Evidence on treat to target strategies in polymyalgia rheumatica and giant cell arteritis: a systematic literature review.

OBJECTIVES: To inform an international task force about current evidence on Treat to Target (T2T) strategies in PMR and GCA. METHODS: A systematic literature research (SLR) was conducted in Medline, EMBASE, Cochrane Library, clinicaltrials.gov from their inception date to May 2022, and in the EULAR/ACR abstract database (2019-2021). Randomised clinical trials (RCTs) and non-randomised interventional studies published in English and answering at least one of the eleven PICO questions on T2T strategies, treatment targets and outcomes, framed by the taskforce, were identified. Study selection process, data extraction and risk of bias assessment were conducted independently by two investigators. RESULTS: Of 7809 screened abstracts, 397 were selected for detailed review and 76 manuscripts were finally included (31 RCTs, eight subgroup/exploratory analyses of RCTs and 37 non-randomised interventional studies). No study comparing a T2T strategy against standard of care was identified. In PMR RCTs, the most frequently applied outcomes concerned treatment (90.9% of RCTs), particularly the cumulative glucocorticoids (GC) dose and GC tapering, followed by clinical, laboratory and safety outcomes (63.3% each). Conversely, the most commonly reported outcomes in RCTs in GCA were prevention of relapses (72.2%), remission as well as treatment-related and safety outcomes (67.0% each). CONCLUSIONS: This SLR provides evidence and highlights the knowledge gaps on T2T strategies in PMR and GCA, informing the task force developing T2T recommendations for these diseases.

Performance of clinical, laboratory and imaging features for diagnosing spondyloarthritis-a systematic literature review and meta-analysis.

OBJECTIVE: The Berlin algorithm was developed to help diagnosing axial spondyloarthritis (axSpA), but new studies suggest some features typical of SpA are less specific than previously assumed. Furthermore, evidence is lacking for other SpA subtypes (e.g. peripheral SpA). We aimed to review the evidence on the performance of SpA features for diagnosing each SpA subtype. METHODS: Systematic literature review of studies reporting the diagnostic performance of ≥ 1 SpA feature in patients with suspected SpA. The external reference was the rheumatologist's diagnosis of SpA. Meta-analysis was performed, separately for each SpA subtype, to estimate pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratios. Meta-regression assessed the effect of covariates (e.g. feature's prevalence) on each feature's performance. RESULTS: Of 13 844 articles screened, 46 were included. Sacroiliitis on magnetic resonance imaging, damage on pelvic radiographs and elevated C-reactive protein (CRP) had the best balance between LR+ and LR- (LR + 3.9-17.0, LR- 0.5-0.7) for diagnosing axSpA. HLA-B27 had an LR+ lower than anticipated (LR + =3.1). Inflammatory back pain (IBP) had low LR + (LR+∼1), but substantially decreased the likelihood of axSpA when absent (LR-=0.3). Conversely, peripheral features and extra-musculoskeletal manifestations showed high LR + (LR+ 1.6-5.0), but were as common in axSpA as no-axSpA (LR-∼1). The specificity of most features was reduced in settings when these were highly prevalent. Limited data precluded a detailed analysis on diagnosing other SpA subtypes. CONCLUSION: Imaging features and CRP have good diagnostic value for axSpA. However, the specificity of other features, especially HLA-B27 and IBP, is lower than previously known.

Efficacy and safety of non-pharmacological and non-biological interventions: a systematic literature review informing the 2022 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis.

