Nonbiologic Disease-modifying Antirheumatic Drugs Research Articles

E034 Drug-induced accelerated nodulosis in a patient with rheumatoid arthritis

Abstract Background/Aims Drug-induced accelerated nodulosis (DIAN) is characterized by the occurrence or progression of multiple subcutaneous nodules in a patient treated for rheumatoid arthritis (RA). It was first and most commonly reported with methotrexate in RA patients. Methods A 37-year-old normotensive, non-diabetic, seropositive rheumatoid arthritis female presented with complaints of nodules over the bilateral hands and feet from the last three months. The treatment history included methotrexate therapy (10 mg/week) for one year. Methotrexate-induced rheumatoid accelerated nodulosis (MIAN) was suspected. Methotrexate was stopped and hydroxychloroquine was added considering the low disease activity. The nodules decreased in number as well as size. On follow-up, she presented with increased multiple joint pain and swelling with ESR 60 mm/hour, CRP 13.6 mg/L, and leflunomide was added. After six months of leflunomide use, she again developed multiple bilateral nodules on the extensor and palmar surface of fingers and feet, ranging from 0.5 to 1 cm. The CRP was 9.2 mg/L, ESR 80 mm/hour, complete blood count showed mild anaemia with normal renal and liver function tests. The nodule biopsy showed palisading granuloma consisting of lymphocytes and histiocytes in mid and deep reticular dermis with large foci of fibrin deposition and collagen degeneration s/o rheumatoid nodule. Leflunomide was stopped. Results The leflunomide was switched to sulfasalazine along with colchicine, and hydroxychloroquine was continued. The patient is doing well on follow-up in terms of disease activity and nodule size. Palmeiro. A.G., et al. 2022 reviewed 39 studies from 1st Jan 1988 to 1st Jan 2022 and found 109 cases of accelerated nodulosis. 99 patients had RA, methotrexate was the culprit drug in 89, followed by etanercept in 7 and leflunomide was in just 3 patients. Although there are no exact treatment guidelines, tumour necrosis factor inhibitors were avoided due to increased nodulosis risk. Recently, Valor-Méndez. L., et al 2020 reported improved nodulosis with Janus Kinase inhibitors like baricitinib, which seems to be a future option. Histologically, rheumatoid nodules and accelerated nodulosis are indistinguishable. The exact pathogenesis is unknown but, polymorphic variants of methionine synthase reductase or haplotype HLA-DRB1*0401, and adenosine A1 receptor promotion in multinucleated giant cells are associated. Conclusion Drug-induced accelerated nodulosis (DIAN) and MIAN are not that rare but diagnosis is challenging. It causes significant morbidity and affects the quality of life because of the predominant involvement of hands and feet. It should be suspected especially when disease activity is low or rapidly progressive nodules with a change in immunotherapy. Partial to total improvement can be achieved by identifying and stopping the culprit drug. We need specific guidelines, more treatment options, and a specific national registry to report such adverse effects with biologics and non-biologic disease-modifying antirheumatic drugs. Disclosure H. Singh: None. R. Kaur: None. G. Mohan: None.

Missed opportunities for treatment of inflammatory arthritis and factors associated with non-treatment: An observational cohort study in United States Veterans with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis

ObjectiveTo identify factors associated with non-treatment with biologic and non-biologic disease modifying anti-rheumatic drugs (DMARDs) during the 12 months after initial inflammatory arthritis (IA) diagnosis. MethodsWe identified Veterans with incident IA diagnosed in 2007–2019. We assessed time to treatment with Kaplan-Meier curves. We identified associations between non-treatment and factors relating to patients, providers, and the health system with multivariate Generalized Estimation Equation (GEE) log-Poisson. Subgroup analyses included IA subtypes (rheumatoid arthritis [RA], psoriatic arthritis [PsA], and ankylosing spondylitis [AS]) and timeframes of the initial IA diagnosis (2007–11, 2012–15, and 2016–19). ResultsOf 18,318 study patients, 40.7 % did not receive treatment within 12 months after diagnosis. In all patients, factors associated with non-treatment included Black race (hazard ratio, 95 % confidence interval: 1.13, 1.08–1.19), Hispanic ethnicity (1.14, 1.07–1.22), Charlson Comorbidity Index ≥2, (1.15, 1.11–1.20), and opiate use (1.09, 1.05–1.13). Factors associated with higher frequency of DMARD treatment included married status (0.86, 0.81–0.91); erosion in joint imaging report (HR: 0.86, 0.81–0.91); female diagnosing provider (0.90, CI: 0.85–0.96), gender concordance between patient and provider (0.91, CI: 0.86–0.97), and diagnosing provider specialty of rheumatology (0.53, CI: 0.49–0.56). ConclusionA high proportion of Veterans with IA were not treated with a biologic or non-biologic DMARD within one year after their initial diagnosis. A wide range of factors were associated with non-treatment of IA that may represent missed opportunities for improving the quality of care through early initiation of DMARDs.

Integrating Nanotechnological Advancements of Disease-Modifying Anti-Rheumatic Drugs into Rheumatoid Arthritis Management.

Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis (RA). Methotrexate, sulfasalazine, hydroxychloroquine, and azathioprine are examples of non-biologic DMARDs that are being used for alleviating pain and preventing disease progression. Biologic DMARDs (bDMARDs) like infliximab, rituximab, etanercept, adalimumab, tocilizumab, certolizumab pegol, and abatacept have greater effectiveness with fewer adverse effects in comparison to non-biologic DMARDs. This review article delineates the classification of DMARDs and their characteristic attributes. The poor aqueous solubility or permeability causes the limited oral bioavailability of synthetic DMARDs, while the high molecular weights along with the bulky structures of bDMARDs have posed few obstacles in their drug delivery and need to be addressed through the development of nanoformulations like cubosomes, nanospheres, nanoemulsions, solid lipid nanoparticles, nanomicelles, liposome, niosomes, and nanostructured lipid carrier. The main focus of this review article is to highlight the potential role of nanotechnology in the drug delivery of DMARDs for increasing solubility, dissolution, and bioavailability for the improved management of RA. This article also focusses on the different aspects of nanoparticles like their applications in biologics, biocompatibility, body clearance, scalability, drug loading, and stability issues.

Efficacy of montelukast as an adjuvant therapy in rheumatoid arthritis patients: A randomized controlled study

ObjectiveThis study aimed to evaluate the efficacy of montelukast in conjunction with non-biologic disease modifying anti-rheumatic drugs (nDMARDs) in rheumatoid arthritis (RA) patients. MethodsThis study was a single-center randomized double-blinded placebo-controlled study. Adult RA patients were included if they had moderate to severe disease activity and were receiving monotherapy or combination of nDMARDs. Eligible patients were randomized, in 1:1 ratio, to receive either 10 mg montelukast or placebo, once daily for 16 weeks. The primary endpoint was the change in the 28-joints disease activity score (DAS28) 16 weeks after treatment. The patients’ quality of life (QoL) was assessed by the Arabic version of the Health Assessment Questionnaire-Disability Index. Moreover, serum levels of vascular adhesion molecule-1 (VCAM-1) were measured. ResultsA total of 87 patients completed the study; 44 in the montelukast arm and 43 in the control arm. After 16 weeks of treatment, disease activity decreased significantly in the montelukast arm with mean change in DAS28 (95% CIs) of −1.5 (−1.7, −1.2) while the control arm showed no improvement (0.2 (0.0, 0.4), p < 0.01). The QoL of the patients improved significantly from baseline in the montelukast arm (p < 0.01) but not in the control arm (p = 0.08). The median (IQR) serum levels of VCAM-1 were significantly lower in the montelukast arm (22.8 (15.0–32.7)) than in the control arm (28.9 (15.4–42.8), p = 0.004). ConclusionThe co-administration of montelukast with nDMARDs in RA patients enhanced the anti-rheumatic effect which was reflected clinically by decreased disease activity.

Incidence of severe infection in patients with rheumatoid arthritis taking biologic agents: a systematic review.

