Matthew C. Sullivan

OARSI guidelines for the non-surgical management of knee osteoarthritis

OBJECTIVE To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis (OA), intended to inform patients, physicians, and allied healthcare professionals worldwide. METHOD Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the OA literature, 29 treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OA Research Society International (OARSI) evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using Assessment of Multiple Systematic Reviews (AMSTAR) criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical sub-phenotypes. Consensus recommendations were produced using the RAND/UCLA Appropriateness Method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical sub-phenotypes and accompanied by 1-10 risk and benefit scores. RESULTS Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical sub-phenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral non-steroidal anti-inflammatory drugs (NSAIDs; COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical sub-phenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation). CONCLUSION These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

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).

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

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

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

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.

Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials

Placebo controls are supposedly ineffectual medical therapies that serve as common comparators with which to establish a null baseline and maintain blinding in evaluations of the effectiveness of medical treatments in clinical trials (1, 2). The extent to which alternative modes of administration of placebo treatments can result in real and clinically significant changes has been subject to both hype and controversy (3, 4). One meta-analysis comparing the placebo groups of randomized, controlled trials with control groups in which patients received no treatment found placebo-related benefits to be small to nonexistent across various clinical conditions and outcomes (3). On the other hand, a reanalysis of these studies concluded that in methodologically adequate trials and clinical conditions amenable to placebos, the placebo effect was robust and neared the efficacy of active treatment (4). Finally, the possibility of nocebo effects can create an experimental design that compares active treatment to something worse than nothing (5). Thus, beyond providing a no treatment group, the placebo response itself may be important because trial results and interpretation depend not only on the response to the active drug but also on the magnitude and direction of the response to the placebo. A systematic variation in the magnitude of response according to the type of placebo delivered would have important implications for the interpretation of results of placebo-controlled trials. However, it is not clear whether differential placebo effects actually exist. The ability and need to distinguish between placebo effects have increased with the advent of network meta-analysis; this type of analysis entails a quantitative synthesis of studies on a set of multiple treatments, not all of which are compared with each other in every study. Network meta-analyses estimate treatment effects between all possible pairs of treatments and can then rank them in order of the sizes of their effects. Network meta-analyses that involve different types of placebo control groups often assume that the different placebo groups have similar (null) effects and combine them into a single network node (treatment group) (6). Combination into a single node can lead to misleading results if the placebo components differ in efficacy (7, 8). Comparing network analyses that separate and combine different placebos within a network provides a mechanism to investigate the existence of differential placebo effects. Our recent paper comparing different pharmacologic treatments for knee osteoarthritis suggested that conclusions might be sensitive to the treatment of alternative placebos within a network model (9). In this report, using knee osteoarthritis as an example, we expanded the previous network model to include more placebo interventions and corresponding active treatments and explored the potential importance and influence of differential effects with alternative types of placebos. The current investigation sought to determine whether the different placebo interventions used in knee osteoarthritis trials differ in efficacy and to quantify the effect of differential placebo effects on active-treatment effect estimates. Methods Data Sources We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, and Google Scholar from inception to 1 June 2015 (Appendix Table 1). We did not restrict the search according to publication status, date, or language (all relevant nonEnglish-language reports were translated). We translated articles from Chinese, French, German, Japanese, Russian, Spanish, and Turkish. We also manually searched reference lists for all retrieved studies, as well as conference proceedings of the Osteoarthritis Research Society International, the British Society for Rheumatology, the European League Against Rheumatism, the American College of Rheumatology, the American Association of Orthopaedic Surgeons, and the International League of Associations for Rheumatology. We searched conference proceedings from January 1990 to June 2015. Unpublished data were identified by searching ClinicalTrials.gov, the U.S. Food and Drug Administration registry, pharmaceutical company Web sites, and product inserts and by contacting manufacturers, study authors, experts, and primary authors of abstracts reporting incomplete data. Appendix Table 1. Literature Search Strategy (MEDLINE) Study Selection All randomized, controlled trials of adults diagnosed with clinical or radiologic knee osteoarthritis were included if they compared at least 2 interventions of interest and reported extractable data for at least 1 pain measure. On the basis of consultation with research and clinical experts, we included 4 alternative placebo interventions and corresponding active comparators, as follows: oral placebo, topical placebo, intra-articular placebo, oral plus topical placebo, acetaminophen, oral nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac, ibuprofen, naproxen), oral cyclooxygenase-2 (COX-2)selective NSAIDs (celecoxib), topical NSAIDs, intra-articular corticosteroids, and intra-articular hyaluronic acid. Studies investigating complementary and alternative interventions, such as tai chi, acupuncture, sham acupuncture, and surgical therapies, were excluded to reduce substantial anticipated heterogeneity, inconsistency, and documented low methodological quality (10). Two reviewers independently screened titles and abstracts identified by the searches. For studies that either reviewer considered potentially relevant, both reviewers obtained full reports and independently assessed them according to the preceding criteria. Any disagreements 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 it as necessary. After completion of an a priori training exercise, the same 2 reviewers independently extracted such data as study design, selection criteria, population characteristics, treatments, outcome measures, length of follow-up, Cochrane risk of bias items (11), and results from each study. The reviewers then evaluated the extractions for consistency and resolved any disagreements by consensus. The outcome measure of interest was change in pain scores from baseline to 3-month follow-up. If 3-month data were not available, we selected the pain score from whichever time point was closest to 3 months within the period from 2 to 6 months from baseline. Intention-to-treat data were used whenever available. When a trial provided data on more than 1 scale, we referred to a hierarchy of osteoarthritis-related outcomes and extracted the outcome that was highest on the list (12, 13). Data Synthesis and Analysis Because the studies used different outcome scales (Western Ontario and McMaster Universities Arthritis Index [WOMAC], visual analogue scale, and Likert), the change from baseline in each study was translated into Hedges g effect sizes (14), defined as the difference in change from baseline between 2 interventions divided by the pooled SD of the differences, with a correction for small sample size. To assess potential heterogeneity among the studies, we calculated the between-study variance and also examined baseline characteristics of participants, interventions, outcomes, and study quality. We quantified the differences between the placebo interventions by using a network meta-analysis, which synthesizes the direct and indirect evidence from a network of studies involving 2 or more of the interventions (15). Figure 1 (panel A) depicts the differential placebo network model with 4 placebo nodes. We used multivariable Bayesian hierarchical random-effects models for mixed multiple-treatment comparisons with noninformative prior distributions (16) to account for the expected clinical and methodological heterogeneity. Consistency between the direct and indirect estimates within the network was assessed by using the node-splitting method (17). Results are presented as median effect size along with 95% central credibility intervals (CrIs). To present the results in a more clinically relevant format, we converted them back to the natural units of the most commonly used scale (WOMAC: 0 to 100) (18). An absolute change of 20 points on a 0-to-100 scale was prespecified as clinically significant improvement according to Osteoarthritis Research Society International/Outcome Measures in Rheumatology responder criteria (19). We performed several sensitivity analyses to explore potential factors influencing the placebo effect. Meta-regression analysis was used to assess the effect of presence or absence of blinding, sample size, and randomization ratio of placebo to active treatment (1 to 1 vs. 1 to >1) (20). Because baseline pain scores were reported on a variety of scales, we normalized all these pain scales onto a 0-to-100 scale. We ran the meta-regression analysis on the normalized baseline pain scores. Figure 1. Network of different placebo comparisons. A. Differential placebo effects model. B. Nondifferential combined placebo effects model. Combined placebo = all 4 placebo groups (oral, topical, IA, and oral plus topical) are combined into a single group. Circle size reflects number of participants, and the line width reflects number of direct comparisons. No connecting line between 2 circles indicates that there was no direct comparison between the 2 treatments. COX = cyclooxygenase; IA = intra-articular; NSAID = nonsteroidal anti-inflammatory drug. To assess the implications of ignoring differential placebo effects on apparent treatment effects, we evaluated 1 other network meta-analysis model (nondifferential combined placebo network model) (Figure 1, panel B). This model assumed that all 4 placebos had the same effect, so we combined them into a single group (combined placebo). We compared these results wit

Mixed Depression: Clinical Features and Predictors of Its Onset Associated with Antidepressant Use

Background: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. Methods: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. Results: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. Conclusions: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

Detecting mood disorder in resource-limited primary care settings: comparison of a self-administered screening tool to general practitioner assessment.

