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ID PMID Title PublicationDate abstract
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.
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.
29526961 Choledochoduodenal Fistula during Chemotherapy with Brentuximab Vedotin for Methotrexate-a 2018 Aug 1 We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin.
30058434 Adverse events, clinical considerations and management recommendations in rheumatoid arthr 2018 Nov A new class of oral synthetic drugs has been developed for the treatment of rheumatoid arthritis (RA) with the aim of blocking the Janus kinase/signal transducer and activator of transcription (JAK-STAT) system. Tofacitinib and baricitinib have been approved for the treatment RA patients who inadequately respond to methotrexate or anti-tumor necrosis factor drugs. The aim of this narrative review is to summarize the data concerning the drugs' basic mechanisms and clinical trial results in order to inform clinicians about the serious and non-serious adverse events associated with JAK inhibitors. Areas covered: The mechanisms, adverse events, and clinical trial data associated with the use of JAK inhibitors in RA patients were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1999 and April 2018 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: Management of the adverse events of JAK inhibitors is challenging because of the lack of robust treatment data used and the heterogeneity of the events themselves. Treatment decisions are often made clinically on the basis of age and the burden of comorbidities, and require the multidisciplinary collaboration of rheumatologists and other specialists.
29502174 Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Re 2018 Jul As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer (Eli Lilly) of baricitinib (BARI; Olumiant(®); a Janus kinase inhibitor that is taken orally) to submit evidence of its clinical and cost effectiveness for the treatment of moderate to severe rheumatoid arthritis (RA) after the failure of disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical-effectiveness evidence in the CS for BARI was based predominantly on three randomised controlled trials comparing the efficacy of BARI against adalimumab or placebo, as well as one long-term extension study. The clinical-effectiveness review identified no head-to-head evidence on the efficacy of BARI against all the comparators within the scope. Therefore, the company performed network meta-analyses (NMAs) in two different populations: one in patients who had experienced an inadequate response to conventional DMARDs (cDMARD-IR), and the other in patients who had experienced an inadequate response to tumour necrosis factor inhibitors (TNFi-IR). The company's NMAs concluded BARI had comparable efficacy as the majority of its comparators in both populations. The company submitted a de novo discrete event simulation model that analysed the incremental cost-effectiveness of BARI versus its comparators for the treatment of RA from the perspective of the National Health Service (NHS) in four different populations: (1) cDMARD-IR patients with moderate RA, defined as a 28-Joint Disease Activity Score (DAS28) > 3.2 and no more than 5.1; (2) cDMARD-IR patients with severe RA (defined as a DAS28 > 5.1); (3) TNFi-IR patients with severe RA for whom rituximab (RTX) was eligible; and (4) TNFi-IR patients with severe RA for whom RTX in combination with methotrexate (MTX) is contraindicated or not tolerated. In the cDMARD-IR population with moderate RA, the deterministic incremental cost-effectiveness ratio (ICER) for BARI in combination with MTX compared with intensive cDMARDs was estimated to be £37,420 per quality-adjusted life-year (QALY) gained. In the cDMARD-IR population with severe RA, BARI in combination with MTX dominated all comparators except for certolizumab pegol (CTZ) in combination with MTX, with the ICER of CTZ in combination with MTX compared with BARI in combination with MTX estimated to be £18,400 per QALY gained. In the TNFi-IR population with severe RA, when RTX in combination with MTX was an option, BARI in combination with MTX was dominated by RTX in combination with MTX. In the TNFi-IR population with severe RA for whom RTX in combination with MTX is contraindicated or not tolerated, BARI in combination with MTX dominated golimumab in combination with MTX and was less effective and less expensive than the remaining comparators. Following a critique of the model, the ERG undertook exploratory analyses after applying corrections to the methods used in the NMAs and two programming errors in the economic model that affected the company's probabilistic sensitivity analysis (PSA) results. The ERG's NMA results were broadly comparable with the company's results. The programming error that affected the PSA of the severe cDMARD-IR population had only a minimal impact on the results, while the error affecting the severe TNFi-IR RTX-ineligible population resulted in markedly higher costs and QALYs gained for the affected comparators but did not substantially modify the conclusions of the analysis. The NICE Appraisal Committee concluded that BARI in combination with MTX or as monotherapy is a cost-effective use of NHS resources in patients with severe RA, except in TNFi-IR patients who are RTX-eligible.
27180974 Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 2018 Nov A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.