The objective of this review was to estimate the population-based incidence and determine the types of severe infection and deaths experienced by patients with rheumatoid arthritis taking biologic agents. Since the late 1990s, various biologic and synthetic drugs have been developed to treat rheumatoid arthritis. In recent years, the incidence of severe infection in patients with rheumatoid arthritis in Western nations has been determined by observational studies; however, no systematic review has been conducted on this topic. The following inclusion criteria were considered: i) observational studies on patients with rheumatoid arthritis treated with biologic agents; ii) studies reporting the number of severe infections requiring hospitalization for treatment; iii) studies reporting person-years of observation data; and iv) studies based on rheumatoid arthritis registries, medical records from rheumatology centers, or insurance claim databases. PubMed, CINAHL, Embase, and Web of Science were searched to identify published studies. The reference lists of all studies selected for critical appraisal were screened for additional studies. Unpublished studies were searched on MedNar and OpenGrey databases. All the searches were updated on December 6, 2021. After removing the duplicates, 2 independent reviewers screened titles and abstracts against the inclusion criteria and then assessed full texts against the criteria. Two reviewers independently appraised the study and outcome levels for methodological quality using the critical appraisal instrument for cohort studies from JBI. Two reviewers extracted the relevant information related to severe infection and drugs. Fifty-two studies from 21 countries reported severe infection rates associated with using 8 biologic agents, plus nonbiologic disease-modifying antirheumatic drugs. In total, 18,428 infections with 395,065 person-years of biologic drug exposure were included in the analysis. Thirty-five studies included infections in outpatients receiving intravenous antibiotic therapy. Fifteen studies reported the first episode of infection, and the remaining studies did not specify either the first or all of the episodes of infection. Inclusion of viral infection and/or opportunistic infection varied among studies. Fifteen studies reported the site of infection; respiratory, skin/soft tissue, urinary tract, and sepsis/bacteremia were commonly reported. Ten studies reported the case fatality rates, ranging from 2.5% to 22.2%. Meta-analysis was conducted for 8 biologic agents and conventional disease-modifying antirheumatic drugs. The infection rate varied from 0.9 to 18.1/100 person-years. The meta-analysis revealed an infection rate of 5.0/100 person-years (95% CI 3.8-6.7) among patients receiving tumor necrosis factor inhibitors (heterogeneity 98.2%). The meta-analysis for the other 3 biologic agents revealed a point estimate of 5.5 to 8.7/100 person-years with high heterogeneity. Sensitivity analysis indicated that registry-based studies were less likely to have very low or very high infection rates compared with other data sources. The definition of infection, the patient composition of the cohorts, and the type of databases appeared to be the primary sources of clinical and methodological heterogeneity. Due to high statistical heterogeneity, the meta-analysis was not suited to estimating a summary measure of the infection rate. Developing standardized data collection is necessary to compare infection rates across studies. PROSPERO CRD42020175137.

The Impact of Perioperative Use of Nonbiologic Disease-Modifying Anti-rheumatic Drugs on Perioperative Blood Loss and Complications in Patients Who Have Rheumatoid Arthritis Undergoing Total Knee Arthroplasty

BackgroundThe use of disease-modifying antirheumatic drugs (DMARDs) before total knee arthroplasty (TKA) was associated with increased risk of postoperative periprosthetic joint and wound infections as well as worse platelet function in patients who have knee rheumatoid arthritis (RA). This study investigated the effects of DMARDS on perioperative blood loss, complications, and blood transfusion in patients undergoing TKA for knee RA. MethodsWe retrospectively enrolled patients undergoing TKA for knee RA at our hospital between 2017 and 2021 who received DMARDs (n = 73) or not (n = 84). Every RA patient was matched with patients who had osteoarthritis (OA) in a ratio of 1:1 or 1:2. Primary outcomes were intraoperative and perioperative blood losses, while secondary outcomes were complications and allogeneic transfusions. ResultsThe mean total (804 versus 728 mL (mL), P = .114), mean intraoperative (113 versus 101 mL, P = .488), or hidden blood losses (705 versus 640 mL, P = .340) did not differ statistically between RA patients who received DMARDs versus those who did not. RA patients who received DMARDs showed significantly greater mean total (804 versus 654 mL, P = .001), intraoperative (113 versus 75 mL, P = .002), and hidden blood losses (705 versus 560 mL, P = .016) than OA patients. No statistical differences were found in complications or allogeneic transfusions. ConclusionAlthough RA patients experienced greater perioperative blood loss than OA patients, there was no statistical difference in perioperative blood loss, complications, or allogeneic transfusions between RA patients who received DMARDs and those who did not.

