse events.

High-Energy Extracorporeal Shock-Wave Therapy for Treating Chronic Calcific Tendinitis of the Shoulder: A Systematic Review

To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).

Did the American Academy of Orthopaedic Surgeons Osteoarthritis Guidelines Miss the Mark

Rotator cuff tendinitis is one of the most common causes of shoulder pain. The term noncalcific tendinitis refers to rotator cuff tendinitis without calcium deposits. The term calcific tendinitis indicates the presence of calcium deposits in the rotator cuff tendons, most commonly in the supraspinatus tendon near its insertion site (1). The prevalence of calcium deposits has been reported as 2% to 20% of asymptomatic shoulders, 6.8% of patients with shoulder pain, and up to 17% of patients with chronic periarthritis (24). The calcifications are most commonly classified into 3 types, according to the Grtner criteria; type 3 is characterized by the highest frequency of spontaneous resorption (5). Although calcium deposits cannot be readily identified by history or clinical examination, they may be identified by plain radiography or sonography, with ultrasonography being somewhat more sensitive (6, 7). Magnetic resonance imaging is not needed to diagnose calcific tendinitis. Conventional therapies used in general practice include rest, ice, nonsteroidal anti-inflammatory drugs, physical therapy, and subacromial corticosteroid injections, although strong evidence to support the efficacy of any of these treatment modalities is lacking (3, 8). Treatment-resistant cases, which are more common with calcific tendinitis, may require surgery, such as arthroscopic debridement of calcifications or subacromial decompression (1). Extracorporeal shock-wave therapy (ESWT) has been suggested as an alternative treatment for refractory shoulder pain due to calcific or noncalcific tendinitis and may be an alternative to expensive and risky surgical interventions. This modality uses sound waves of high or low energy that impart rapid fluctuations of pressure to tissues. The degree of energy imparted to the tissues is measured as energy flux density (EFD). There are many manufacturers of ESWT devices. Shock waves are delivered transcutaneously in an office setting with or without local anesthesia for 10 to 30 minutes. The use of ESWT has gained popularity in many countries worldwide for treating numerous musculoskeletal disorders (9, 10), although it is less common in the United States. Initially used for lithotripsy to treat nephrolithiasis, the application of shock waves to soft-tissue structures has demonstrated promising results in treating such conditions as tendinitis, plantar fasciitis, nonunion long-bone fractures, and avascular necrosis of the femoral head (911). In the United States, ESWT devices have been approved by the U.S. Food and Drug Administration for the treatment of lateral epicondylitis and plantar fasciitis refractory to conventional conservative therapies (913). Although ESWT may provide a nonsurgical alternative to treating multiple soft-tissue conditions, its appropriate use, dosage, and efficacy are still uncertain. Many randomized, controlled trials (RCTs) examining the effects of ESWT on calcific and noncalcific tendinitis showed disparate results regarding resolution of pain and effect on shoulder mobility. To provide evidence-based conclusions about the efficacy of ESWT for calcific and noncalcific tendinitis of the shoulder, we aimed to address the following key questions. 1. In patients with rotator cuff tendinitis, what are the benefits and harms of ESWT compared with placebo? 2. In patients with rotator cuff tendinitis, what are the benefits and harms of different energy levels of ESWT? 3. How do outcomes differ among subgroups of patients with calcific versus noncalcific tendinitis treated with ESWT? 4. In patients with rotator cuff tendinitis, what are the benefits and harms of ESWT compared with other treatment modalities? Methods Data Sources and Searches We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, and Google Scholar from inception to 1 November 2013 by using the following search terms: shoulder joint, shoulder pain, tendinitis, tendonitis, tendinosis, tendinopathy, calcific tendinitis, calcinosis, bursitis, extracorporeal shock wave therapy, extracorporeal shock-wave therapy, extracorporeal shockwave therapy, and lithotripsy. We also hand-searched review articles, manuscripts, and medical journal supplements for additional references. We placed no restrictions on language and translated relevant nonEnglish-language articles. Study Selection Three independent reviewers screened abstracts and the full text of articles and determined eligibility by consensus. We included all RCTs in humans that studied treatment of calcific or noncalcific tendinitis of the shoulder and compared different energy levels of ESWT against each other or placebo or weighed ESWT against other treatments. We included studies that reported clinical, radiologic, or sonographic outcomes. Outcomes of interest included shoulder pain and function measurements and evaluation of calcification resolution (for calcific tendinitis trials only). We excluded nonrandomized comparative studies, single-cohort studies, and case reports. Data Extraction and Quality Assessment After an a priori training exercise, 3 reviewers independently evaluated the included trials and recorded data on a standardized form. Data on participants demographic characteristics, treatment characteristics, outcomes, adverse events, and study design were obtained. We also recorded information on study quality indicators, including randomization, allocation concealment, blinding, and intention-to-treat analysis and assessed the risk of bias (14). Energy Levels Shock-wave therapy is usually classified as high, medium, or low energy, according to the EFD administered. Although there is no consensus on the threshold values, a commonly used grouping defines EFD less than 0.08 mJ/mm2 as low energy, 0.08 to less than 0.28 mJ/mm2 as medium energy, and 0.28 mJ/mm2 to 0.6 mJ/mm2 as high energy (1517). Once a given EFD is selected, it is applied in pulses to the affected area. The number of pulses per dose typically ranges from 1000 to 3000, and several doses may be given in a course of treatment. The EFD applied to patients varied among the trials in our study. Owing to a paucity of studies comparing different energy levels with each other or with placebo, we categorized the trials as high-energy ESWT (EFD 0.28 mJ/mm2) or low-energy ESWT (EFD <0.28 mJ/mm2). Outcome Measurements The included trials evaluated pain predominantly by using a visual analogue scale pain score: a grading tool for subjective measurement of pain, typically ranging from 0 or 1 (no pain) to 10 (worst pain). Shoulder function was most frequently evaluated by using the Constant score (or ConstantMurley score), a standardized tool that assesses clinical shoulder function by using a 100-point scale (on which 0 is the worst score) to evaluate subjective and objective variables (18). The subjective variables evaluate perception of pain and ability to perform normal tasks of daily living, and the objective variables assess the active range of motion and shoulder power (18). Other reported shoulder function measurement instruments were range of motion, the Shoulder Pain and Disability Index, and the function subscale of the UCLA Shoulder Rating Scale. Resolution of calcification resolution was evaluated only in calcific tendinitis trials and was measured radiographically or sonographically. Role of the Funding Source The study did not receive external funding. Results Trial Selection Our literature search yielded 376 articles (Appendix Figure). After we screened the titles and abstracts and removed duplicates, 38 articles were considered potentially relevant. Seven articles were excluded after full-text review because they described 6 nonrandomized comparative studies and thus did not meet our inclusion criteria (1925). In total, we included 28 RCTs that reported results in 31 publications. Of the 28 RCTs used in our analysis, 20 compared different ESWT energy levels with placebo (2645) and 8 (in 11 publications) compared ESWT with other treatment modalities (4656). Appendix Figure. Summary of evidence search and selection. ESWT = extracorporeal shock-wave therapy. * 38 articles describing 34 studies. 7 articles describing 6 studies. 31 articles describing 28 studies. Trial Characteristics Appendix Tables 1 and 2 show the characteristics of the included trials. Overall, there were 1745 participants, with a mean age of 51 years (range, 47 to 56 years), and the average proportion of women was 58% (range, 39% to 76%). The minimum duration of symptoms ranged from 3 to 12 months. Except for 2 trials from Taiwan (37, 51), all studies were conducted in Europe. Among trials that compared different ESWT energy levels with placebo, 16 (in 15 publications) evaluated calcific tendinitis (2640), and 4 (in 5 publications) evaluated noncalcific tendinitis (4145). Appendix Table 1. Characteristics of Studies Comparing Different ESWT Energy Levels and Placebo Appendix Table 2. Characteristics of Studies Comparing ESWT With Other Active Treatments or Applied to Different Shoulder Sites Quality of Included Trials The quality of trials varied in several respects and was generally low (Appendix Tables 3 and 4). All trials reported a parallel-group design. The sample sizes ranged from 20 to 144 participants. Trial duration ranged from 3 to 12 months. Only 6 trials were double-blinded; the rest were either single-blinded (15 trials) or did not report blinding (7 trials). Withdrawal rates ranged from 0% to 33%, with 3 trials reporting a withdrawal rate of more than 20% (27, 29, 30). Intention-to-treat analysis was reported in 14 trials. No trial reported only on resolution of calcifications without accompanying clinical outcomes. Appendix Table 3. Quality of Included Studies Comparing Different ESWT Energy Levels and Placebo Appendix Table 4. Quality of Included Studies Comparing ESWT With Other Treatment Modalities Possible Sources of Heterogeneity and Bias The trials had numerou

Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis

The American Academy of Orthopaedic Surgeons (AAOS) 2013 guidelines for knee osteoarthritis recommended against the use of viscosupplementation for failing to meet the criterion of minimum clinically important improvement (MCII). However, the AAOSs methodology contained numerous flaws in obtaining, displaying, and interpreting MCII-based results. The current state of research on MCII allows it to be used only as a supplementary instrument, not a basis for clinical decision making. The AAOS guidelines should reflect this consideration in their recommendations to avoid condemning potentially viable treatments in the context of limited available alternatives.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis: ACR Guideline for Glucocorticoid-Induced Osteoporosis Prevention and Treatment

PURPOSE Intra-articular (IA) hyaluronic acid (HA) is considered a safer alternative to oral Non-Steroidal Antiinflammatory Drugs (NSAIDs) and opioids for knee osteoarthritis (OA). A recent review raised potential safety concerns about HA, warranting further review of safety outcomes. We examined the risks of HA compared with IA placebo and investigated whether the risks vary among individual HA preparations. METHODS We searched all relevant databases from inception to October 2015 and sought unpublished data. We included all knee OA trials which compared any of the 18 HA products and reported on adverse events (AEs) and withdrawals. We calculated odds ratios for safety data reported at the longest follow-up. Network meta-analysis was performed using a Bayesian hierarchical random effects model for mixed multiple treatment comparisons. RESULTS We identified 74 studies involving 13,032 participants aged between 45 and 75 years. The proportion of women ranged from 28% to 100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported AEs were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. None of the HA products were statistically significantly different from IA placebo or from each other with regard to incidence of AEs. Three treatment-related serious adverse events (SAEs) were reported among 9214 participants. CONCLUSIONS Given the very low incidence of any particular AEs, we conclude that HA products are relatively well tolerated. These products have a similar safety profile compared to each other. This information along with the comparative effectiveness profile and relative cost would be helpful for clinicians in delivering individualized patient care.