First-line Disease-modifying Antirheumatic Drug Research Articles

Efficacy and safety of first-line biological DMARDs in rheumatoid arthritis patients with chronic kidney disease

ObjectiveTo evaluate the efficacy and safety of first-line biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) with chronic kidney disease (CKD), including those undergoing haemodialysis (HD).MethodsThis retrospective...

Towards stratified treatment of JIA: machine learning identifies subtypes in response to methotrexate from four UK cohorts

Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year. Clusters of MTX 'response' were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65-0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA. Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and the National Institute for Health Research.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis

BackgroundSarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes.MethodsWe conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores.ResultsThree SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity.ConclusionsThese findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Tofacitinib versus methotrexate as the first-line disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis: An open-label randomized controlled trial.

To compare tofacitinib and methotrexate (MTX) as first-line disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA). This open-label, randomized controlled, parallel-group, 3-month trial randomly assigned 100 RA patients to tofacitinib 10 mg daily (49 patients) or MTX 25 mg subcutaneously weekly (51 patients). The primary end point was low disease activity (LDA) measured with Disease Activity Score-28 with C-reactive protein (DAS28-CRP), and the secondary end point was LDA and remission measured by DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Health Assessment Questionnaire Disability Index (HAQ-DI) response and mean reduction of core set of outcomes from baseline at 12 weeks were also analyzed as secondary end points. In addition, acute-phase reactants and composite measurements among groups were examined. LDA in DAS28-CRP was achieved in 17 (34.7%) tofacitinib patients and 18 (35.3%) MTX patients (p = .95). Fourteen (28.6%) and 11 (21.6%) tofacitinib andMTX patients, respectively, achieved LDA by DAS28-ESR (p = .42). Tofacitinib and MTX groups achieved LDA similarly in CDAI (36.7% against 37.3%; p = .96) and SDAI (38.8% vs. 39.2%; p = .96). There was no significant difference in achieving remission between the groups. At 12 weeks, tofacitinib reduced ESR and CRP (p < .05). Composite measures and functional status decreased within groups but not between groups (p > .05). Five (13.51%) tofacitinib patients developed hypertension. MTX caused gastrointestinal problems in 12 (30%) individuals. Two MTX (5%) and two tofacitinib (5.4%) patients had increased liver enzymes and renal impairment, respectively. Tofacitinib had 5.4% infection compared with 5% for MTX. As tofacitinib may be more effective than MTX according to previous reports such as the ORAL Start study, high-dose MTX (25 mg/week, subcutaneously) used in this study may be as efficacious as tofacitinib in patients with established RA who were DMARD naive or had not received a therapeutic dose of DMARDs. However, adverse effects differed between groups. Registered on: ClinicalTrials.gov; ID: NCT04464642.

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

BackgroundManagement of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the...

The Methotrexate Story: How did a Cancer Chemotherapeutic Agent Become a Disease-modifying Antirheumatic Drug

Abstract Weekly mini-pulse of low-dose methotrexate (LD-MTX) is presently the first-line conventional synthetic disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA) and several other systemic immunoinflammatory rheumatic diseases (SIRDs). Yet, most of the younger generation of rheumatologists around the world may be unaware of the interesting journey of MTX, from being an antifolate agent for use as cancer chemotherapy to becoming the mainstay of treatment for inflammatory arthritides and other SIRDs. This short essay narrates the journey of MTX from its precursor analog aminopterin to treat childhood leukemia, its name change from aminopterin to MTX, which became one of the major chemotherapeutic agents in oncology and then evolving as the mainstay of drug treatment for RA and other SIRDs. The seminal role of Gubner et al. from New York in 1953 in recognizing its steroid-sparing property in inflammatory diseases at doses much lower than that needed to treat cancer is highlighted.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Risk of Liver Fibrosis in Methotrexate-Treated Patients: A Systematic Review.

Methotrexate (MTX), an antifolate agent, is recommended as the first-line disease-modifying antirheumatic drug (DMARD). In this systematic review, our goals were to assess liver fibrosis in methotrexate-treated patients, evaluate liver fibrosis in relation to treatment duration and cumulative dose, and identify differences based on the underlying disease. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the systematic review. We thoroughly searched PubMed, PubMed Central (PMC), and Cochrane library databases to identify relevant articles based on predefined selection criteria. Studies were selected based on the following predefined eligibility criteria: English language, papers from the last 20 years, systematic reviews, observational studies, randomized controlled trials (RCTs), and clinical trials, which included papers on MTX playing roles in the development of liver fibrosis with the derived data transferred to a template.Following that, quality was assessed using the appropriate assessment tool for each study. The initial search yielded 512 results. Following a thorough review, 10 studies were chosen for final consideration: eight observational studies and two systematic reviews. Liver enzyme (LE) elevations during MTX therapy are a common but transient problem. Serial abnormal LE tests may be associated with liver pathology, but fibrosis development is uncommon. However, it is unclear from the literature how therapy should be adjusted in the case of elevated LE and to what extent MTX is linked to liver toxicity; definitive conclusions cannot be drawn because more research is needed.