Disease control in patients with ankylosing spondylitis in real clinical practice in Spain: Results of the MIDAS study

Introduction and objectivesUnderstanding the disease activity is fundamental to improve patient prognosis and patients’ quality of life. MiDAS study described disease activity in ankylosing spondylitis (AS) Spanish patients and the proportion of them with controlled disease. MethodsObservational, cross-sectional, multicenter study carried out under conditions of routine clinical practice. Adult (≥18 years) patients with ≥6 months since AS diagnosis treated ≥3 months prior to inclusion. The primary endpoint was the percentage of patients with low disease activity assessed through BASDAI (primary endpoint) and ASDAS-CRP (secondary endpoint). Results313 AS patients included: 75.7% male; 78.5% HLA-B*27 positive; mean (SD) baseline age of 50.4 (12.0) years; mean (SD) disease duration of 15.5 (11.6) years; 73.5% were treated with biological disease-modifying antirheumatic drugs (DMARDs), 22.4% with non-biological DMARDs and 53.7% with non-steroidal anti-inflammatory drugs, alone or in combination. Monotherapy with biologics and non-biologics was used by 29.7% and 26.8% of patients, respectively. According to BASDAI, 38.0% were in remission (BASDAI≤2) and 64.5% showed adequate disease control (BASDAI<4). According to ASDAS-CRP, 29.4% achieved remission (ASDAS-CRP<1.3) and 28.1% low disease activity (1.3≤ASDAS-CRP<2.1). ConclusionsAlmost two thirds of the AS patients recruited had low disease activity, with about one third of them being in remission (BASDAI≤2, ASDAS-CRP<1.3). These results highlight the existing room for improvement in treating AS patients in clinical practice.

Hydroxychloroquine and Risk of Long QT Syndrome in Rheumatoid Arthritis: A Veterans Cohort Study With Nineteen-Year Follow-up.

Recent evidence suggests that hydroxychloroquine use is not associated with higher 1-year risk of long QT syndrome (LQTS) in patients with rheumatoid arthritis (RA). Less is known about its long-term risk, the examination of which was the objective of this study. We conducted a propensity score-matched active-comparator safety study of hydroxychloroquine in 8,852 veterans (mean age 64 ± 12 years, 14% women, 28% Black) with newly diagnosed RA. A total of 4,426 patients started on hydroxychloroquine and 4,426 started on another nonbiologic disease-modifying antirheumatic drug (DMARD) and were balanced on 87 baseline characteristics. The primary outcome was LQTS during 19-year follow-up through December 31, 2019. Incident LQTS occurred in 4 (0.09%) and 5 (0.11%) patients in the hydroxychloroquine and other DMARD groups, respectively, during the first 2 years. Respective 5-year incidences were 17 (0.38%) and 6 (0.14%), representing 11 additional LQTS events in the hydroxychloroquine group (number needed to harm 403; [95% confidence interval (95% CI)], 217-1,740) and a 181% greater relative risk (95% CI 11%-613%; P=0.030). Although overall 10-year risk remained significant (hazard ratio 2.17; 95% CI 1.13-4.18), only 5 extra LQTS occurred in hydroxychloroquine group over the next 5 years (years 6-10) and 1 over the next 9 years (years 11-19). There was no association with arrhythmia-related hospitalization or all-cause mortality. Hydroxychloroquine use had no association with LQTS during the first 2 years after initiation of therapy. There was a higher risk thereafter that became significant after 5 years of therapy. However, the 5-year absolute risk was very low, and the absolute risk difference was even lower. Both risks attenuated during longer follow-up. These findings provide evidence for long-term safety of hydroxychloroquine in patients with RA.

Treatment escalation patterns to start biologics in refractory moderate juvenile dermatomyositis among members of the Childhood Arthritis and Rheumatology Research Alliance

BackgroundDespite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking.MethodsThe Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher’s exact test was used to compare the distribution of responses to each survey question.ResultsOne hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1–2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience.ConclusionMost respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.

The Role of Biologics in Rheumatoid Arthritis: A Narrative Review.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can cause cartilage and bone damage as well as a disability. Various cytokines play an essential role in disease formation such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-17, and macrophages; osteoclast is also activated by the cytokines, which cause bone degradation. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterized risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and using conventional, biological, and new non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favorable, many still do not respond to current therapies. The biologics have changed the disease progression over the past few decades, such as TNF-alpha inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab), IL-1 inhibitors (anakinra), IL-6 inhibitors (tocilizumab), CD20 inhibitors (rituximab), and cytotoxic T-lymphocyte associated antigen (CTLA)-4 inhibitors (abatacept). In treatment with biologics, only little is known if "biologic-free" remission is possible in patients with sustained remission following intensive biological therapy. Infliximab and etanercept, in the long run, develop the drug antibody. This article has reviewed the action of the cytokine on joints and biological drug's action in blocking the cytokine degradation effect, benefits of biologics, and adverse effects in the long and short term. They are also effective alone or in combination with other drugs.

How do non-biologic disease-modifying antirheumatic drugs (DMARDs) combined with steroids compare with steroids alone or with each other for adults with non-infectious intermediate, posterior, and panuveitis (NIIPPU)?

How do non-biologic disease-modifying antirheumatic drugs (DMARDs) combined with steroids compare with steroids alone or with each other for adults with non-infectious intermediate, posterior, and panuveitis (NIIPPU)?

Эффективность применения ритуксимаба у пациентов с юношеским артритом без системных проявлений

Juvenile idiopathic arthritis (JIA) is arthritis of unknown cause lasting more than 6 weeks, which starts in children under 16 years old with the exclusion of other joint disorder. According to the recommendations for the treatment of JIA, patients who does not responded to with antirheumatic therapy, we prescribe biological therapy, primarily TNF-alpha inhibitors. Despite their high effectiveness, in some patients, the TNF-alpha inhibitors has no proper therapeutic effect, which requires studying the possibility of using other therapy, in particular- rituximab. Objective. To evaluate the efficacy and safety of rituximab in patients with JIA without systemic manifestations Patients and methods. Retrospective cohort study included 33 patients who received rituximab. Treatment was initiated in the Department of Rheumatology, National Medical Research Center for Children's Health (Moscow) between December 2006 and April 2022. All patients were treated with non-steroid anti-inflammatory drugs (NSAIDs), non-biologic disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biological agents with other mechanism of action. There was ineffectiveness of previous antirheumatic therapy in all patients. Patients were divided into two groups: with RF-positive polyarthritis (n = 30) and other non-systemic JIA (n = 13). Efficacy was evaluated in 1, 3, 6, 9, 12 months after first rituximab infusion and every 6 months till discontinuation or 18 years old achievement. Inactive disease/remission was registered according to Juvenile Arthritis Disease Activity Score (JADAS71) &lt;1, С.Wallace criteria (2011) and The American College of Rheumatology (ACR) Pediatric criteria for assessing joint status (ACR Pedi 30, 50, 70, and 90). Results. Among 16 patients with RF-positive JIA 8 (50%) achieved 90% improvement according to ACR Pedi, inactive disease/remission according to С.Wallace was registered in 12 (75%) 12 months after rituximab initiation. In patients with other nonsystemic JIA (n = 13) 90% improvement according to ACR Pedi was registered in 5 (45%) patients, inactive disease/remission according to С.Wallace was registered in 6 (54, 5%) patients. Conclusion. Rituximab is highly effective in patients with JIA without systemic manifestation, who failed to previous treatment with NSAIDs, DMARDs and biological agents with other mechanism of action and it could be considered as next escalation therapy. Key words: rituximab, juvenile idiopathic arthritis, efficiency of therapy

Comanagement with rheumatology and prescription biologics filled during pregnancy in women with rheumatic diseases: a retrospective analysis of US administrative claims data

ObjectivesTo evaluate comanagement with rheumatology and biological prescriptions filled during pregnancy among women with axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA) and to examine factors associated with...

Post-switch Effectiveness of Etanercept Biosimilar Versus Continued Etanercept in Rheumatoid Arthritis Patients with Stable Disease: A Prospective Multinational Observational Study.

To better inform clinicians about the use of etanercept biosimilar (SB4) in patients with rheumatoid arthritis (RA), COMPANION-B, a prospective real-world observational study, evaluated the effectiveness of the voluntary switch from originator (etanercept, ETN) to SB4 in patients with stable RA (low-disease activity/remission). The study recruited adult patients (18years or older) with RA (2010 American College of Rheumatology criteria) prescribed ETN as their first or second biologic for at least 6months across 14 sites in Canada and five in Australia. Patients had stable disease (Disease Activity Score-28 using erythrocyte sedimentation rate [DAS28-ESR] less than 3.2) at enrollment with no evidence of flare within the previous 3months. Concomitant disease-modifying antirheumatic drugs (DMARDs) were permitted. Patients could elect to continue ETN or voluntarily switch to SB4 in consultation with their doctors. The primary effectiveness measure was the proportion of patients with disease worsening (defined as a DAS28-ESR increase of at least 1.2 from baseline and minimum score of at least 3.2 or a defined modification in RA treatment) during 12months of follow-up. The secondary effectiveness measure was the proportion of patients with disease worsening at month6. Serious adverse events (SAEs) and non-serious adverse reactions (NSARs) were recorded. Of 163 patients enrolled, 109 elected to continue on ETN and 54 switched to SB4; 65.8% of patients received non-biologic DMARD(s), 52.6% methotrexate, and 10.5% oral corticosteroid(s). At month12, the proportion of patients with disease worsening was comparable in the ETN group (22.8% [95%CI 15.0-32.2]) and SB4 group (17.6% [95%CI 8.4-30.9]). Similarly, the proportions of patients with disease worsening were also comparable at month6 (ETN: 7.9% [95%CI 3.5-15.0]; SB4: 7.8% [95%CI 2.2-18.9]). SAEs were low and similar across both groups (ETN: 8.7%; SB4: 5.7%). NSARs were slightly higher in the SB4 vs. ETN group (13.2% vs. 2.9%). SB4 demonstrated comparable effectiveness to ETN over 12months in patients with stable RA who voluntarily switched to the biosimilar in a real-world setting.

Efficacy and safety of guselkumab in biologic-naïve patients with active axial psoriatic arthritis: study protocol for STAR, a phase 4, randomized, double-blinded, placebo-controlled trial

BackgroundAxial involvement constitutes a specific domain of psoriatic arthritis (PsA). Interleukin (IL)-23 inhibitors have demonstrated improvement in axial PsA (axPsA) symptoms, but have not shown efficacy in treating ankylosing spondylitis (AS), suggesting differences in axPsA processes and treatments. In a post hoc, pooled analysis of patients with investigator- and imaging-confirmed sacroiliitis in two phase 3, randomized, placebo-controlled studies (DISCOVER-1 and DISCOVER-2), patients treated with guselkumab, an IL-23p19 inhibitor, had greater axial symptom improvements compared with placebo. Confirmatory imaging at baseline was restricted to the sacroiliac (SI) joints, occurred prior to/at screening, and was locally read.MethodsThe STAR study will prospectively assess efficacy outcomes in PsA patients with magnetic resonance imaging (MRI)-confirmed axial inflammation. Eligible, biologic-naïve patients with PsA (N = 405) for ≥ 6 months and active disease (≥ 3 swollen and ≥ 3 tender joints, C-reactive protein [CRP] ≥ 0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs will be randomized (1:1:1) to guselkumab every 4 weeks (Q4W); guselkumab at week (W) 0, W4, then every 8 weeks (Q8W); or placebo with crossover to guselkumab at W24, W28, then Q8W. Patients will have Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4, spinal pain component score (0–10 visual analog scale) ≥ 4, and screening MRI-confirmed axial involvement (positive spine and/or SI joints according to centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥ 3 in ≥ 1 region). The primary endpoint is mean change from baseline in BASDAI at W24; multiplicity controlled secondary endpoints at W24 include AS Disease Activity Score employing CRP (ASDAS), Disease Activity Index for PsA (DAPSA), Health Assessment Questionnaire – Disability Index (HAQ-DI), Investigator’s Global Assessment of skin disease (IGA), and mean changes from baseline in MRI SI joint SPARCC scores. Centrally read MRIs of spine and SI joints (scored using SPARCC) will be obtained at W0, W24, and W52, with readers blinded to treatment group and timepoint. Treatment group comparisons will be performed using a Cochran-Mantel-Haenszel or chi-square test for binary endpoints and analysis of covariance, mixed model for repeated measures, or constrained longitudinal data analysis for continuous endpoints.DiscussionThis study will evaluate the ability of guselkumab to reduce both axial symptoms and inflammation in patients with active PsA.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04929210, on 18 June 2021.Protocol version: Version 1.0 dated 14 April 2021.

Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials

ObjectiveEvaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS...

Temporal Relationship Between Juvenile Idiopathic Arthritis Disease Activity and Uveitis Disease Activity.

To determine whether there is a temporal association between arthritis and uveitis activity among children with juvenile idiopathic arthritis-associated uveitis (JIA-U). Uveitis and arthritis data from patients with JIA-U age ≤21 years were collected from July 2013 to December 2019 at a tertiary care center. Arthritis activity was assessed at each rheumatology visit, and the primary outcome was the presence of active uveitis at ophthalmologic examination within 45 days of the rheumatology visit. Repeated-measures logistic regression was used to evaluate the temporal association between any uveitis activity within 45 days of arthritis activity. Models were adjusted for demographic-, disease-, and treatment-related factors. A total of 98 patients were included: 81 (83%) female, 67 (69%) antinuclear antibody positive, 59 (60%) oligoarticular, and 13 (13%) enthesitis-related arthritis (ERA) subtypes. There were 1,229 rheumatology visits, with a median of 13 visits per patient (interquartile range 7-18). Concordance between arthritis and uveitis activity was observed 73% of the time (694 of 947). There was an independent temporal association between uveitis and arthritis activity (odds ratio 2.47 [95% confidence interval 1.72-3.54]; P < 0.01), adjusted for demographic and disease characteristics. Use of combination biologic and nonbiologic disease-modifying antirheumatic drugs, female sex, HLA-B27 positivity, and ERA and polyarticular (rheumatoid factor negative) subtypes were associated with decreased odds of active uveitis at any time point. In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity. These novel results suggest that an arthritis flare should prompt an expedited referral to the ophthalmologist.

Canadian Adalimumab Postmarketing Observational Epidemiological Study Assessing Effectiveness in Psoriatic Arthritis (COMPLETE-PsA): 12-month Results of Comparative Effectiveness of Adalimumab and nbDMARDs.

COMPLETE-PsA was an observational study of biologic-naïve Canadian adults with active psoriatic arthritis (PsA) treated with adalimumab (ADA) or a nonbiologic disease-modifying antirheumatic drug (nbDMARD) regimen, after inadequate response/intolerance to a current nbDMARD treatment regimen. The aim of this analysis was to assess the 12-month effectiveness of ADA vs nbDMARDs. Patients enrolled between March 2012 and November 2017 were included. The following clinical variables and patient-reported outcomes were collected/calculated per routine care: Disease Activity Index for Psoriatic Arthritis in 28 joints (DAPSA28), Disease Activity Score in 28 joints (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein, physician global assessment (PGA), patient global assessment (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), 12-item Short Form Health Survey, enthesitis, dactylitis, body surface area (BSA), and time to achieving American College of Rheumatology (ACR) 50, ACR70, and modified minimal disease activity (mMDA). Two hundred and seventy-seven ADA-treated and 148 nbDMARD-treated patients were included. At baseline, ADA-treated patients were less likely to be employed, had longer morning stiffness, higher DAPSA28, DAS28, PGA, PtGA, pain, and HAQ-DI, and lower prevalence of dactylitis (all P < 0.05). ADA-treated patients showed lower baseline-adjusted DAPSA28 (16.5 vs 26.6), DAS28 (2.8 vs 3.9), PGA (25.3 vs 37.1), and ESR (10.4 vs 15.0 mm/h) after 3 months compared to nbDMARD-treated patients, with observed improvements maintained to month 12. Time to achievement of ACR50, ACR70, and mMDA was significantly shorter (P < 0.001) among ADA-treated patients, with the likelihood of having dactylitis (odds ratio [OR] 0.4, 95% CI 0.2-0.6) and BSA< 3% (OR 2.7, 95% CI 1.5-5.0) significantly lower and higher, respectively. Switching to another biologic was less likely in ADA-treated vs nbDMARD-treated patients (hazard ratio 0.3, 95% CI 0.2-0.5). In a real-world Canadian population of patients with PsA, ADA was more effective than nbDMARDs at reducing disease activity and the severity of skin involvement, and demonstrated higher retention. [ClinicalTrials.gov: NCT01559038].

The risk of newly diagnosed cancer in patients with rheumatoid arthritis by TNF inhibitor use: a nationwide cohort study

BackgroundTumor necrosis factor (TNF) inhibitors use in patients with rheumatoid arthritis (RA) has raised safety concerns about cancer risk, but study results remain controversial. This largest nationwide study to date compared cancer risk in TNF inhibitor users to non-biologic disease-modifying anti-rheumatic drug (nbDMARD) users in Korean patients with RA.MethodsData on all the eligible patients diagnosed with RA between 2005 and 2016 were retrieved from the Korean National Health Information Database. The one-to-one matched patients consisted of the matched cohort. The risks for developing all-type and site-specific cancers were estimated using incidence and incidence rate (IR) per 1000 person-years. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using a Cox regression model.ResultsOf the 22,851 patients in the before matching cohort, 4592 patients were included in the matched cohort. Treatment with TNF inhibitors was consistently associated with a lower risk of cancer than in the nbDMARD cohort (IR per 1000 person-years, 6.5 vs. 15.6; adjusted HR, 0.379; 95% CI, 0.255–0.563). The adjusted HR (95% CI) was significantly lower in the TNF inhibitor cohort than the nbDMARD cohort for gastrointestinal cancer (0.432; 0.235–0.797), breast cancer (0.146; 0.045–0.474), and genitourinary cancer (0.220; 0.059–0.820).ConclusionsThe use of TNF inhibitors was not associated with an increased risk of cancer development, and rather associated with a lower cancer incidence in Korean patients with RA. Cautious interpretation is needed not to oversimplify the study results as cancer-protective effects of TNF inhibitors. A further study linking claims and clinical data is needed to confirm our results.

Upadacitinib as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs for psoriatic arthritis.

ObjectiveTo assess the efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA.MethodsPooled data were analysed from patients with prior inadequate response or intolerance to one or more nbDMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) who received placebo, UPA 15 mg once daily (QD) or UPA 30 mg QD as monotherapy or in combination with two or fewer nbDMARDs for 24 weeks. Efficacy outcomes included achievement of ACR responses, Psoriasis Area and Severity Index responses, minimal disease activity and change from baseline and clinically meaningful improvement in the HAQ Disability Index. Adverse events (AEs) were summarized.ResultsA total of 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects for a 20% improvement in ACR criteria at week 12 were 33.7% (95% CI 24.4, 43.1) and 34.0% (95% CI 27.9, 40.1) for UPA 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (95% CI 36.9, 54.5) and 39.6% (95% CI 33.7, 45.5) for UPA 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for UPA monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy.ConclusionThe efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of UPA with or without nbDMARDs in PsA.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov): SELECT-PsA 1 (NCT03104400), SELECT-PsA 2 (NCT03104374)