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.
29895378 Effect of anti-rheumatic treatment on selenium levels in inflammatory arthritis. 2018 Sep OBJECTIVES: The reason for increased cardiovascular risk in inflammatory arthritis (IA) is unclear. Interestingly, selenium-deficiency is suspected to contribute to the development of cardiovascular disease (CVD) in the general population. Although the reference range of serum selenium (s-selenium) is 50-120 μg/L, there are indications that levels up to 85 μg/L might not be sufficient for optimal cardioprotection. Our aim was to examine s-selenium levels in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), to evaluate the effect of anti-rheumatic treatment on s-selenium levels, and to assess relationships between s-selenium levels and clinical and laboratory parameters including markers of disease activity and CVD risk. METHODS: We examined 64 patients with RA, 40 with PsA and 26 with AS starting with methotrexate (MTX) monotherapy or anti-tumor necrosis factor therapy (anti-TNF) with or without methotrexate (anti-TNF ± MTX) due to active disease. S-selenium, inflammatory biomarkers, endothelial function (EF) and other variables were examined at baseline and after 6 weeks and 6 months of treatment. RESULTS: In the total IA group, s-selenium increased within 6 weeks of anti-rheumatic treatment, and thereafter the levels remained stable until the end of the 6 months follow-up period. There were no significant differences in s-selenium changes between the three diagnostic groups and between the two treatment regimens. Changes in s-selenium were negatively related to changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there were no significant relationships to any other of the examined risk parameters for CVD including EF. CONCLUSION: IA patients had s-selenium within the reference range, but below the level that might be necessary for optimal CVD protection. Anti-rheumatic treatment had a relatively rapid and sustained effect on s-selenium levels. The increase in s-selenium was related to reduction in inflammatory activity. In theory, anti-rheumatic drugs might improve s-selenium levels through inhibition of pro-inflammatory processes or through other mechanisms. Although we have not revealed any significant relationships between s-selenium and CVD risk parameters, the role of suboptimal s-selenium levels in pathogenesis of premature CVD in IA cannot be ruled out.
30357484 Tocilizumab-induced psoriasis-like eruption resolved by shortening the dose interval in a 2019 Jan Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption.
30075534 Tofacitinib, an oral Janus kinase inhibitor, in patients from Brazil with rheumatoid arthr 2018 Aug BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Efficacy and safety of tofacitinib in Brazilian patients from Phase 2 (P2) and Phase 3 (P3) global studies of up to 24 months' duration were evaluated. METHODS: Data were pooled from Brazilian patients with RA and an inadequate response to conventional synthetic or biologic disease-modifying antirheumatic drugs enrolled in P2/P3 tofacitinib studies who received tofacitinib 5 or 10 mg twice daily (BID), or placebo, as monotherapy or in combination with methotrexate. Efficacy, safety, and patient-reported outcomes were assessed over 24 months. RESULTS: Patients (226) from Brazil were treated in tofacitinib global P2/P3 studies. At Month 3, there were improvements in American College of Rheumatology 20/50/70 response rates, Disease Activity Score in 28 joints, erythrocyte sedimentation rate, and Health Assessment Questionnaire-Disability Index scores with both tofacitinib doses. Improvements from baseline in pain, fatigue, and health-related quality of life with tofacitinib 5 and 10 mg BID were reported. Efficacy improvements were sustained up to Month 24. The most frequent class of adverse events was infections and infestations. No cases of tuberculosis or other opportunistic infections were reported. CONCLUSION: In a Brazilian subpopulation of patients with RA, tofacitinib reduced disease signs and symptoms and improved physical function up to Month 24, with a safety profile consistent with findings from global studies.