Glabridin Plays Dual Action to Augment the Efficacy and Attenuate the Hepatotoxicity of Methotrexate in Arthritic Rats.

Glabridin is chemically an isoflavane class of natural phenols and is found mainly in the roots of Glycyrrhiza glabra. It has several beneficial pharmacological actions for the management of inflammatory disorders as well as can counteract drug-induced toxic effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. However, its treatment is associated with major side effects like hepatotoxicity. In the quest to explore a suitable combination therapy that can improve the efficacy and reduce the hepatotoxicity of MTX, we hypothesized that glabridin might serve the purpose for which there is no literature precedent to date. We explored the antiarthritic efficacy of MTX in the presence or the absence of glabridin using Mycobacterium-induced arthritic model in rats. The results of reduction in paw swelling, inhibition of serum cytokines (TNF-α, IL-6, and IL-1β), and improvement in the bone joints from radiological and histopathological findings suggest that glabridin can substantially augment the antiarthritic efficacy of MTX. Further, results of concomitant glabridin treatment with MTX in the experimental time frame demonstrate that glabridin could considerably prevent the MTX-induced hepatic alteration in serum biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde (MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a marked effect in impeding the regulation of NF-κB/IκBα and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous administration of glabridin with MTX in the rat model indicate that glabridin had no pronounced effect of causing severe alteration in the pharmacokinetic behavior of MTX. In summary, glabridin can significantly potentiate the antiarthritic efficacy of MTX and can also minimize its hepatotoxicity via the inhibition of inflammation and oxidative stress. Further research should be performed to develop glabridin as a phytotherapeutics for the improved efficacy and better tolerability of MTX at the reduced dose level of MTX.

Case report: Safety and efficacy of adalimumab in treating difficult-to-treat rheumatoid arthritis in a human immunodeficiency virus-positive patient, one year follow-up

Rheumatoid arthritis (RA) is a joint-disabling inflammatory disease associated with the pathology of synovitis. Some patients with RA are difficult to treat, using disease-modifying anti-rheumatic drugs (DMARDs). Biology and targeted synthetic DMARDs (b/tsDMARDs) are options for patients with RA. Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by the human immunodeficiency virus (HIV). Adalimumab is an anti-tumor necrosis factor therapy commonly used in patients with RA. However, there are no reports or related data on patients with RA-HIV/AIDS treated with adalimumab are available. In this report, we described the first successful case of a 60-year-old HIV-positive woman with difficult-to-treat RA treated with ADA after being screened for hepatitis virus, latent tuberculosis (LTBI), and other infections. She contracted HIV from sexual exposure while on adalimumab therapy. As the patient was resistant to first-line DMARDs, she continued adalimumab along with the initiation of highly active antiretroviral therapy (HAART). The patient was treated with adalimumab therapy for a year; her CD4+ lymphocyte count was normal, HIV-1 RNA decreased, and no new infections were triggered. The patient achieved clinical remission of RA. In conclusion, adalimumab is a safe option for patients with RA-HIV and may slow the progression of HIV infection. Furthermore, HAART has the potential to reduce joint pain and fatigue in patients with difficult-to-treat RA.ConclusionsAdalimumab is a safe option for patients with RA-HIV, and may slow down the progression of HIV infection. The HAART therapy has the potential to reduce joint pain and fatigue in patients with difficult-to-treat RA.

