Biologics In Rheumatoid Arthritis Research Articles

Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.

Biologics in rheumatoid arthritis: a lifetime treatment or possibility of drug holidays?

Biologics in rheumatoid arthritis: a lifetime treatment or possibility of drug holidays?

Increased remission with fewer corticosteroids and more biologics in rheumatoid arthritis at 7-year follow-up in real-life conditions

Remission in rheumatoid arthritis (RA) is an important therapeutic target that is not easy to achieve in real-life conditions. Some prognostic factors have been identified but the literature is variable. The objectives of this study were to evaluate the remission rate and the maintenance of remission in patients with RA over 7 years of follow-up in real-life conditions and to identify prognostic factors of long-term remission. Patients with RA seen at the Poitiers University Hospital were identified and clinical and biological data were collected. Data were analysed after 1 year and 7 years. Twice as many patients were in remission at 7 years than at 1 year of follow-up. 48.6% of patients who were not in remission at 1 year obtained remission at 7 years of follow-up. Patients achieving remission were more often receiving coprescription of csDMARDs and bDMARDs. Patients not in remission at 7 years were given more corticosteroids at higher doses. After 7 years of follow-up, low initial disease activity and use of csDMARDs and bDMARDs appeared to be independent positive predictive factors. Once obtained at one year, remission was maintained for 76% of our patients. As a conclusion, modern management of RA, whatever disease duration, leads to remission rates similar to those of early RA after 7 years of follow-up.

Factors Determining Retreatment Time Interval of Rituximab in Korean Patients With Rheumatoid Arthritis.

Unlike other biologic agents for rheumatoid arthritis (RA) that are administered at regular intervals even without flare, rituximab can be administered according to the timing of retreatment determined by the physician. Recently, there has been a tendency to prefer on-demand administration for disease flares rather than regular retreatment. We aimed to investigate the retreatment patterns of rituximab in patients with RA and to identify factors associated with extension of the time interval between retreatment courses. This study included RA patients on rituximab treatment who were enrolled in the Korean Rheumatology Biologics registry (KOBIO) or treated at Ajou University Hospital. Previous or current concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), corticosteroids, number of previous biologic agents, withdrawal, and time intervals of rituximab retreatment were collected. In case of treatment failure, the reasons such as lack of efficacy, adverse events, and others, were also identified. A total of 82 patients were enrolled. The mean follow-up period from the first cycle of rituximab was 46.1 months, and the mean interval between the retreatment courses was 16.3 months. The persistent rates of rituximab after 5 years was 72.4%. Concomitant use of at least two csDMARDs (β = 4.672; 95% CI: 0.089–9.255, p = 0.046) and concomitant use of corticosteroids (β = 7.602; 95% CI: 0.924–14.28, p = 0.026) were independent factors for extending the time interval between the retreatment courses. In conclusion, RA patients treated with rituximab in Korea show high persistence rates. Concomitant use of two or more csDMARDs and concomitant use of corticosteroids with rituximab are associating factors of extending the retreatment time interval. These findings should be considered when selecting rituximab as a treatment for patients with RA.

Not the same, but is it the same? Cycling of biologic agents in rheumatoid arthritis. Experience in the Instituto Mexicano del Seguro Social