29303707 The influence of disease-modifying anti-rheumatic drugs and corticosteroids on the associa 2018 May OBJECTIVES: To investigate the influence of corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs, including conventional synthetic and biologic DMARDs) treatment on the association between rheumatoid arthritis (RA) and non-melanoma skin cancer (NMSC). METHODS: This nationwide retrospective case-control study retrieved data from Taiwan National Health Insurance Research Database during 1995-2013. Cases with newly-diagnosed NMSC (n=19,603) were matched with control without NMSC in a 1:1 ratio according to age, sex, and reference date. The aforementioned association was analysed using conditional logistic regression and adjustments for age, sex, residential regions, occupations, and co-morbidities. Causality cannot be inferred by case-control study. RESULTS: Compared to patients without RA, the patients with RA had a significantly higher association with NMSC (adjusted odds ratio (AOR)=2.23, 95% confidence interval (CI) 1.6-3.1, p<0.001), especially those using cyclosporine (AOR=5.7, 95%CI 2.2-14.86; ≥65 years: AOR=7.28, 95%CI 2.16-24.56), etanercept (AOR=5.27, 95%CI 1.15-24.27; ≥65 years: AOR=8.95, 95%CI 1.12-71.85), and d-penicillamine (AOR=4.79, 95%CI 1.63-14.12; ≥65 years: AOR=3.81, 95%CI 1.26-11.52); those using higher cumulative doses of corticosteroids and methotrexate (corticosteroids: >10g: AOR=2.96, 95%CI 1.67-5.22; >10g and ≥65years: AOR=3.5, 95%CI 1.77-6.92; methotrexate: 1-3g: AOR=2.57, 95%CI 1.13-5.82; >3g: AOR=4.64, 95%CI 1.74-12.4; >3g and ≥65 years: AOR=10.17, 95%CI 2.34-44.26); and those using more kinds of DMARDs (any 3: AOR=3.72, 95%CI 1.67-8.26; any 5: AOR=2.81, 95%CI 1.13-7.04; any 6: AOR=5.23, 95%CI 1.14-24.14; 7-8: AOR=4.06, 95%CI 1.14-14.49). CONCLUSIONS: The patients with RA had significantly increased associations with NMSC, especially those receiving cyclosporine, etanercept, and d-penicillamine; higher cumulative doses of corticosteroids and methotrexate; or more kinds of DMARDs in combination or in sequence. The aforementioned associations were much stronger in the elderly.
30057321 Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheum 2019 Feb OBJECTIVES: To evaluate the prophylactic effect of sulfasalazine against Pneumocystis jirovecii pneumonia (PJP) among rheumatoid arthritis (RA) patients. METHODS: We used a nationwide Japanese multicenter RA database to extract data from 2005 and 2014. To identify PJP cases, we selected patients hospitalized for PJP and verified their diagnosis. Two control groups, one unmatched and the other matched for age, sex, glucocorticoid, methotrexate, and tacrolimus dosage, and the use (and type, if used) of biological disease-modifying antirheumatic drug were selected by incidence-density sampling. The odds ratios for PJP associated with sulfasalazine use and other clinical factors were estimated by exact and standard conditional logistic regression. RESULTS: From 18,668 participants, 60 cases, 356 unmatched controls, and 337 matched controls were selected. None of the cases received sulfasalazine before PJP onset. A comparison of the cases with the unmatched controls showed that sulfasalazine use carried a decreased risk of PJP (adjusted odds ratio 0.18, 95% confidence interval 0.00-0.92). A comparison of the cases and matched controls also showed that sulfasalazine use had a decreased risk of PJP (0.08, 0.00-0.36). In an analysis of the cases and unmatched controls who did not receive sulfasalazine, an increased risk of PJP was associated with lung disease (3.88, 1.89-7.95) and the use of glucocorticoid (5.71, 2.68-12.19), methotrexate (5.25, 2.01-13.74), and tumor necrosis factor inhibitors (2.32, 1.10-4.93). CONCLUSIONS: The results of this nested case-control study demonstrated the preventive effect of sulfasalazine against PJP. The results await confirmation by future prospective studies.
29954352 Highly suspected primary intraocular lymphoma in a patient with rheumatoid arthritis treat 2018 Jun 28 BACKGROUND: To describe a case of highly suspected primary intraocular lymphoma (PIOL) in a patient using etanercept for the treatment of rheumatoid arthritis. CASE PRESENTATION: A 50-year-old female patient presented with decreased vision in her left eye that lasted for a week. She had a 15-year history of seropositive rheumatoid arthritis (RA), and had been taking weekly etanercept for the preceding 8 months. Funduscopic examination and SD-OCT showed a swollen ellipsoid zone (EZ) and a retinal pigment epithelium (RPE) irregularity of the right eye. We also noted EZ disruption and a RPE irregularity in the left eye. As subretinal infiltration was aggravated in the right eye after the initial treatment, we completed a vitrectomy. Vitreous cytology revealed PIOL with positive CD20 immunostaining. She was treated with serial intravitreal methotrexate injections and systemic chemotherapy. After the treatment, subretinal infiltration and subRPE deposits were decreased in the right eye with no evidence of recurrence in either eye. CONCLUSIONS: This case suggests a potential relationship between immunosuppression with anti-TNFα medication, and increased risk for lymphoma, especially in patients with underlying rheumatologic disorders and especially in patients with suspected chronic refractory uveitis.