OBJECTIVE: To update the evidence of non-biological treatments for axial spondyloarthritis (axSpA), as a basis for the 2022 Assessment of SpondyloArthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. METHODS: A systematic literature review (2016-2021) on efficacy and safety of non-pharmacological and non-biological pharmacological treatments was performed, up to 1 January 2022. The research question was formulated according to the PICO format: Population: adult patients with r-axSpA and nr-axSpA; Intervention: non-pharmacological and non-biological pharmacological treatments; Comparator: active comparator or placebo; Outcomes: all relevant efficacy and safety outcomes. Type of studies included were: randomised controlled trials (RCTs), observational studies (for efficacy of non-pharmacological treatments, and safety), qualitative studies. Cohen's effect size (ES) was calculated for non-pharmacological and risk ratio (RR) for pharmacological treatments. RESULTS: Of 107 publications included, 63 addressed non-pharmacological interventions, including education (n=8) and exercise (n=20). The ES for education on disease activity, function, mobility was small to moderate (eg. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), ES: 0.06-0.59). Exercise had moderate to high ES on these outcomes (eg. BASDAI, ES: 0.14-1.43). Six RCTs on targeted synthetic disease-modifying antirheumatic drugs (DMARDs) showed efficacy of tofacitinib, upadacitinib and filgotinib (phase 2 only) in r-axSpA (range RR vs placebo for ASAS20: 1.91-3.10), while apremilast and nilotinib were not efficacious. Studies on conventional synthetic DMARDs (n=3), non-steroidal anti-inflammatory drugs (NSAIDs, n=8) and other drugs (n=12) did not provide new evidence on efficacy/safety (efficacy of NSAIDs confirmed; limited efficacy of short-term glucocorticoids in one RCT). CONCLUSIONS: Education, exercise and NSAIDs confirmed to be efficacious in axSpA. JAKi were proved efficacious in r-axSpA.

Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis.

OBJECTIVE: To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. METHODS: Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included. RESULTS: In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naïve and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi. CONCLUSIONS: New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety. PROSPERO REGISTRATION NUMBER: CRD42021257588.

Treating spondyloarthritis early: does it matter? Results from a systematic literature review.

OBJECTIVE: To summarize evidence on the relationship between early treatment (definition based on symptom/disease duration or radiographic damage) and treatment clinical response in patients with SpA. METHODS: A systematic literature review was conducted in studies on SpA patients treated with NSAIDs or biological/targeted synthetic DMARDs addressing the impact of symptom/disease duration or presence of radiographic damage on treatment response assessed by any disease activity outcome. For categorical outcomes, relative risk, relative risk ratio and number needed to treat were calculated, and for continuous outcomes, differences in differences, to compare groups stratified based on symptom/disease duration or the presence of radiographic damage. RESULTS: From the 8769 articles retrieved, 25 were included and 2 added by hand-search, all in axial SpA (axSpA), most of them with low risk of bias. Twenty-one studies compared groups based on symptom duration (n = 6) or disease duration (n = 15) and seven studies based on absence/presence of radiographic damage (two studies used two comparisons). When early axSpA was defined by symptom duration (<5 years) in randomized controlled trials, early treatment was associated with better outcomes in patients with non-radiographic axSpA [n = 2, ASAS40 relative risk ratio 5.24 (95% CI 1.12, 24.41) and 1.52 (0.60, 3.87)] but not in radiographic axSpA (n = 1) [ASAS20 0.96 (0.53-1.73)]. When early axSpA was defined based on disease duration or radiographic damage, no differences were found between groups. CONCLUSION: Evidence towards better outcomes in early axSpA is very limited and restricted to non-radiographic axSpA and <5 years symptom duration. When early axSpA is defined based on disease duration or radiographic damage, no differences in response to treatment are found.

Prevalence of frailty and pre-frailty in patients with rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: Frailty is a common geriatric syndrome and is characterised by a decreased physiological reserve and increased vulnerability to stressors. Pre-frailty is a risk-state before frailty. A systematic literature review (SLR) and meta-analysis was conducted to: (1) estimate the prevalence of (pre-)frailty in RA patients; (2) explore whether variation in instruments influences (pre-)frailty prevalence. METHODS: An SLR for the period 2001-2021 was undertaken. All studies (including conference abstracts) that reported on the prevalence of (pre)-frailty in patients with RA were included. Assessment of risk of bias, data extraction and data synthesis were performed by two reviewers independently. A meta-analysis was conducted for studies that used the most commonly accepted frailty instrument (Fried criteria), by obtaining pooled estimates of (pre-) frailty prevalences by random effects models. RESULTS: 25/1,363 studies were included in the SLR. Weighted average age was 58.0 years. Pre-frailty prevalence rates ranged between 20.4%-71% (median: 35.8%); for frailty, rates between 1.2%-75.1% (median: 23.1%) were found. The meta-analysis (Fried criteria), showed a pooled prevalence of 52.8% (95%-CI=42.7-62.8; I2=99%) for pre-frailty and 24.0% (95%-CI= 19.4-28.6; I2=96%) for frailty. (Pre-)frailty was highly prevalent in all age groups. Prevalence was generally higher when the frailty instrument also included psychological and social domains, as compared to instruments that solely focused on the physical domain. CONCLUSIONS: (Pre-)frailty is common in RA patients. Large part of the variation is explained by clinical and methodological heterogeneity. High-quality studies with validated frailty instruments specifically for RA patients are needed.

Work participation in patients with systematic lupus erythematosus: a systematic review.

OBJECTIVES: This systematic review assessed which variables are associated with or are predictors for work participation outcomes in patients with systematic lupus erythematosus (SLE). METHODS: A literature search using MEDLINE, The Cochrane Library, Embase and CINAHL was conducted to identify all studies published from inception (1947) to June 2021 on factors related to and/or predicting employment status, absenteeism and/or presenteeism in SLE patients aged ≥18 years. The quality of included articles was assessed using the QUIPS tool. Narrative summaries were used to present the data. RESULTS: Fifteen studies (nine on associations, four on predictions, and two assessing both) were included, encompassing data of 3800 employed patients. Younger age, Caucasian ethnicity, higher educational level, lower disease activity score, shorter disease duration, absence of specific disease manifestations, higher levels of physical functioning and less physical job demands and higher levels of psychological/cognitive functioning were associated with or predicted favorable work outcomes. Older age, non-Caucasian ethnicity, female gender, never being married, poverty, lower educational level, higher disease activity score, longer disease duration, specific disease manifestations, lower levels of physical functioning, more physical job demands and low job control, less job tenure and lower levels of cognitive functioning were associated with or predicted an unfavorable work outcome. Limitations of the evidence were the quality of the studies and the use of heterogeneous outcome measures, applied statistical methods and instruments used to assess work participation. CONCLUSION: We recommend applying the EULAR points to consider for designing, analysing and reporting on work participation in inflammatory arthritis also to SLE studies on work participation, to enhance the quality and comparability between studies and to better understand the impact of SLE on work participation. TRIAL REGISTRATION: registration in PROSPERO (CRD42020161275; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=161275).

Pharmacological treatment of psoriatic arthritis: a systematic literature research for the 2019 update of the EULAR recommendations for the management of psoriatic arthritis.

OBJECTIVE: To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA). METHODS: This is a systematic literature research of 2015-2018 publications on all DMARDs in patients with PsA, searching Medline, Embase and the Cochrane Library. Efficacy was assessed in randomised controlled trials. For safety, cohort studies, case-control studies and long-term extensions (LTEs) were analysed. RESULTS: 56 publications (efficacy: n=33; safety n=23) were analysed. The articles were on tumour necrosis factor (TNF) inhibitors (n=6; golimumab, etanercept and biosimilars), interleukin (IL)-17A inhibitors (n=10; ixekizumab, secukinumab), IL-23-p19 inhibitors (n=2; guselkumab, risankizumab), clazakizumab (IL-6 inhibitor), abatacept (CD80/86 inhibitor) and ABT-122 (anti-TNF/IL-17A), respectively. One study compared ustekinumab (IL-12/23i) with TNF inhibitor therapy in patients with entheseal disease. Three articles investigated DMARD tapering. Trials on targeted synthetic DMARDs investigated apremilast (phosphodiesterase-4 inhibitor) and Janus kinase inhibitors (JAKi; tofacitinib, filgotinib). Biosimilar comparison with bio-originator showed non-inferiority. Safety was evaluated in 13 LTEs, 9 cohort studies and 1 case-control study investigating malignancies, infections, infusion reactions, multiple sclerosis and major cardiovascular events, as well as efficacy and safety of vaccination. No new safety signals were identified; however, warnings on the risk of venous thromboembolic events including pulmonary embolism when using JAKi were issued by regulators based on other studies. CONCLUSION: Many drugs in PsA are available and have demonstrated efficacy against placebo. Efficacy varies across PsA manifestations. Safety must also be taken into account. This review informed the development of the European League Against Rheumatism 2019 updated PsA management recommendations.

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis.

OBJECTIVES: To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). METHODS: A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. RESULTS: 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. CONCLUSION: This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis.

OBJECTIVES: To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). METHODS: An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures. RESULTS: Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors. CONCLUSION: Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

Importance: There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective: To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants: Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures: Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures: Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results: A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.

Attention to threat in posttraumatic stress disorder as indexed by eye-tracking indices: a systematic review.