IntroductionAvailable data for biocomparable drugs are not enough to make clear decisions with respect to the potential consequences of a change for non-medical reasons in efficacy, security and inmunogenicity in patients. In the near future, options on biological treatments, biocomparable drugs, non biocomparable drugs and new chemical synthesis options will grow. Therefore, it is important to know how patients behave in persistence of treatment after a change for non- medical reasons, which already happens on a regular basis in social security institutions in Mexico. This information will help us to better understand the standard of treatment for patients with chronic immunomediated conditions. ObjectiveThe primary objective was to measure the impact of change for non-medical reasons in patients with rheumatoid arthritis (RA) treated with an innovative biological on persistence of treatment after changing to a biocomparable drug or a non-biocomparable drug, compared with those patients staying with the innovative biological. Study designThis is an observational study (non-interventionist) of paired cohorts, where an historic cohort obtained by review of clinical records of stable patients in which no modifications to treatment were made for at least six months is compared with two cohorts of patients whose treatments were switched to another treatment with the same therapeutic mechanism for-non-medical reasons (cycling). ResultsWe included 264 RA patients (ACR/EULAR, 2010); 132 were switched for non-medical reasons, and 132 were not switched. Two-hundred and thirty (87.1%) were female. Average age was 53.9 years, ranging from 16 to 84 years. Two-hundred and sixty-three patients were Latino (99.6%); one was Caucasian. Persistence of treatment 12 months after the change was 84.8% (85.8% in Enbrel/Infinitam, 78.9% for Remicade/Remsima). No statistical difference was found with respect to RA clinical activity measured by DAS28 12 months after the switch (P > .05). In the 134 switched patients, 20 discontinued the new treatment due to lack of efficacy of the new drug and were changed to a different drug with a different biologic target. Although no differences were found in the cohorts of switched patients with respect to DAS 28 after 12 months of use, we did find differences in the frequency of adverse events. Forty-two patients had an adverse event in the drug switch cohorts: 33 in the Enbrel-Infinitam group and 9 in the Remicade-Remsima group. ConclusionsThe persistence of treatment after switching from an innovative drug to a biocomparable or a non- biocomparable in RA patients did not show statistically significative differences in our cohorts, but we did find a higher number of adverse events when comparing those who were changed with those who continued on an innovative drug. Twenty patients in the switch groups had to receive a new drug with a different biological target due to lack of efficacy of the switched drug.

Patient Preference for Treatment Mode of Biologics in Rheumatoid Arthritis: A 2020 Web-based Survey in Japan.

IntroductionAlthough the proportion of patients with rheumatoid arthritis (RA) using biologic disease-modifying antirheumatic drugs (bDMARDs) has increased steadily, the relationship between patient background and preference for bDMARDs has not been fully investigated.MethodsWe conducted a web-based questionnaire survey among patients aged ≥ 20 years with RA receiving bDMARDs. Participants were recruited through an internet research company in Japan. Study endpoints included factors affecting the preferred bDMARD treatment mode, namely, in-hospital intravenous infusion (infusion), in-hospital subcutaneous injection (in-hospital injection), or self-administered subcutaneous injection (self-injection), and discrepancies between the current and preferred treatment mode.ResultsOf the 400 patients surveyed for preferred treatment mode, 15.3% preferred infusion, 18.0% preferred in-hospital injection, and 66.8% preferred self-injection. A preference for infusion (odds ratio [OR] 2.218 and 6.165) and in-hospital injection (OR 4.735 and 6.026) versus self-injection was significantly associated with higher current frequency of hospital visits and anxiety or other hurdles related to self-injection. A flexible administration setting was significantly associated with a preference for self-injection versus infusion (OR 0.401) and versus in-hospital injection (OR 0.445). Further, age (< 40 vs. ≥ 60 years) was significantly associated with a preference for self-injection versus in-hospital injection (OR 0.120). Many patients reported no discrepancy between their current and preferred treatment mode (patients receiving infusion, 68.0%; in-hospital injection, 71.2%; and self-injection, 94.0%). However, > 90% of patients responded that they would change their current mode in the future following a recommendation by a medical professional, aging, or a change in RA symptoms.ConclusionsThis web-based survey showed that patient preference for bDMARD treatment mode was significantly associated with age, frequency of hospital visits, flexible administration setting, and anxiety or other hurdles to self-injection. Changes in patient background which affect the preferred treatment mode should be considered in decision-making for RA therapy with bDMARDs.Trial registrationR000048089 (UMIN-CTR)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00325-9.

Severe infection risk in patients treated with biologics for rheumatoid arthritis: a systematic review protocol.

The objective of this review is to estimate the population-based incidence and to determine the types of severe infection experienced by patients with rheumatoid arthritis who are taking biological agents. Since the late 1990s, a variety of biological and synthetic drugs have been developed to treat rheumatoid arthritis. In recent years, the incidence of severe infection in patients with rheumatoid arthritis in Western nations has been reported by observational studies; however, no systematic review has been conducted on this topic. The following criteria will be considered for inclusion: i) observational studies on patients with rheumatoid arthritis who are taking biological agents; ii) studies reporting the number of severe infections requiring hospitalization for treatment; and iii) studies with person-years of observational data. MEDLINE, CINAHL, Embase, and Web of Science will be searched to identify published studies. The reference lists of all studies that are selected for critical appraisal will be screened for additional studies. The search for unpublished studies will include MedNar and OpenGrey. Only studies published in English from 1999 to the present will be included. Screening of studies, assessment of methodological quality, and data extraction will be performed by two independent reviewers. If possible, studies will be pooled in statistical meta-analysis. PROSPERO CRD42020175137.

Role of comorbidities on therapeutic persistence of biological agents in rheumatoid arthritis: results from the RECord-linkage On Rheumatic Disease study on administrative healthcare databases

Objectives: This study aimed to evaluate the impact of different comorbidities on thereflecting its safety profile persistence of biological disease-modifying anti-rheumatic drugs (bDMARDs) in rheumatoid arthritis (RA), taking advantage of a retrospective analysis of administrative healthcare databases (AHDs). Method: A retrospective observational study was conducted on AHDs of the Lombardy region, Italy (2004–2013). Among RA patients treated with bDMARDs, drug survival was estimated using Cox proportional hazard models [hazard ratio (HR), 95% confidence interval (CI)], crude and adjusted for prespecified confounders (gender, age, disease duration, concomitant use of non-steroidal anti-inflammatory drugs, glucocorticoids, conventional DMARDs, specific bDMARDs), in first-line and subsequent lines of treatment. The role of comorbidities in administration of specific bDMARDs was analysed through multinomial logistic models. Results: The study included 4657 RA patients. In the first-line treatment strategy, the Charlson Comorbidity Index (CCI) (RA excluded) was significantly associated with an increased rate of bDMARD failure (CCI = 1: HR 1.28, 95% CI 1.13–1.46; CCI ≥ 2: HR 1.26, 95% CI 1.03–1.53). Among selected comorbidities, chronic obstructive pulmonary disease (HR 1.38, 95% CI 1.01–1.91), diabetes (HR 1.18, 95% CI 1.01–1.37), and previous-year bacterial infections (HR 1.18, 95% CI 1.07–1.30) were slightly associated with risk of bDMARD failure, while acute myocardial infarction (HR 1.30, 95% CI 0.97–1.75), mild liver disease (HR 1.21, 95% CI 0.91–1.60), and solid tumours (HR 1.19, 95% CI 0.93–1.53) were not. In the following treatment lines, neoplasms were associated with reduced risk of failure (HR 0.64, 95% CI 0.41–0.99). Multiple comorbidities were associated with first-line abatacept and rituximab administration. Conclusions: Comorbidities affect treatment decisions in RA and influence bDMARD failure, and should be considered when analysing the persistence of biological therapy.

Monitoring the transition of patients on biologics in rheumatoid arthritis: Consensus guidance for pharmacists

