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In a 24-week trial involving patients with rheumatoid arthritis that was refractory to biologic agents, the JAK1 inhibitor upadacitinib was superior to the T-cell costimulation modulator abatacept in reducing disease activity as assessed by a composite measure of joint changes and C-reactive protein level.

To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. This study was registered on www.ClinicalTrials.gov (NCT01981473).

BackgroundOsteoarthritis (OA) is a chronic joint disease characterized by progressive loss of articular cartilage and abnormal bone formation. Furthermore, there are changes in periarticular muscles, such as loss of muscle mass, strength and function. These features may contribute to functional impairment among patients.ObjectivesThis study aimed to investigate the molecular pathways involved in muscle wasting in an animal model of OA induced by anterior cruciate ligament (ACL) transection in rats.MethodsFemale Wistar rats were allocated into two groups: OA (submitted to the ACL transection; n=9) and SHAM (submitted to surgical procedures without ACL transection; n=8) [1]. Spontaneous exploratory locomotion, nociception and body weight of animals were evaluated weekly. Twelve weeks after the disease induction, animals were euthanized and the right knee joints were collected for further confirmation of the disease by histopathology, accordingly to OARSI histologic scoring system [2]. Gastrocnemius muscle from the right hind paw were dissected and weighed. Gastrocnemius was used for evaluation of muscle atrophy [3] and protein expression of myostatin, MuRF-1, MyoD and myogenin. Data were compared by Student's t test or ANOVA followed by Tukey's test or ANOVA followed by Mann–Whitney's U-test. The results are expressed as mean values ± standard deviation (SD) for symmetric variables and as medians with interquartile range for asymmetric variables. Significance was accepted at P<0.05.ResultsHistopathology of the right knee joints confirmed the development of the disease in animals from OA group. Gastrocnemius area of animals from OA group had a reduction of about 10% compared to animals from SHAM group. Protein expression of myostatin was increased in OA group, while myogenin expression was decreased. MuRF-1 and MyoD expression was similar in both OA and SHAM groups. Spontaneous exploratory locomotion, nociception, body weight and weight of gastrocnemius showed no difference between OA and SHAM groups.ConclusionsGastrocnemius atrophy in OA induced by ACL transection involves increased protein expression of myostatin and decreased protein expression of myogenin. In this model, muscle wasting may be linked to myostatin-induced deficits in satellite-cell differentiation due to decreased expression of myogenin.References Elsaid KA, Machan JT, Waller K, Fleming BC, Jay GD. The Impact of Anterior Cruciate Ligament Injury on Lubricin Metabolism and the Effect of Inhibiting Tumor Necrosis Factor alpha on Chondroprotection in an Animal Model. Arthritis and Rheumatism. 2009;60(10):2997–3006.Gerwin N, Bendele AM, Glasson S, Carlson CS. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis and Cartilage. 2010;18:S24-S34.Filippin LI, Teixeira VN, Viacava PR, Lora PS, Xavier LL, Xavier RM. Temporal development of muscle atrophy in murine model of arthritis is related to disease severity. Journal of Cachexia Sarcopenia and Muscle. 2013;4(3):231–8.de Oliveira Nunes Teixeira V, Filippin LI, Viacava PR, de Oliveira PG, Xavier RM. Muscle wasting in collagen-induced arthritis and disuse atrophy. Exp Biol Med (Maywood). 2013;238(12):1421–30. Disclosure of InterestNone declared

Objective To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. Methods ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2. Results 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients. Conclusions Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.

Objective To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. Methods ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. Results Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). Conclusions Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. Trial registration number NCT00810199.

The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17–0.65, p Bonf = 0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African-derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8–1854.7, p Bonf = 0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients.

Introduction The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Methods Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. Results The LTE was comprised of 91.4% ( n  = 277/303) of patients that initially received UPA15, and 89.6% ( n  = 277/309) that initially received ABA. Of patients on UPA15 in the LTE ( n  = 547), 28.3% ( n  = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient’s assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n  = 263/303, 86.8%; ABA to UPA15: n  = 273/309, 88.3%) showed similar responses to the total population. Conclusions The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343. Plain Language Summary A long-term study looked at a drug named upadacitinib to treat people with rheumatoid arthritis (RA), a disease that causes joint pain and damage. The study included patients whose RA was not improved by other injectable medicines. The study compared upadacitinib with another drug called abatacept. After 24 weeks, patients who were taking abatacept switched to upadacitinib, and patients taking upadacitinib continued on upadacitinib treatment for over 4 years. The researchers looked at how well the treatments worked over the long-term and if there were any side effects. The side effects with upadacitinib treatment in this long-term study were similar to side effects reported in previous studies with upadacitinib. The researchers also found that upadacitinib helped to lessen the symptoms of RA over time and helped patients complete their daily activities and reduced their pain and tiredness. This was true for patients who switched from abatacept to upadacitinib after 24 weeks and for patients who took upadacitinib from the start of the study. Patients who had not responded to other medicines also had similar improvements with upadacitinib. In conclusion, upadacitinib can help people with RA over the long term and no new safety risks were found.

BackgroundSystemic sclerosis (SSc) is a rare multisystem disease with underlying immune mechanisms, whose pathogenesis remains unclear. Few previous reports have evaluated lymphocyte subpopulations in SSc and your results are conflicting.ObjectivesThe present study aimed to analyze the lymphocyte subsets in SSc patients in comparison to healthy individuals.MethodsPeripheral blood (PB) samples to analyze lymphocyte subsets were obtained from a non-random convenience sample of 20 SSc patients. Twenty healthy individuals recruited from the blood bank were used as sex and age-matched controls. Blood samples were analyzed by flow cytometry for total T cells, CD4+ and CD8+ T cells subsets, CD19+ B cells and total NK cells. Statistical analyses were performed using the IBM Statistical Package for Social Sciences (SPSS 18.0). Data are expressed as mean ± SD and median and range. Non-parametric Mann–Whitney U test was used for analyses of the flow cytometry. A probability p<0.05 was considered statistically significant.ResultsThe mean (SD) age of SSc patients was 57.9 (14.2) years, 95% were female and 31.6% presented diffuse cutaneous SSc (dcSSc). Patients presented a lower mean total lymphocyte count compared to healthy controls (23.7% vs. 29.6%, p=0.026) (Table 1.). No statistically significant differences were found in the percentages or the absolute numbers of T, B or NK cells.PatientsControlspa Leukocytes8.02±1.516.79±3.390.108Lymphocytes%23.53±14.0629.97±15.080.026*Absolute1.70±1.592.06±0.030.512CD45%99.79±0.1199.71±0.110.165CD3%71.20±3.5775.11±1.790.398Absolute1.35±1.201.60±0.070.478CD4%48.59±4.0947.76±8.780.289Absolute0.85±0.940.99±0.120.620CD8%25.10±0.0428.38±1.190.277Absolute0.48±0.290.51±0.030.301CD19%8.89±11.5710.44±2.070.478Absolute0.20±0.020.17±0.030.512NK%6.73±8.396.71±5.400.883Absolute0.14±0.350.14±0.090.947RatioT/B8.54±4.117.31±2.30.383CD4/CD81.93±0.231.73±0.330.157ConclusionsOur data support previous reports indicating that depletion of lymphocyte in the PB of SSc patients. However, we found no significant difference in relation to lymphocyte subtypes, which differs from the literature data.References T and NK Cell Phenotypic Abnormalities in Systemic Sclerosis: a Cohort Study and a Comprehensive Literature Review. Almeida et al, 2015.Liu M, Wu W, Sun X, Yang J, Xu J, Fu W, Li M. New insights into CD4+ T cell abnormalities in systemic sclerosis. Cytokine & Growth Factor Reviews, 2016; 28:31–36.Gambichler T, Tigges C, Burkert B, Höxtermann S, Altmeyer P, Kreuter A. Absolute count of T and B lymphocyte subsets is decreased in systemic sclerosis. Eur J Med Res 2010; 15:44–46. Disclosure of InterestNone declared

BackgroundSystemic sclerosis (SSc) is a rare multisystem disease with underlying immune mechanisms, whose pathogenesis remains unclear. Few previous reports have evaluated lymphocyte subpopulations in SSc and your results are conflicting.ObjectivesThe present study aimed to analyze the lymphocyte subsets in SSc patients in comparison to healthy individuals.MethodsPeripheral blood (PB) samples to analyze lymphocyte subsets were obtained from a non-random convenience sample of 20 SSc patients. Twenty healthy individuals recruited from the blood bank were used as sex and age-matched controls. Blood samples were analyzed by flow cytometry for total T cells, CD4+ and CD8+ T cells subsets, CD19+ B cells and total NK cells. Statistical analyses were performed using the IBM Statistical Package for Social Sciences (SPSS 18.0). Data are expressed as mean ± SD and median and range. Non-parametric Mann–Whitney U test was used for analyses of the flow cytometry. A probability p<0.05 was considered statistically significant.ResultsThe mean (SD) age of SSc patients was 57.9 (14.2) years, 95% were female and 31.6% presented diffuse cutaneous SSc (dcSSc). Patients presented a lower mean total lymphocyte count compared to healthy controls (23.7% vs. 29.6%, p=0.026) (Table 1.). No statistically significant differences were found in the percentages or the absolute numbers of T, B or NK cells.ConclusionsOur data support previous reports indicating that depletion of lymphocyte in the PB of SSc patients. However, we found no significant difference in relation to lymphocyte subtypes, which differs from the literature data.References T and NK Cell Phenotypic Abnormalities in Systemic Sclerosis: a Cohort Study and a Comprehensive Literature Review. Almeida et al, 2015.Liu M, Wu W, Sun X, Yang J, Xu J, Fu W, Li M. New insights into CD4+ T cell abnormalities in systemic sclerosis. Cytokine & Growth Factor Reviews, 2016; 28:31–36.Gambichler T, Tigges C, Burkert B, Höxtermann S, Altmeyer P, Kreuter A. Absolute count of T and B lymphocyte subsets is decreased in systemic sclerosis. Eur J Med Res 2010; 15:44–46. Disclosure of InterestNone declared