Incident and recurrent herpes zoster for first-line bDMARD and tsDMARD users in seropositive rheumatoid arthritis patients: a nationwide cohort study

BackgroundThere is limited information regarding disease-modifying antirheumatic drug (DMARD)-dependent risks of overall, incident, and recurrent herpes zoster (HZ) during first-line biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) treatment among patients with seropositive rheumatoid arthritis (RA) in terms of HZ risk.MethodsA total of 11,720 patients with seropositive RA who were prescribed bDMARD or tofacitinib between January 2011 and January 2019 from the Korean Health Insurance Review & Assessment Service database were studied. A multivariate Cox proportional hazards regression model was adopted to evaluate the adjusted hazard ratio (aHR) with 95% confidence interval (CI) for the risk of HZ dependent on the choice of first-line bDMARDs or tsDMARD, including etanercept, infliximab, adalimumab, golimumab, tocilizumab, rituximab, tofacitinib, and abatacept.ResultsDuring the 34,702 person-years of follow-up, 1686 cases (14.4%) of HZ were identified, including 1372 (11.7%) incident and 314 (2.7%) recurrent HZs. Compared with that of the abatacept group, tofacitinib increased the overall risk (aHR, 2.46; 95% CI, 1.61–3.76; P<0.001), incidence (aHR, 1.99; 95% CI, 1.18–3.37; P=0.011), and recurrence (aHR, 3.69; 95% CI, 1.77–7.69; P<0.001) of HZ. Infliximab (aHR, 1.36; 95% CI, 1.06–1.74; P=0.017) and adalimumab (aHR, 1.29; 95% CI, 1.02–1.64; P=0.032) also increased the overall HZ risk. Moreover, a history of HZ was found to be an independent risk factor for HZ (aHR, 1.54; 95% CI, 1.33–1.78; P<0.001).ConclusionsHZ risk is significantly increased in RA patients with a history of HZ after the initiation of bDMARDs or tsDMARD. The risk of incident and recurrent HZ was higher after tofacitinib treatment in patients with RA than that after treatment with bDMARDs. Individualized characteristics and history of HZ should be considered when selecting bDMARDs or tsDMARD for RA patients considering HZ risks.

Predictors of Treatment Change Among Patients with Rheumatoid Arthritis Treated with TNF Inhibitors as First-Line Biologic Agent in the USA: A Cohort Study from Longitudinal Electronic Health Records.

Previous observational studies utilizing administrative claims data have largely been unable to consider clinical factors that may be related to patterns of drug use among patients with rheumatoid arthritis (RA). To understand predictors of treatment changes following initiation of a tumor necrosis factor inhibitor (TNFi) using nation-wide electronic health record (EHR) data in the USA. The Optum Immunology Condition EHR data (01/01/2011-09/30/2019) was used to identify a population of adult patients with RA initiating a TNFi as the first line biologic disease-modifying anti-rheumatic drug (DMARD). The primary outcome was any treatment change during the 1-year post-index period defined as cycling to a different TNFi or switching to non-TNFi biologic or targeted synthetic DMARDs. Secondary outcomes were the individual components of TNFi cycling and switching, examined separately. To identify predictors of DMARD treatment changes, we used a least absolute shrinkage and selection operator (LASSO) regression model. Model c-statistics and odds ratios (ORs, 95% confidence intervals (CIs)) of predictors were reported. We identified 24,871 patients with RA who initiated a TNFi. The mean age was 55.5 (±13.7) years and 77.2% were female. Among the TNFi initiators, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Predictors that are associated with higher likelihood of TNFi cycling or switching included female gender (OR: 1.26, 95% CI: 1.16-1.36) and glucocorticoid use (OR: 1.30, 95% CI: 1.21-1.40). In contrast, inflammatory bowel disease (OR: 0.62, 95% CI: 0.48-0.78), psoriasis (OR: 0.82, 95% CI: 0.70-0.95), recent use of methotrexate (OR: 0.89, 95% CI: 0.81-0.97), and vitamin D intake (OR: 0.92, 95% CI: 0.85-0.99) were negatively associated with TNFi cycling or switch. Gender, glucocorticoid use, inflammatory bowel disease, psoriasis, and vitamin D intake were identified as significant predictors of TNFi cycling or switching for TNFi initiators in the RA population. Predicting treatment change remains challenging even with large detailed EHR data. This study aimed to identify key determinants of treatment changes among patients with rheumatoid arthritis (RA) initiating a tumor necrosis factor inhibitor (TNFi) as their first-line biologic disease-modifying antirheumatic drug (DMARD) in routine care settings using a US nation-wide longitudinal electronic health record (EHR). Among 24,871 patients with RA who initiated a TNFi, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Female patients and those who used glucocorticoids were more likely to experience TNFi cycling or switching, whereas inflammatory bowel disease, psoriasis, recent methotrexate use, and vitamin D intake were negatively associated with the outcome. However, predicting treatment change remains challenging even with larger detailed EHR data potentially due to unmeasured factors such as prescriber's preference or patient's belief in the medication.

Iguratimod versus salazosulfapyridine in rheumatoid arthritis patients with an inadequate response to methotrexate: Adjusted with propensity score matching.

Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group's 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

POS1356 TREATMENT OF IMMUNE CHECKPOINT INHIBITOR-INDUCED INFLAMMATORY ARTHRITIS AND POLYMYALGIA RHEUMATICA

BackgroundTherapy with immune check point inhibitors (ICIs) has revolutionized cancer treatment during the last years. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events, the immune-related adverse events (irAEs). Inflammatory arthritis and polymyalgia rheumatica (PMR) are two of the most common rheumatic irAEs. The optimal management of irAEs remains unclear. Treatment guidelines largely support the use of glucocorticoids (GCs) as first line therapy [1]. Preclinical data raise concerns regarding the potential risk of impaired antitumoral effect with use of GCs. The high efficacy and potential synergistic effect (according to recent findings) [2] of targeted immunomodulation, such as interleukin 6 (IL-6) blockade, could support a paradigm shift, where targeted treatments are considered earlier in the treatment sequence.ObjectivesTo assess how frequently a disease modifying anti-rheumatic drug (DMARD) treatment in patients with ICI induced arthritis and/or PMR, after inadequate response to GCs, is initiated and to assess its effectiveness.MethodsWe retrospectively identified patients who were diagnosed with inflammatory arthritis and/or PMR at the rheumatology department at Karolinska University Hospital, after referral from the oncology department due to suspicion of a rheumatic irAE, between Jan 2020 and Dec 2021. Treatment response was defined as sustained low disease activity or remission according to the rheumatologist evaluation at 6 months (+/- 1 month) after initiation of DMARD.ResultsA total of 20 patients were identified, who were diagnosed with arthritis (N=11), PMR (N=6) or both (N=3). The median (IQR) age was 70 (46-76) years; 50% of patients were females. The type of cancer was urogenital (N=8), melanoma (N=6), lung cancer (N=2), and other (N=4). 14 patients received a PD-1 inhibitor (9 nivolumab, 4 pembrolizumab, 1 cemiplimab), 3 received a PDL-1 inhibitor (2 atezolizumab, 1 avelumab), 2 received a combination of nivolumab and the CTLA-4 inhibitor ipilimumab and one patient combination of nivolumab and pembrolizumab. The median time from start of ICI treatment to symptom debut was 2 (1.25-3.75) months.83% of patients with PMR and/or arthritis responded well to GCs without the need for treatment escalation. On the contrary,11 out of 14 patients (79%) with inflammatory arthritis (with or without PMR) responded inadequately to GC treatment, despite receiving moderate-high doses (median 20mg/day Prednisolone or equivalent), or flared when the dose was reduced below 10mg/day. A conventional synthetic DMARD was initiated in 7 patients (methotrexate N=6, hydroxychloroquine N=1), with a response rate of 71%. 3 patients received a biologic DMARD as first-line DMARD, either because of contraindication for methotrexate and/or high disease activity, and 2 patients after methotrexate failure. All 5 patients tocilizumab, with a response rate of 100%. Subsequently 1 of these patients discontinued tocilizumab due to suspected side effects, and started with a TNF inhibitor. After initiation of tocilizumab all patients were able to reduce the dose of GCs to less than 5mg/day.ConclusionThe majority of patients developing ICI-induced arthritis are refractory to GCs and need a DMARD treatment, although selection bias cannot be formally excluded, since the most severe forms of arthritis might be referred to the rheumatology department. csDMARDs are effective in a significant proportion of patients. Tocilizumab is highly effective and well tolerated in ICI-induced arthritis. ICI-induced PMR seems to respond adequately to GCs.

Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept

BackgroundAlterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota.The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA.MethodsIn this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment.The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons.ResultsWe did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept.Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes.There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept.ConclusionsTreatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.

Relationship Between Depression and Disease Activity in United States Veterans With Early Rheumatoid Arthritis Receiving Methotrexate.