Objectives Although efficacious treatments for mood disorders are available in primary care, under-diagnosis is associated with under-treatment and poorer outcomes. This study compares the accuracy of self-administered screening tests with routine general practitioner (GP) assessment for detection of current mood disorder. Methods 197 consecutive patients attending primary care centres in Santiago, Chile enrolled in this cross-sectional study, filling out the Patients Health Questionnaire-9 (PHQ-9) for depression and the Mood Disorder Questionnaire (MDQ) for bipolar disorder, after routine GP assessment. Diagnostic accuracy of these self-administered tools was compared with GP assessment, with gold standard diagnosis established by a structured diagnostic interview with trained clinicians (SCID-I). Results The sample was 75% female, with a mean age of 48.5 (SD 16.8); 37% had a current mood disorder (positive SCID-I result for depression or bipolar disorder). Sensitivity of the screening instruments (SI) was substantially higher than GP assessment (SI: 0.8, [95% CI 0.71, 0.81], versus GP: 0.2, [95% CI 0.12, 0.25]: p-value < 0.0001), without sacrifice in specificity (SI: 0.9, [95% CI 0.86, 0.96], versus GP: 0.9, [95% CI 0.88, 0.97]: p-value = 0.7). This led to improvement in both positive predictive value (SI: 0.8, [95% CI 0.82, 0.90], versus GP: 0.6, [95% CI 0.50, 0.64]: p-value < 0.001) and negative predictive value (SI: 0.9, [95% CI 0.78, 0.91] versus GP: 0.7, [95% CI 0.56, 0.72]: p-value < 0.01). Conclusion Self-administered screening tools are more accurate than GP assessment in detecting current mood disorder in low-income primary care. Such screening tests may improve detection of current mood disorder if implemented in primary care settings.

Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial.

Background We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). Methods Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. Results In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. Conclusions The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

Diminishing Perceived Threat of AIDS and Increasing Sexual Risks of HIV Among Men Who Have Sex with Men, 1997–2015

Community-wide awareness that antiretroviral therapies (ART) provides protection against HIV has the potential to increase perceived safety and thereby increase condomless anal sex among men who have sex with men (MSM). Furthermore, reductions in condom use can increase exposure to sexually transmitted infections, which in turn can reduce the protective effects of ART on HIV transmission. The current study extends previous community-based behavioral surveillance research on beliefs regarding use of ART for HIV prevention and sexual practices among MSM. Anonymous cross-sectional community surveys were collected from 1831 men at the same gay pride event in Atlanta, GA four times over nearly two decades; 1997, 2005–2006 (the 2006 survey over-sampled African-Americans to diversify the study), and 2015. Results indicate clear and consistent trends of increasing beliefs that HIV treatments reduce HIV transmission risks, reflecting the dissemination of HIV prevention research findings. Changes in treatment beliefs coincide with increased rates of condomless anal intercourse. Increased beliefs that treatments prevent HIV and increased condomless anal sex were observed for both HIV positive men and men who had not tested HIV positive. Results illustrate the emergence of an era where ART is the focus of HIV prevention and community-held beliefs and behaviors regarding definitions of risk create a new and potentially problematic environment for HIV transmission.

Safety of Repeated Injections of Sodium Hyaluronate (SUPARTZ) for Knee Osteoarthritis A Systematic Review and Meta-Analysis

Objective Though there is no consensus on its efficacy, knee osteoarthritis is symptomatically managed with intra-articular hyaluronic acid (IAHA). Recent reports suggest that IAHA may delay the need for total knee replacement, with the magnitude of delay proportional to the number of injection series. However, the safety of repeated injection series is reported to vary between commercial products. This report describes a systematic review of safety data on repeated treatment courses of SUPARTZ. Design We performed a systematic search of MEDLINE, Cochrane database, EMBASE, Web of Science, Google Scholar, and unpublished data. We included all human randomized controlled trials or observational studies with adverse event (AE) data for SUPARTZ in knee osteoarthritis. Two independent reviewers extracted data and evaluated study quality. Data were analyzed separately for the first and subsequent series of injections. Results The primary sources for repeated-injection data on SUPARTZ were a postmarket registry (N = 7404), 4 prospective studies (N = 127 total), and a retrospective study (N = 220). None of the sources reported increased frequency or severity of AEs with repeated injections. In the registry, 95% of multiple-injection-series patients who reported an AE did so during the first series. None of the AEs was serious, and most resolved spontaneously without medical intervention. The overall adverse event rate after repeat courses of SUPARTZ was 0.008 (95% confidence interval: 0.001-0.055). Conclusions Multiple courses of SUPARTZ injections appear to be at least as safe, and probably safer, than the first course. This study supports the safety of repeat courses of SUPARTZ injections for knee osteoarthritis.