BACKGROUND: Cognitive models of posttraumatic stress disorder (PTSD) implicate threat-related attentional biases in the etiology and phenomenology of the disorder. However, extant attentional research using reaction time (RT)-based paradigms and measures has yielded mixed results. Eye-tracking methodology has emerged in recent years to overcome several inherent drawbacks of RT-based tasks, striving to better delineate attentional processes. METHODS: A systematic review of experimental studies examining threat-related attention biases in PTSD, using eye-tracking methodology and group-comparison designs, was conducted conforming to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were selected following a systematic search for publications between 1980 and December 2017 in PsycINFO, MEDLINE and the National Center for PTSD Research's Published International Literature on Traumatic Stress (PILOTS) database. Additional records were identified by employing the Similar Articles feature in PubMed, and the Cited Reference Search in ISI Web of Science. Reference sections of review articles, book chapters and studies selected for inclusion were searched for further studies. Ongoing studies were also sought through Clinicaltrials.gov. RESULTS: A total of 11 studies (n = 456 participants in total) were included in the final review. Results indicated little support for enhanced threat detection, hypervigilance and attentional avoidance. However, consistent evidence emerged for sustained attention on threat (i.e. attention maintenance) in PTSD. CONCLUSIONS: This review is the first to systematically evaluate extant findings in PTSD emanating from eye-tracking studies employing group-comparison designs. Results suggest that sustained attention on threat might serve as a potential target for therapeutic intervention.

A look at the increasing demographic representation within behavioral medicine.

Meeting the behavioral medicine research and clinical needs of an increasingly diverse United States population is an issue of national concern. We examine the trends in the demographic representation of the behavioral medicine scientific workforce through an analysis of the training grants funded by National Institutes of Health for the field of behavioral medicine from 1980 to 2018. We report the topics of these training grants, and we depict the demographic representation of the training leaders. We provide the demographic representation of the trainees, and of the first authors of publications reported within those training grants. Finally, we report the topics addressed in these behavioral medicine publications, to determine if topic diversity increased as the behavioral medicine scientific workforce diversified. Visualizations are presented that tell a story of how we have, and have not, advanced representation within the field of behavioral medicine. Best practices for launching future successful behavioral medicine scientists are then presented, to ensure optimal representation and diversification occurs in our workforce, our science, and our delivery of our clinical care.

Interventions to Increase Depression Treatment Initiation in Primary Care Patients: a Systematic Review.

INTRODUCTION: Nearly 50% of depressed primary care patients referred to mental health services do not initiate mental health treatment. The most promising interventions for increasing depression treatment initiation in primary care settings remain unclear. METHODS: We performed a systematic search of publicly available databases from inception through August 2017 to identify interventions designed to increase depression treatment initiation. Two authors independently selected, extracted data, and rated risk of bias from included studies. Eligible studies used a randomized or pre-post design and assessed depression treatment initiation (i.e., ≥ 1 mental health visit or antidepressant fill) among adults, the majority of whom met criteria for depression. Interventions were classified as simple or complex and sub-classified into intervention strategies that were graded for strength of evidence. RESULTS: Of 9516 articles identified, we included 14 unique studies representing 16 (4 simple and 12 complex) interventions and 8 treatment initiation strategies. We found low to moderate strength of evidence for collaborative/integrated care (3 studies), treatment preference matching (2 studies), and case management (2 studies) strategies. However, there was insufficient evidence to determine the benefit of cultural tailoring (2 studies), motivation (alone, with reminders or with cultural tailoring (5 studies)), education (1 study), and shared decision-making strategies (1 study). Overall, we found moderate strength of evidence for complex interventions (8 of 12 complex interventions demonstrated statistically significant effects on treatment initiation). DISCUSSION: Collaborative/integrated care, preference treatment matching, and case management strategies had the best evidence for improving depression treatment initiation, but none of the strategies had high strength of evidence. While primary care settings can consider using some of these strategies when referring depressed patients to treatment, our review highlights the need for further rigorous research in this area.

Personalized (N-of-1) Trials for Depression: A Systematic Review.

PURPOSE/BACKGROUND: Personalized (N-of-1) trials are single-patient, crossover-design trials that may be useful for personalizing the selection of depression treatments. We conducted a systematic review of published N-of-1 trials for depression to determine the feasibility and suitability of this methodology for personalizing depression care. METHODS/PROCEDURES: Electronic databases were searched from database inception through October 2016. Studies were selected if they enrolled depressed patients, included a within-subject crossover design, and systematically assessed depressive symptoms during the N-of-1 trial. FINDINGS/RESULTS: Five eligible studies reporting on 47 depressed patients (range, 1-18 patients) were identified. Two studies were conducted among adults with treatment-resistant depression, 1 study among depressed inpatients, and 2 studies among patients from special populations (geriatric nursing home, human immunodeficiency virus-associated encephalopathy). All studies evaluated the effects of pharmacologic treatments (methylphenidate, D-amphetamine, ketamine, and sulpiride). Three studies compared an off-label treatment with placebo, 1 study compared 2 off-label treatments, and 1 study compared escalating doses of an off-label treatment with placebo. All 4 studies with more than 1 participant demonstrated heterogeneous treatment effects. All studies produced data that could personalize treatment selection for individual patients. No studies reported on recruitment challenges, compliance with self-tracking, or satisfaction with participation. IMPLICATIONS/CONCLUSIONS: The feasibility of N-of-1 trials for depression was demonstrated for a limited number of second-line pharmacologic treatments in treatment-resistant patients or in patients with comorbidities that would have excluded them from conventional randomized controlled trials. Additional research is needed to determine whether N-of-1 trials are suitable for improving the selection of depression treatments in clinical practice.

N-of-1 Randomized Intervention Trials in Health Psychology: A Systematic Review and Methodology Critique.

Background: Single-patient, multiple cross-over designs (N-of-1 or single-case randomized clinical trials) with systematic data collection on treatment effects may be useful for increasing the precision of treatments in health psychology. Purposes: To assess the quality of the methods and statistics, describe interventions and outcomes, and explore the heterogeneity of treatment effect of health psychology N-of-1 trials. Methods: We conducted a systematic review of N-of-1 trials from electronic database inception through June 1, 2015. Potentially relevant articles were identified by searching the biomedical electronic databases Ovid, MEDLINE, EMBASE, all six databases in the Cochrane Library, CINAHL, and PsycINFO, and conference proceedings, dissertations, ongoing studies, Open Grey, and the New York Academy's Grey Literature Report. Studies were included if they had health behavior or psychological outcomes and the order of interventions was randomized. We abstracted study characteristics and analytic methods and used the Consolidated Standards of Reporting Trials extension for reporting N-of-1 trials as a quality checklist. Results: Fifty-four N-of-1 trial publications composed of 1,193 participants were included. Less than half of these (36%) reported adequate information to calculate the heterogeneity of treatment effect. Nearly all (90%) provided some quantitative information to determine the superior treatment; 79% used an a priori statistical cutoff, 12% used a graph, and 10% used a combination. Conclusions: N-of-1 randomized trials could be the next major advance in health psychology for precision therapeutics. However, they must be conducted with more methodologic and statistical rigor and must be transparently and fully reported.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis.

OBJECTIVES: To assess the safety of synthetic (s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA) to inform the European League Against Rheumatism recommendations for the management of RA. METHODS: Systematic literature review (SLR) of observational studies comparing any DMARD with another intervention for the management of patients with RA. All safety outcomes were included. A comparator group was required for the study to be included. Risk of bias was assessed with the Hayden's tool. RESULTS: Twenty-six observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria (15 on serious infections, 4 on malignancies). Substantial heterogeneity precluded meta-analysis. Together with the evidence from the 2013 SLR, based on 15 studies, 7 at low risk of bias, patients on bDMARDs compared with patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1 to 1.8)-without differences across bDMARDs-a higher risk of tuberculosis (aHR 2.7 to 12.5), but no increased risk of infection by herpes zoster. Patients on bDMARDs did not have an increased risk of malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). CONCLUSIONS: These findings confirm the known safety pattern of bDMARDs, including both tumour necrosis factor-α inhibitor (TNFi) and non-TNFi, for the treatment of RA.

Role of Ambulatory and Home Blood Pressure Monitoring in Clinical Practice: A Narrative Review.

Hypertension, a common risk factor for cardiovascular disease, is usually diagnosed and treated based on blood pressure readings obtained in the clinic setting. Blood pressure may differ considerably when measured inside versus outside of the clinic setting. Over the past several decades, evidence has accumulated on the following 2 approaches for measuring blood pressure outside of the clinic: ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM). Both of these methods have a stronger association with cardiovascular disease outcomes than clinic blood pressure measurement. Controversy exists about whether ABPM or HBPM is superior for estimating risk for cardiovascular disease and under what circumstances these methods should be used in clinical practice for assessing blood pressure outside of the clinic. This review describes ABPM and HBPM procedures, the blood pressure phenotypic measurements that can be ascertained, and the evidence that supports the use of each approach to measuring blood pressure outside of the clinic. It also describes barriers to the successful implementation of ABPM and HBPM in clinical practice, proposes core competencies for the conduct of these procedures, and highlights important areas for future research.

Association Between Learning Environment Interventions and Medical Student Well-being: A Systematic Review.

Importance: Concerns exist about the current quality of undergraduate medical education and its effect on students' well-being. Objective: To identify best practices for undergraduate medical education learning environment interventions that are associated with improved emotional well-being of students. Data Sources: Learning environment interventions were identified by searching the biomedical electronic databases Ovid MEDLINE, EMBASE, the Cochrane Library, and ERIC from database inception dates to October 2016. Studies examined any intervention designed to promote medical students' emotional well-being in the setting of a US academic medical school, with an outcome defined as students' reports of well-being as assessed by surveys, semistructured interviews, or other quantitative methods. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles. Data were extracted into tables to summarize results. Study quality was assessed by the Medical Education Research Study Quality Instrument (MERQSI), which has a possible range of 5 to 18; higher scores indicate higher design and methods quality and a score of 14 or higher indicates a high-quality study. Findings: Twenty-eight articles including at least 8224 participants met eligibility criteria. Study designs included single-group cross-sectional or posttest only (n = 10), single-group pretest/posttest (n = 2), nonrandomized 2-group (n = 13), and randomized clinical trial (n = 3); 89.2% were conducted at a single site, and the mean MERSQI score for all studies was 10.3 (SD, 2.11; range, 5-13). Studies encompassed a variety of interventions, including those focused on pass/fail grading systems (n = 3; mean MERSQI score, 12.0), mental health programs (n = 4; mean MERSQI score, 11.9), mind-body skills programs (n = 7; mean MERSQI score, 11.3), curriculum structure (n = 3; mean MERSQI score, 9.5), multicomponent program reform (n = 5; mean MERSQI score, 9.4), wellness programs (n = 4; mean MERSQI score, 9.0), and advising/mentoring programs (n = 3; mean MERSQI score, 8.2). Conclusions and Relevance: In this systematic review, limited evidence suggested that some specific learning environment interventions were associated with improved emotional well-being among medical students. However, the overall quality of the evidence was low, highlighting the need for high-quality medical education research.

Outcomes assessed in trials of gout and accordance with OMERACT-proposed domains: a systematic literature review.

OBJECTIVE: The aim of this study was to systematically review outcome domains and measurement tools used in gout trials and their accordance with the preliminary OMERACT gout recommendations published in 2005. METHODS: Randomized controlled trials (RCTs) and quasi-RCTs investigating any intervention for gout published up to February 2013 were included. Recruitment start dates and all measured outcomes were extracted. Risk of bias (RoB) was assessed with the Cochrane Collaboration tool. Numbers of OMERACT domains were compared for trials at low vs unclear/high RoB and for recruitment start date before 2005 or 2005 and later. RESULTS: Of 9784 articles screened, 38 acute and 30 chronic gout trials were included. Mean (s.d.) number of OMERACT outcomes was 2.9 (1.1) (out of 5) and 2.5 (1.2) (out of 9) for acute and chronic gout trials, respectively. Health-related quality of life, participation and joint damage imaging were not assessed in any trial. Tools used to measure individual domains varied widely. There were no differences in the number of OMERACT outcomes reported in acute or chronic gout trials recruiting before 2005 vs 2005 or later [mean (s.d.): 3.0 (1.1) vs 3.5 (1.3), P = 0.859 and 2.7 (1.1) vs 2.8 (1.4), P = 0.960, respectively]. While both acute and chronic trials at low RoB reported more OMERACT domains than trials at unclear/high RoB, these differences were not significant. Industry-funded trials and trials performed by OMERACT investigators reported more OMERACT outcome domains. CONCLUSION: We found no appreciable impact of the OMERACT recommendations for gout trials to date.