29558044 Efficacy and safety of golimumab as add-on therapy to standard disease-modifying antirheum 2018 Apr BACKGROUND: The GO-MORE study was an open-label, multinational, prospective study that investigated the efficacy and safety of adding golimumab to synthetic disease-modifying antirheumatic drugs (sDMARDs) in patients with active rheumatoid arthritis (RA). OBJECTIVES: The aim of this study was to assess the efficacy and safety of golimumab add-on therapy in the Polish subpopulation of the GO-MORE study. MATERIAL AND METHODS: Patients were administered 50 mg subcutaneous doses of golimumab once a month for 6 months, while continuing therapy with sDMARDs and/or glucocorticoids (GCS). The primary clinical endpoint was the proportion of patients with moderate or good European League Against Rheumatism (EULAR) response based on the 28-joint disease activity score (DAS28) erythrocyte sedimentation rate (ESR) after 6 months. RESULTS: The Polish subpopulation (129 patients) was similar to the overall study population (3,280 patients) with regard to age, sex, mean baseline DAS28, inflammatory markers, average methotrexate dose, and GCS use; however, they had a longer disease duration (median: 6.04 vs 4.9 years) and more Polish patients (85.9% vs 78.7%) had high disease activity (DAS28-ESR ≥3.2). At 6 months, 84.5% of Polish patients showed good or moderate EULAR response, 26.4% had low disease activity and 17.1% were in clinical remission, compared with 82.9%, 37.4% and 23.9%, respectively, in the overall study population. Golimumab safety profile was consistent with previous studies and comparable to the overall study population. CONCLUSIONS: The addition of golimumab to sDMARD therapy in Polish RA patients showed good or moderate EULAR DAS28-ESR response in 84.5% of patients, mirroring the overall study population.
29968101 [S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. 2018 Aug BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.
29392511 Comparative efficacy and safety of biosimilar adalimumab and originator adalimumab in comb 2018 May We aimed to assess the relative efficacy and safety of biosimilar adalimumab and originator adalimumab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA) who showed an inadequate response to MTX. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of biosimilar + MTX and adalimumab + MTX versus placebo + MTX (MTX group) in patients with active RA despite treatment with MTX. A total of eight RCTs involving 2543 patients met the inclusion criteria. The ACR20 response rate was significantly higher in the biosimilar + MTX (odds ratio [OR] 2.91, 95% credible interval [CrI] 1.57-5.74) and adalimumab + MTX (OR 2.80, 95% CrI 1.81-4.46) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar + MTX and adalimumab + MTX groups. Biosimilar + MTX had the highest probability of being the best treatment in terms of the ACR20 response rate (surface under the cumulative ranking curve [SUCRA] = 0.7896), followed by adalimumab + MTX (SUCRA = 0.7082) and MTX (SUCRA = 0.0022). The ACR50 and ACR70 response rates showed a distribution pattern similar to that of the ACR20 response rate. Safety based on the number of serious adverse events did not differ significantly among the three interventions in the follow-up period of 12 to 24 weeks. Biosimilar and originator adalimumab, in combination with MTX, represent an effective intervention for active RA despite treatment with MTX. No significant difference was found between biosimilar and originator adalimumab in terms of efficacy and safety. However, follow-up in RCTs is short and not all safety outcomes can be assessed in RCTs. Thus, additional long-term evaluations are needed.