Depression is common in patients with rheumatoid arthritis (RA), exacerbates disease activity, and may decrease response to first-line disease-modifying antirheumatic drugs. This study aimed to determine if depression affects disease activity among veterans with early RA prescribed methotrexate (MTX). Participants included veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with early RA (onset < 2 yrs) prescribed MTX. Depression was assessed at enrollment using the International Classification of Diseases, 9th revision codes (296.2-296.39, 300.4, 311). Disease activity was measured using the Disease Activity Score in 28 joints (DAS28) and other core measures of RA disease activity. Propensity score weights were used to adjust depressed (n = 48) and nondepressed (n = 220) patients on baseline confounders within imputed datasets. Weighted estimating equations were used to assess standardized mean differences in disease activity between depressed and nondepressed patients at 6-month, 1-year, and 2-year follow-ups. The analytic sample was composed of 268 veterans with early RA prescribed MTX who were predominantly male (n = 239, 89.2%) and older (62.7 yrs, SD 10.6) than patients with RA in the general population. Adjusted estimates indicated that depression was associated with significantly higher DAS28 at 6 months (β 0.35, 95% CI 0.01-0.68) but not at the 1- or 2-year follow-up. Also, depression was associated with significantly worse pain at 6 months (β 0.39, 95% CI 0.04-0.73) and 1 year (β 0.40, 95% CI 0.04-0.75). In early RA, depression is associated with greater short-term disease activity during MTX treatment, as well as more persistent and severe pain.

Role of Serum MRP8/14 in Predicting Response to Methotrexate in Children With Juvenile Idiopathic Arthritis.

Nearly 40% of children with juvenile idiopathic arthritis (JIA) might not respond to first-line disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX). Hence, there is a need for a biomarker that can predict MTX response and help in tailoring initial therapy. Our objective was to study the role of serum myeloid-related protein (MRP) 8/14, and other inflammatory cytokines, as predictors of response to MTX among children with JIA. We did a longitudinal follow-up study among children diagnosed with JIA at our institute. All MTX-naive children with JIA requiring DMARDs were eligible for this study; those who either took corticosteroids or DMARDs for more than 6 weeks at time of presentation were excluded. The demographic and clinical information was collected using a pretested semistructured questionnaire, and selected biomarkers were collected at baseline and again at 3 months. Response at 3 months was assessed using the American College of Rheumatology (ACR) criteria; responders were children who achieved ACR50, whereas those failing to achieve ACR30 were classified as nonresponders. Multivariate binary logistic regression was done to assess determinants of being a responder. We enrolled 69 children (36 boys) with JIA, of which 48 (69.5%) were responders. The baseline value of serum MRP8/14 was significantly higher in responders (median, 144.34 [interquartile range, 88.54-188.34] ng/mL) compared with the nonresponders (median, 95.34 [interquartile range, 76.54-130.28] ng/mL), p = 0.047. Being a responder was significantly associated with baseline serum MRP8/14 with adjusted odds ratio of 1.01 (95% confidence interval, 1.00-1.02). The baseline levels of MRP8/14 were significantly raised in children meeting ACR50 at follow-up and suggest a prognostic value in predicting response to MTX.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update

ObjectiveTo update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA).MethodsAccording to the EULAR standardised operating procedures, a systematic literature review was followed by...

Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach.

Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6-21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.

Insensitivity versus poor response to tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective cohort study

BackgroundWith advancement in the treatment options of rheumatoid arthritis (RA), optimising the outcomes of difficult-to-treat patients has become increasingly important in clinical practice. In particular, insensitivity to first-line biologic disease-modifying anti-rheumatic drugs (bDMARD) is becoming a significant problem because it may decrease the treatment adherence of patients. This study aimed to compare RA patients with an insensitivity and those with a poor response to initial treatment with tumour necrosis factor inhibitors (TNFis), which are the most frequently used bDMARDs.MethodsThis is a retrospective cohort study using clinical data from the FIRST registry. bDMARD-naïve RA patients treated with tumour necrosis factor inhibitors (TNFis) from August 2003 to May 2019 were included and categorised into three groups: TNFi insensitivity, poor response to TNFis and controls. TNFi insensitivity was defined as follows: (1) discontinuation of TNFi treatment within 22 weeks due to lack of any response, or (2) an increase in the disease activity score in 28 joints–C-reactive protein (DAS28-CRP) of > 0.6 at week 22 compared with week 0. Among the remaining patients, those with a DAS28-CRP > 2.6 at week 22 were categorised in the poor response group.ResultsOf the included patients, 94 were classified in the insensitivity, 604 in the poor response and 915 in the control. A higher DAS28-CRP before treatment was a risk factor for a poor response but not for insensitivity. In contrast, dose escalation of infliximab decreased the risk of a poor response but not that of insensitivity.ConclusionsIn future research, poor and insensitivity to bDMARDs should be assessed separately to fully elucidate the aetiology of, and risk factors for, bDMARD refractoriness.