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Knee osteoarthritis (OA) is a heterogeneous disease associated with substantial effects on quality of life, and its clinical management is difficult. Among the several available guidelines for the management of knee OA, those from OARSI and ESCEO were updated in 2019. Here, we examine the similarities and differences between these two guidelines and provide a narrative to help guide health-care providers through the complexities of non-surgical management of knee OA. OARSI and ESCEO both recommend education, structured exercise and weight loss as core treatments, topical NSAIDs as first-line treatments and oral NSAIDs and intra-articular injections for persistent pain. Low-dose, short-term acetaminophen, pharmaceutical grade glucosamine and chondroitin sulfate are recommended by ESCEO whereas OARSI strongly recommends against their use (including all glucosamine and chondroitin formulations). Despite this difference, the two guidelines are consistent in the majority of their recommendations and provide useful treatment recommendations for individuals with OA and health-care providers.A working group including authors of the latest OARSI and ESCEO recommendations for the management of knee osteoarthritis and independent experts compare and contrast these guidelines, and provide insights into their differences that could help inform application of the recommendations.

Introduction Patients with rheumatoid arthritis (RA) are at an increased risk of malignancies compared with the general population. This has raised concerns regarding these patients, particularly with the widespread use of immunomodulating therapies, including biologic disease-modifying antirheumatic drugs (DMARDs). We performed a systematic literature review and analysis to quantify the incidence of malignancies in patients with RA and the general population to update previously published data. Methods A literature search was conducted that was consistent with and similar to that in a meta-analysis published in 2008. MEDLINE, BIOSIS Previews, Embase, Derwent Drug File and SciSearch databases were searched using specified search terms. Predefined inclusion criteria identified the relevant observational studies published between 2008 and 2014 that provided estimates of relative risk of malignancy in patients with RA compared with the general population. Risk data on overall malignancy and site-specific malignancies (lymphoma, melanoma and lung, colorectal, breast, cervical and prostate cancer) were extracted. The standardized incidence ratios (SIRs; a measure of risk) relative to the general population were evaluated and compared with published rates. Results A total of nine publications met the inclusion criteria. Seven of these reported SIRs for overall malignancy; eight for lymphoma, melanoma, and lung, colorectal and breast cancer; seven for prostate cancer; and four for cervical cancer. Compared with those in the general population, the SIR estimates for patients with RA suggest a modest increased risk in overall malignancy, as previously observed. Patients with RA continued to show an increased risk of lymphoma and lung cancer compared with the general population. Overall, SIR estimates for colorectal and breast cancers continued to show a decrease in risk, whereas cervical cancer, prostate cancer and melanoma appeared to show no consistent trend in risk among patients with RA compared with the general population. Conclusions The additional data evaluated here are consistent with previously reported data. Patients with RA are at an increased risk of lung and lymphoma malignancies compared with the general population. Quantifying differences in malignancy rates between non-biologic and biologic DMARD-treated patients with RA may further highlight which malignancies may be related to treatment rather than to the underlying disease.

ObjectivesTo compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain.MethodsDouble-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2–3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0–500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.ResultsThe adjusted mean change (95% CI) in WOMAC pain was −185.7 (−200.3 to −171.1) (50.1% decrease) with CS+GH and −186.8 (−201.7 to −171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of −40: −1.11 (−22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups.ConclusionsCS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.Trial registration number:NCT01425853.

Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA). The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, <25, 25-30, >30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes. We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed ≥7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI >30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI ≤25. DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups.

ObjectiveThe FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.MethodsPatients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40–90, a subgroup at risk (SAR) of progression.Results378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%–98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (−10.08; 95% CI −25.68 to 5.53).ConclusionIn the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.Trial registration number NCT01919164

ObjectivesIn the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.MethodsPatients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.ResultsThinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.ConclusionsSprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.Trial registration number NCT01919164.

Background Patients with rheumatoid arthritis (RA) are at an increased risk of developing certain cancers and infections compared with the general population. Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are effective treatment options for RA, but limited evidence is available on the comparative risks among b/tsDMARDs. We assessed the risk of malignancies and infections in patients with RA who initiated abatacept versus other b/tsDMARDs in a real-world setting. Methods This retrospective, observational study used administrative data from three large US healthcare databases (MarketScan, PharMetrics, and Optum) to identify patients treated with abatacept or other b/tsDMARDs. In both groups, age-stratified incidence rates (IRs) with 95% confidence intervals (CIs) were calculated for total malignancy and hospitalized infections; propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs for total malignancy, lung cancer, lymphoma, breast cancer, non-melanoma skin cancer (NMSC), hospitalized infections, opportunistic infections, and tuberculosis (TB), both within individual databases and in meta-analyses across the three databases. Results A rounded total of 19.2, 13.6, and 4.2 thousand patients initiating abatacept and 55.3, 40.8, and 13.8 thousand initiating other b/tsDMARDs were identified in the MarketScan, PharMetrics, and Optum databases, respectively. The IRs for total malignancy and hospitalized infections were similar between the two groups in each age stratum. In meta-analyses, total malignancy risk (HR [95% CI] 1.09 [1.02–1.16]) of abatacept versus other b/tsDMARDs was slightly but statistically significantly increased; small, but not statistically significant, increases were seen for lung cancer (1.10 [0.62–1.96]), lymphoma (1.27 [0.94–1.72]), breast cancer (1.15 [0.92–1.45]), and NMSC (1.10 [0.93–1.30]). No significant increase in hospitalized infections (0.96 [0.84–1.09]) or opportunistic infections (1.06 [0.96–1.17]) was seen. For TB, low event counts precluded meta-analysis. Conclusions In this real-world multi-database study, the risks for specific cancers and infections did not differ significantly between patients in the abatacept and other b/tsDMARDs groups. The slight increase in total malignancy risk associated with abatacept needs further investigation. These results are consistent with the established safety profile of abatacept.