30299241 Efficacy of tocilizumab monotherapy after response to combined tocilizumab and methotrexat 2019 May OBJECTIVES: The aim of the JUST-ACT study was to assess whether the add-on effect of tocilizumab (TCZ) to background methotrexate (MTX) observed in MTX-inadequate responders with active rheumatoid arthritis (RA), would be sustained when MTX is withdrawn. METHODS: A double-blind, parallel-group, phase 3 study in biologic-naïve RA patients with a disease activity score 28 (DAS28)>3.2 despite MTX which were treated with TCZ+MTX for an initial 16-week period. Patients who at week 16 achieved low disease activity (LDA) (DAS28≤3.2) were randomised to continue with TCZ+MTX or switch to TCZ + placebo (PBO) for an additional 12 weeks. The primary endpoint was the change in DAS28-ESR from the randomisation at week 16 to week 28. Non-inferiority was confirmed if the upper limit of the two-sided 95%CI for the treatment difference between TCZ+MTX and TCZ monotherapy groups was lower than the selected non-inferiority margin of 0.6. RESULTS: 261 patients completed the first 16 weeks of TCZ+MTX treatment and 165 were randomised (83 to TCZ+MTX and 82 to TCZ+PBO). For the primary endpoint, the adjusted treatment difference (95% CI) in mean change of DAS28-ESR was -0.06 (-0.40 to 0.27), and therefore the non-inferiority of switching to TCZ monotherapy versus continuing with TCZ+MTX was demonstrated. In both treatment groups, the percentage of patients in clinical remission from 16 to 28 weeks was similar as were the improvements in disease activity, functional disability and quality of life. CONCLUSIONS: In MTX non-responder patients achieving LDA with TCZ+MTX, switching to TCZ monotherapy is non-inferior to continuing the combination.
29871962 Severe bone marrow suppression due to methotrexate toxicity following aceclofenac-induced 2018 Jun 5 Methotrexate is one of the most commonly used drugs in autoimmune disorders like rheumatoid arthritis. Gastrointestinal symptoms like nausea and stomatitis, skin rashes, alopecia, central nervous system symptoms like headache and confusion, hepatotoxicity and myelosuppression are some of the adverse effects. However, low oral doses on a weekly basis seldom show any signs of toxicity. Leucovorin or folinic acid is given along with methotrexate as rescue to reduce the toxic effects like bone marrow suppression. Non-steroidal anti-inflammatory drugs, like aceclofenac, are also used in chronic inflammatory conditions like rheumatoid arthritis and osteoarthritis. Nephrotoxicity is one of the adverse effects of both methotrexate and non-steroidal anti-inflammatory drugs; and its combined administration should be done with caution. This is a case of an elderly woman, a known case of rheumatoid arthritis, who presented in severe bone marrow suppression due to methotrexate toxicity following aceclofenac-induced acute kidney injury.
29720237 Factors associated with physicians' prescriptions for rheumatoid arthritis drugs not fille 2018 May 2 BACKGROUND: This study estimated the extent and predictors of primary nonadherence (i.e., prescriptions made by physicians but not initiated by patients) to methotrexate and to biologics or tofacitinib in rheumatoid arthritis (RA) patients who were newly prescribed these medications. METHODS: Using administrative claims linked with electronic health records (EHRs) from multiple healthcare provider organizations in the USA, RA patients who received a new prescription for methotrexate or biologics/tofacitinib were identified from EHRs. Claims data were used to ascertain filling or administration status. A logistic regression model for predicting primary nonadherence was developed and tested in training and test samples. Predictors were selected based on clinical judgment and LASSO logistic regression. RESULTS: A total of 36.8% of patients newly prescribed methotrexate failed to initiate methotrexate within 2 months; 40.6% of patients newly prescribed biologics/tofacitinib failed to initiate within 3 months. Factors associated with methotrexate primary nonadherence included age, race, region, body mass index, count of active drug ingredients, and certain previously diagnosed and treated conditions at baseline. Factors associated with biologics/tofacitinib primary nonadherence included age, insurance, and certain previously treated conditions at baseline. The area under the receiver operating characteristic curve of the logistic regression model estimated in the training sample and applied to the independent test sample was 0.86 and 0.78 for predicting primary nonadherence to methotrexate and to biologics/tofacitinib, respectively. CONCLUSIONS: This study confirmed that failure to initiate new prescriptions for methotrexate and biologics/tofacitinib was common in RA patients. It is feasible to predict patients at high risk of primary nonadherence to methotrexate and to biologics/tofacitinib and to target such patients for early interventions to promote adherence.
28859470 Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of be 2018 Jan BACKGROUND/AIMS: To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors. METHODS: A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence. RESULTS: The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease-modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (p = 0.872). In univariate analysis, beliefs in necessity and concerns of medication differed significantly in adherent and nonadherent patients (intentional or unintentional). When controlling for other factors that may impact medication nonadherence, less belief in necessity of medication (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.68 to 0.95) and greater emotional response to disease (OR, 1.19; 95% CI, 1.01 to 1.40) were important predictors of intentional nonadherence. CONCLUSIONS: Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes.