Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
28927738 DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthrit 2017 Nov 1 BACKGROUND: Patients with rheumatoid arthritis (RA) exhibit an increased risk of dementia. Disease-modifying antirheumatic drugs (DMARDs) are commonly used to slow RA progression, but studies investigating the relationship between DMARDs and dementia in patients with RA are lacking. We investigated the relationship between DMARDs and dementia in patients with RA. METHODS: Using the National Health Insurance Research Database, patients aged ≥20years, who were newly diagnosed with RA between 2000 and 2011 were identified. Patients with RA who had dementia comprised the dementia group, and patients with RA who did not have dementia comprised the control group. The groups were matched at a 1:1 ratio by the propensity score. DMARDs were categorized into conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs). Logistic regression models were used to calculate the odds ratio and 95% confidence interval (CI) to evaluate the association between DMARD use and the risk of dementia in patients with RA. RESULTS: A total of 957 patients with RA and dementia, and 957 patients with RA but not dementia, were enrolled. The risk of dementia was determined to be 1.63-fold higher in patients with RA with csDMARD use than in those without csDMARD use (95% CI=1.33-2.00). No significant risk of dementia was observed in patients with RA who used bDMARDs compared with their counterparts. However, patients with RA who used hydroxychloroquine, methotrexate, and sulfasalazine exhibited significant risks of dementia, irrespective of cumulative exposure days. CONCLUSION: Patients with RA who used csDMARDs exhibit significant association with dementia.
28199814 Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. 2017 Feb 16 BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).
29042358 Safety, immunogenicity and efficacy after switching from reference infliximab to biosimila 2018 Feb OBJECTIVES: Efficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2. METHODS: Patients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78. RESULTS: Efficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%-69.4% with INF/INF and 65.6%-68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively. CONCLUSIONS: The efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2. TRIAL REGISTRATION NUMBER: NCT01936181; EudraCT number: 2012-005733-37.
27312466 Efficacy and safety of methotrexate plus certolizumab pegol or placebo in active rheumatoi 2017 Aug OBJECTIVES: This study aimed to assess the relative efficacy and safety of certolizumab pegol (CZP) 200 and 400 mg + methotrexate (MTX) compared to placebo + MTX in patients with active rheumatoid arthritis (RA). METHODS: We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of CZP 200 and 400 mg + MTX and placebo + MTX (MTX group) in patients with active RA despite receiving MTX or a disease-modifying antirheumatic drug (DMARD). RESULTS: Six RCTs (30349 patients) met the inclusion criteria. The ACR20 response rate was significantly higher in the CZP 200 and 400 mg + MTX group than in the MTX group (OR 7.30, 95 % credible interval [CrI] 3.31-16.92 and OR 5.48, 95 % CrI 2.98-10.30, respectively). CZP 400 mg + MTX tended to be more efficacious than CZP 200 mg + MTX (OR 1.33, 95 % CrI 0.61-2.97). A surface under the cumulative ranking curve (SUCRA)-based ranking probability indicated that CZP 400 mg + MTX had the highest probability of achieving the ACR20 response rate, followed by CZP 200 mg + MTX and MTX (SUCRA = 0.9007, 0.7156, and 0.0002, respectively). The ACR20, 50, and 70 response rate distributions were comparable. However, the safety based on the number of adverse event (AE)-related withdrawals did not differ significantly among the three interventions. CONCLUSIONS: CZP, at dosages of 200 and 400 mg, in combination with MTX, was the efficacious intervention for active RA without causing a significant risk of AE-related withdrawals.
28107255 High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asi 2017 Apr BACKGROUND: It is unclear whether erythrocyte methotrexate polyglutamate levels (MTX-glun) are associated with response or adverse effects to methotrexate in rheumatoid arthritis. This preliminary study evaluated their utility in Asian Indian patients over 24 weeks. METHODS: Rheumatoid arthritis patients were started on oral methotrexate at a dose of 15 mg/wk, which was escalated to 25 mg by 12 weeks and continued till 24 weeks. Erythrocyte (RBC) MTX-glu1 to MTX-glu5 levels (nmol/L RBC) were determined at 4, 8, 16, and 24 weeks by using reverse-phase high-performance liquid chromatography. Area under the concentration curve (AUC) of MTX-glu1-5, MTX-glu3-5, and MTX-glu3 levels was compared between groups with regards to response and adverse effects. RESULTS: This study included 117 patients with mean (SD) age of 42.7 (±11.9) years and disease duration of 2.0 (1.7) years. Mean (SD) RBC MTX-glu1-5 levels at 4, 8, 16, and 24 weeks were 93 (±29), 129 (±46), 143 (±49), and 159 (±65) nmol/L RBC; the highest individual polyglutamate was MTX-glu3 (40%). There was significant correlation between MTX-glu1-5 (r = 0.38, P < 0.001) and MTX-glu3 (r = 0.49, P < 0.001) with methotrexate dose. There was no significant difference of AUC MTX-glun between responders and nonresponders. However, AUC MTX-glu3 was significantly (P = 0.03) higher in patients with adverse effects. On logistic regression, AUC of MTX-glu3 [odds ratio = 1.004 (95% confidence interval 1.002-1.007)] and methotrexate dose at 24 weeks were independent predictors of adverse effects. CONCLUSIONS: In this preliminary study, higher levels of RBC MTX-glu3 were found to be the independent predictors for adverse effects in rheumatoid arthritis patients.
28962586 Further Treatment Intensification in Undifferentiated and Rheumatoid Arthritis Patients Al 2017 Sep 30 BACKGROUND: It is recommended to optimise treatment as long as a predefined treatment target is not met, but should the aim be remission if patients are in low disease activity (LDA)? The aim of this study was to assess if, in patients with rheumatoid arthritis (RA) or patients with undifferentiated arthritis (UA) with Disease Activity Score (DAS) ≤ 2.4 (LDA), treatment intensification results in better functional ability. METHODS: In the IMPROVED study 610 patients with early RA or UA were treated with methotrexate + tapered high-dose prednisone. After 4 months, patients with DAS ≥ 1.6 were randomised to either of two treatment strategies. Patients with DAS < 1.6 tapered treatment. Over 5 years, patients with DAS ≥ 1.6 required treatment intensification, but protocol violations occurred, which allowed us to test the effect of treatment intensification regardless of subsequent DAS. A linear mixed model was used to test, in patients in LDA, the relationship between treatment intensification and functional ability (Health Assessment Questionnaire [HAQ]) over time. RESULTS: The number of patients in LDA per visit ranged from 88 to 146. Per visit, 27-74% of the patients in LDA had treatment intensification. We found a statistically significant effect of treatment intensification on ΔHAQ, corrected for baseline HAQ, age, sex and treatment strategy (β = -0.085, 95% CI -0.13 to -0.044). When ΔDAS was added, the effect of treatment intensification was partly explained by ΔDAS, and the association with HAQ was no longer statistically significant (β = -0.022, 95% CI -0.060 to 0.016). When the interaction between treatment intensification and time in follow-up was added, a statistically significant interaction was found (β = 0.0098, 95% CI 0.0010 to 0.019), indicating lesser improvement in HAQ after treatment intensification if follow-up time increased. CONCLUSIONS: For patients with early RA and patients with UA already in LDA, further treatment intensification aimed at DAS remission does not result in meaningful functional improvement. TRIAL REGISTRATION: ISRCTN, 11916566 . Registered on 28 December 2006. EudraCT, 2006-006186-16 . Registered on 16 July 2007.
29259050 Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the sim 2018 Apr OBJECTIVE: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. RESULTS: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. CONCLUSION: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. TRIAL REGISTRATION NUMBER: NCT02357069.
28550389 Clinical effectiveness and safety of leflunomide in inflammatory arthritis: a report from 2017 Jul Leflunomide is indicated for the treatment of adults with rheumatoid arthritis, yet is underutilized. Given the cost of biologic therapy, understanding real-life effectiveness, safety, and sustainability of leflunomide, particularly in patients who have failed methotrexate, would be of value. The primary objective was to assess the proportion of patients achieving clinically meaningful benefit following an adequate trial of leflunomide. A retrospective analysis of a cohort supplemented with patient self-reported data using a standardized questionnaire. Data were analyzed using descriptive statistics, with a database multivariate logistic regression analysis to determine predictors of leflunomide response. Of the cohort available (N = 2591), 1671 patients with confirmed leflunomide use were included in the retrospective analysis, of whom 249 were incident users. Low disease activity (DAS-28 < 3.2) was achieved or maintained by 20% of incident users, with 19% achieving a clinical response (DAS-28 decrease ≥1.2) at 3 months. Adverse effects (AE) were reported by 29% of incident users and after 1 year, 45% remained on leflunomide. Achievement of "minimal or no joint symptoms" was reported by 34% in the 661 analyzable survey responses (39% response rate). AE were reported by 55%, with nuisance (hair loss, nausea, stomach pain) AE and diarrhea being most common. Leflunomide was discontinued by 67% of responders within 1 year. An important proportion of patients, the majority of whom had previously failed methotrexate, achieved disease response with leflunomide with a low risk of serious adverse effects, suggesting that a trial of leflunomide may be a reasonable and cost-effective strategy prior to biologic therapy.
27723271 Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or 2017 Mar OBJECTIVE: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs. METHODS: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. RESULTS: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. CONCLUSION: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
28121204 Efficacy of golimumab for preventing large joint destruction in patients with rheumatoid a 2017 Nov OBJECTIVES: The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis. METHODS: We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed. RESULTS: The mean age of the study population was 61.29 ± 14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6 ± 12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n = 18), 3 (n = 26), and 4 (n = 1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431 ± 1.044. Patients were treated with methotrexate (mean dose 6.44 ± 1.78 mg/week), prednisolone (PSL) (mean dose 1.078 ± 1.871 mg/d), and golimumab (44.4% of 100 mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp-van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly. CONCLUSIONS: Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.
27432356 Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Sli 2017 Mar OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.
28288508 Isoniazid treatment for latent tuberculosis infection is tolerable for rheumatoid arthriti 2018 Sep BACKGROUND/AIMS: To evaluate the impact of isoniazid (INH) treatment for latent tuberculosis infection (LTBI) on the development of liver function test (LFT) abnormality and the persistence of tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients. METHODS: We retrospectively enrolled patients with RA who were treated with TNF inhibitors at a university hospital between December 2000 and November 2011. After dividing the patients into two groups based on the occurrence of LFT abnormality during follow-up, we compared demographic and clinical features between the two groups. A multivariable logistic regression analysis was performed to identify the impact of INH treatment on LFT abnormality. The impact of INH treatment on the persistence of TNF inhibitors was also evaluated with the log-rank test and the Cox-proportional hazards model. RESULTS: A total of 312 RA patients including 96 patients (30.9%) who took INH for LTBI were included in this analysis. Thirty-nine patients (12.5%) experienced LFT abnormalities while using TNF inhibitors. The use of INH was associated with LFT abnormalities (odds ratio, 3.01; 95% confidence interval [CI], 1.39 to 6.48) after adjusting for covariates, including methotrexate use. However, the persistence of TNF inhibitors over 5 years did not differ between patients receiving or not receiving INH treatment (49.4 vs. 54.6%, p = 0.79). INH treatment was not a risk factor for discontinuation of TNF inhibitors (hazard ratio, 1.01; 95% CI, 0.66 to 1.57). CONCLUSION: INH treatment for LTBI in RA patients who started TNF inhibitors is associated with the occurrence of LFT abnormality; however, it does not lead to discontinuation of TNF inhibitors.
28118534 Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-Expressing Memory B 2017 Jun OBJECTIVE: In rheumatoid arthritis (RA), autoreactive B cells are pathogenic drivers and sources of anti-citrullinated protein antibodies (ACPAs) that are a diagnostic biomarker and predictor of worse long-term prognosis. Yet, the immunobiologic significance of persistent ACPA production at the cellular level is poorly understood. This study was undertaken to investigate the representation of ACPA-expressing switched-memory B cells in RA. METHODS: In a cross-sectional study of RA patients, we investigated the presence of continued defects in immune homeostasis as a function of disease activity. Using an enzyme-linked immunosorbent assay (ELISA) and a sensitive multiplex bead-based immunoassay, we characterized fine binding antibody specificities in sera, synovial fluid (SF), and B cell culture supernatants. In this manner, we determined the frequency and epitope reactivity patterns of ACPAs produced by SF B cells and switched-memory blood B cells and compared the latter to serum ACPA levels and disease activity scores. RESULTS: Cultured B cells from SF were shown to spontaneously secrete ACPAs, while constitutive IgG autoantibody production by peripheral blood mononuclear cells (PBMCs) was substantially less frequent. After in vitro stimulation, PBMCs secreted IgG ACPA that was overwhelmingly from switched-memory B cells, across all patient groups treated with methotrexate and/or a tumor necrosis factor inhibitor. Intriguingly, the frequencies of ACPA-expressing switched-memory B cells significantly correlated with serum IgG anti-cyclic citrullinated peptide 3 (r = 0.57, P = 0.003). Moreover, treatment-induced clinical remission had little or no effect on the circulating burden of switched-memory ACPA-expressing B cells, in part explaining the continued dysregulation of humoral immunity. CONCLUSION: Our findings rationalize why therapeutic cessation most often results in disease reactivation and clinical flare. Hence, a clinical disease activity score is not a reliable indicator of the resolution of pathologic recirculating B cell autoimmunity.
28829236 A review of tofacitinib efficacy in rheumatoid arthritis patients who have had an inadequa 2017 Oct Tofacitinib is a pan JAK inhibitor with specificity for JAK3 over JAK1 over JAK2, which is approved in many countries for the treatment of rheumatoid arthritis (RA), including the United States and the European Union, either as monotherapy or in combination with conventional synthetic disease modifying anti-arthritis drugs (csDMARDs). Phase 2, 3 and 4 clinical trials have investigated the efficacy and safety of tofacitinib given either as monotherapy or in combination with csDMARDs. Areas covered: This review reports the safety, clinical, functional, and radiographic efficacy, of tofacitinib used as monotherapy in the treatment of adult patients with RA reported in the prospective, double-blind, controlled randomized trials reported to date. One critical clinical question is whether tofacitinib monotherapy has similar efficacy as tofacitinib in combination with methotrexate (MTX); this question has recently been addressed. A literature search on tofacitinib monotherapy was carried out using the PubMed database up to July 2017. Expert opinion: Although tofacitinib plus MTX is statistically more clinically effective, tofacitinib monotherapy is effective in many patients with RA.
28676912 Clinical characteristics of methotrexate-associated lymphoproliferative disorders: relatio 2017 Oct Several reports have shown that patients with rheumatoid arthritis (RA) are at increased risk of developing lymphoproliferative disorders (LPD). Methotrexate (MTX) has been recognized as a major cause of LPD. Sometimes spontaneous regression (SR) occurs after withdrawal of MTX. Recent studies suggest that the early recovery of the absolute lymphocyte count (ALC) after withdrawal of MTX is associated with the spontaneous regression of MTX-LPD. We retrospectively analyzed 26 patients with MTX-LPD to identify predictive factors for spontaneous regression. The spontaneous regression after withdrawal of MTX occurred in 13 of 26 (50%) cases. We assessed the ALC at the time of MTX cessation and 1 month after cessation in 23 evaluable cases. The spontaneous regression was observed in 3 of 11 in the ALC recovery group (27%) and in 8 of the 12 in the ALC non-recovery group (67%). Thus, we could not detect any relationship between the recovery of ALC after withdrawal of MTX and the spontaneous regression. The patients in the ALC recovery group had a poorer prognosis than those in the ALC non-recovery group (2-year overall survival: 65.6 vs. 100%, p = 0.05). According to these results, the recovery of the ALC might not be useful as a predictor of the spontaneous regression. Furthermore, the existence of extranodal sites and advanced-stage were associated with non-SR. It is suspected that MTX-LPD patients with high disease activity at the time of their diagnosis might have little hope of spontaneous regression. This result indicated the importance of the early detection of MTX-LPD.
28502927 Mizoribine Synchronized Methotrexate Therapy should be Considered when Treating Rheumatoid 2017 Objective The objective of this study was to confirm the efficacy of low-dose mizoribine (MZR), an inhibitor of inosine monophosphate dehydrogenase, as part of synchronized methotrexate (MTX) therapy for rheumatoid arthritis (RA) patients with an inadequate response to various combination therapies of MTX, other synthetic disease-modifying anti-rheumatic drugs (DMARDs) and biological DMARDs. Methods Low-dose MZR was administered to 56 uncontrolled RA patients being treated with MTX and various biological DMARDs. The observation period was 12 months, and the disease activity was evaluated based on the Disease Activity Score in 28 joints (DAS28)-ESR, Simplified Disease Activity Index (SDAI) and serum MMP-3 level. Results All of the disease activity indices were significantly improved within three months, and the serum MMP-3 levels were also significantly decreased around four months after starting low-dose MZR therapy. No patients experienced any adverse effects. Conclusion The present preliminary findings suggest that low-dose MZR therapy with MTX should be considered for the treatment of RA patients with an inadequate response to various combination therapies including MTX, other synthetic DMARDs and biological DMARDs or in whom increasing the dose of MTX is difficult for reasons such as adverse effects and complications.
28569209 In-vivo monitoring of anti-folate therapy in arthritic rats using [(18)F]fluoro-PEG-folate 2017 May 31 BACKGROUND: Folate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). In rheumatoid arthritis, FRβ is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [(18)F]fluoro-PEG-folate. The purpose of this study was to examine whether this folate tracer can also be used to monitor therapeutic efficacy of MTX in arthritic rats. METHODS: Arthritic rats received either no treatment or MTX therapy (1 mg/kg, either 2× or 4×). Healthy rats did not receive any arthritic induction or therapy. [(18)F]fluoro-PEG-folate PET-CT scans (60 min) were performed before and after MTX therapy. Following PET, the ex-vivo tissue distribution of radioactivity was determined in excised knees and multiple tissues. Synovial macrophage infiltration in knee sections was quantified by immunohistochemistry using ED1 and ED2 antibodies. RESULTS: PET scans clearly visualized increased uptake of [(18)F]fluoro-PEG-folate in arthritic knees compared with contralateral knees. Significantly lower standard uptake values (1.5-fold, p < 0.01) were observed in arthritic knees of both MTX-treated groups after therapy, approximating the levels seen in healthy rats. Consistently, ex-vivo tissue distribution demonstrated a 2-4-fold lower tracer uptake in the arthritic knee of 2× and 4× MTX-treated rats, respectively, compared with control rats. These results were corroborated with significantly reduced (2-4-fold, p < 0.01) ED1-positive and ED2-positive synovial macrophages in arthritic knees of the MTX-treated rats compared with those of the control rats. CONCLUSION: This study in arthritic rats underscores the potential and usefulness of [(18)F]fluoro-PEG-folate PET as a therapeutic monitoring tool of MTX therapy and potentially other anti-folate treatment of arthritis.
28637670 A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rit 2017 Sep OBJECTIVES: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. METHODS: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration-time curve from study drug infusion to infinity (AUC(0-inf)). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24. RESULTS: The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. CONCLUSIONS: Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. TRIAL REGISTRATION NUMBER: NCT01274182; Results.
28388820 Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus 2017 Oct OBJECTIVE: Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA. METHODS: RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks. RESULTS: Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup. CONCLUSION: In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response.
28079512 Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etane 2017 May OBJECTIVES: To observe long-term clinical response and drug survival in a prospective two-year cohort study in rheumatoid arthritis (RA) patients starting adalimumab or etanercept treatment, with or without methotrexate (MTX), after failure of conventional DMARD therapy, including MTX. METHODS: Disease activity score of 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were collected of 873 consecutive RA patients, treated with adalimumab or etanercept, prospectively at baseline, 4, 16, 28, 40, 52, 78 and 104 weeks of biological therapy. Sustained minimal disease activity (MDA), DAS28 <2.6 for at least 24 consecutive weeks, biological discontinuation, ΔHAQ and ΔDAS28 were compared between patients treated with or without concomitant MTX for etanercept and adalimumab separately. RESULTS: More patients treated with adalimumab and MTX (42%) achieved sustained MDA than patients without MTX (18%). The hazard ratio (HR) was 2.3 [1.4-3.9]. No significant difference was found in etanercept treatment (with MTX 33% vs. 28% without MTX), HR 1.1 [0.8-1.6]. More patients treated without MTX discontinued treatment than patients with MTX co-treatment in adalimumab (HR 2.1 [1.5-3.0]) and etanercept (HR 1.9 [1.0-3.4]). The mean decrease in DAS28 over time was higher for patients treated with MTX in adalimumab (regression coefficient (RC): 0.57, p<0.001), but was not significantly different in etanercept treatment (RC 0.05, p=0.427). No significant differences were found in ΔHAQ. CONCLUSIONS: Treatment discontinuation is lower in patients treated with MTX in both adalimumab and etanercept treatment. However, considering good clinical response, in contrast to etanercept, a synergetic effect of MTX is observed only in adalimumab treatment.