Psoriatic arthritis (PsA) is a heterogeneous disease with several clinical subtypes including peripheral arthritis, dactylitis, enthesitis, nail disease, and axial arthritis. Nonsteroidal anti-inflammatory drugs, glucocorticoids, and conventional disease-modifying agents are used as first line in the treatment of active PsA. For moderate-to-severe PsA failing conventional therapy, antitumor necrosis factor inhibitors have historically been the drugs of choice. In recent years, novel interleukin-23/interleukin-17 pathway targets such as ustekinumab and secukinumab, and phosphodiesterase-4 inhibitor apremilast have been approved for use in the United States and Europe. Two sets of recommendations for the management of PsA were published in 2016 with consideration for these newer therapies. Since then, the results from a Phase III randomized controlled trial demonstrated that abatacept has efficacy in the treatment of PsA. Abatacept, a cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4)-Ig human fusion protein, acts to prevent naïve T-cell activation through the inhibition of the critical CD28 co-stimulatory signal. In the 2017 Active Psoriatic Arthritis Randomized Trial (ASTRAEA), 424 participants were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly versus placebo. At week 24, 39.4% of those who received abatacept achieved a minimum of 20% improvement in the American College of Rheumatology (ACR) response compared to 22.3% in the placebo arm, a statistically significant finding ( <0.001). The 2011 Phase II study published by Mease et al demonstrated statistically significant improvements in the ACR20 response by week 169 in participants treated with intravenous abatacept 10 mg/kg (48%) and 30/10 mg/kg (42%) when compared with placebo (19%). This article reviews the data supporting the efficacy of abatacept in the management of PsA and attempts to place this agent in the context of other biologic disease-modifying antirheumatic drugs and targeted small molecules used in the treatment of patients with PsA.

Background Cardiovascular (CV) disease has a major impact on patients with rheumatoid arthritis (RA), however, the relative contributions of traditional CV risk factors and markers of RA severity are unclear. The authors examined the relative importance of traditional CV risk factors and RA markers in predicting CV events. Methods A prospective longitudinal cohort study was conducted in the setting of the CORRONA registry in the USA. Baseline data from subjects with RA enrolled in the CORRONA registry were examined to determine predictors of CV outcomes, including myocardial infarction, stroke or transient ischemic attack. Possible predictors were of two types: traditional CV risk factors and markers of RA severity. The discriminatory value of these variables was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) in logistic regression. The authors then assessed the incidence rate for CV events among subjects with an increasing number of traditional CV risk factors and/or RA severity markers. Results The cohort consisted of 10 156 patients with RA followed for a median of 22 months. The authors observed 76 primary CV events during follow-up for a composite event rate of 3.98 (95% CI 3.08 to 4.88) per 1000 patient-years. The c-statistic improved from 0.57 for models with only CV risk factors to 0.67 for models with CV risk factors plus age and gender. The c-statistic improved further to 0.71 when markers of RA severity were also added. The incidence rate for CV events was 0 (95% CI 0 to 5.98) for persons without any CV risk factors or markers of RA severity, while in the group with two or more CV risk factors and three or more markers of RA severity the incidence was 7.47 (95% CI 4.21 to 10.73) per 1000 person-years. Conclusions Traditional CV risk factors and markers of RA severity both contribute to models predicting CV events. Increasing numbers of both types of factors are associated with greater risk.

Purpose This study evaluates sex differences and predictors of anti-osteoporosis medication (AOM) use following a hip fracture, with a focus on older men who exhibit higher mortality rates post-fracture compared to women over the age of 65. Methods Participants included 151 men and 161 women aged 65 and older with hip fractures. The outcome, AOM use, was assessed at baseline (≤ 22 days of hospitalization) and at 2, 6, and 12 months post-hip fracture. Generalized estimating equations (GEE) modeled sex differences and predictors of AOM use during the year post-fracture in 255 participants with complete baseline data and ≥ 1 follow-up observation. Results Of the 312 participants, only 53 used AOM at baseline, and 35 initiated use during follow-up. In the unadjusted GEE model, AOM use was significantly less likely in men (OR = 0.42; 95% CI, 0.22–0.78) compared to women. For both men and women, baseline use of AOM was a significant predictor (OR = 28.3; 95% CI, 5.4–148.0 vs. 41.6; 95% CI, 14.0–123.0). The other significant predictors by sex were osteoporosis diagnosis (OR = 3.19; 95% CI, 1.16–8.77) and minimal alcohol use (OR = 3.26; 95% CI, 1.34–7.94) for women versus age (OR = 1.09; 95% CI, 1.01–1.18) for men. Conclusion In older adults with hip fractures, AOM use is low over the year post-fracture and men are less likely to report AOM use compared to women which has implications for important sex differences in predictors of use. Further research is needed to address overall disparities and sex differences in AOM use.