Background:Recent approvals for novel agents such as the small molecule Janus kinase inhibitors (JAKi), combined with the advent of biosimilars has widened the gamut of available therapeutic options in the treatment of rheumatoid arthritis (RA). This combined with the introduction of mandatory non- medical switches to biosimilars in some jurisdictions by both public and private payors has led to a significant increase in the volume of therapeutic changes for patients. Pharmacists are well positioned to ensure effective and safe transitions, however there is a significant unmet need for objective and subjective clinical guidance around therapy as well disease state monitoring in RA that facilitates best practices throughout the patient journey.Objective:In this paper we aim to create a consensus derived monitoring algorithm for pharmacists to facilitate best practices throughout therapeutic transitions from originator biologic to other originator biologics, biosimilars, and Janus kinase inhibitors in RA.Methods:The Nominal Group Technique (NGT) was used to understand if consensus could be found among the participants. Clinically relevant questions were developed to capture solutions to the identified unmet need. The faculty considered the questions as individuals, and privately generated answers/ideas. After discussion and consideration, the participants ranked the ideas and established a consensus.Results:Based on the outcome of the consensus discussions, an algorithm was created to help guide pharmacists through therapeutic transitions in RA. The tool covers important topics such as pre-transition considerations, avoiding the nocebo effect for biosimilars, specific considerations for each drug or class, monitoring efficacy, and when to refer.Conclusions:New classes of anti-rheumatic drugs including JAKi, along with the introduction of biosimilars are presenting more opportunity for therapeutic changes and monitoring in patients with RA. We hope our evidence-based consensus derived guidance tool will assist frontline pharmacists in supporting their patients to a successful therapeutic transition in RA.

From publication bias to lost in information: why we need a central public portal for clinical trial data

The availability of clinical trial records has increased markedly. This article outlines the challenges faced in information retrieval for evidence syntheses and provides a proposal for ensuring efficient and complete...

Algorithms using genome-wide association studies for prediction of effectiveness of biologics in rheumatoid arthritis

Algorithms using genome-wide association studies for prediction of effectiveness of biologics in rheumatoid arthritis

Reduction of biologics in rheumatoid arthritis: a systematic review and meta-analysis.

The effects of dose reduction or spacing of all types of biologics in rheumatoid arthritis has not been consistently assessed in systematic reviews. We aimed to assess the effects of biologics reduction compared with dose maintenance in patients with rheumatoid arthritis in low disease activity or remission. We performed a systematic review with meta-analysis according to a previously registered protocol (PROSPERO registration: CRD42017069080); and searched MEDLINE, Embase, Scopus, Cochrane Library and trial registers up to July, 2020. Two researchers selected, extracted and assessed the risk of bias of controlled trials that randomized patients to reduction/spacing or dose maintenance of biologics. Low disease activity, disability and other clinically important outcomes were summarized in random effect meta-analyses. We rated the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation approach. We included ten studies (n = 1331 patients), which assessed reduction or spacing of abatacept, adalimumab, certolizumab pegol, etanercept, or tocilizumab. Risk of bias was high in over half of trials, mainly due to lack of blinding. No statistically significant difference was found in low disease activity (RR = 0.90; 95% CI 0.78-1.04; I2 = 60%, very low certainty), and other outcomes. Subgroup analysis of blinded studies led to homogeneous results, which remained heterogeneous in open-label studies. Reduction or spacing biologics did not affect disease activity and other important outcome. Changes in the doses regimen should consider patient preferences, considering the low certainty of evidence.

SAT-571 Rare Case of Tocilizumab-Induced Severe Hypertriglyceridemia

Tocilizumab (TCZ) is a monoclonal antibody against the IL-6receptor used in the treatment of rheumatoid arthritis (RA). Hypertriglyceridemia is a rare side effect of TCZ, occurring in<1% of cases (1).A 37 year-old woman presented with abdominal pain, nausea and diarrhea. Her past medical history included RA and dyslipidemia; she had no history of diabetes, hypothyroidism, renal disease, alcoholism or recent medication changes. Following failure of other immunosuppressant agents, IV TCZ was initiated. After two and a half years, TCZ formulation was changed to subcutaneous injections for convenience about 6 weeks prior to presentation. Family history included mother with dyslipidemia. Her vital signs were normal on admission with labs remarkable for lipase of 332 and triglycerides (TG) of 5680. Her TG 2months prior to initiating subcutaneous tocilizumab therapy was 1373. CT abdomen demonstrated findings of acute pancreatitis (AP). She was subsequently admitted to the ICU and started on an insulin drip, fibrate, statin and fish oil along with supportive care. TCZ was held. Because her TGs remained severely elevated, she was transferred to our facility for plasmapheresis with subsequent improvement of the same to 768 after two treatments.TCZ was considered the probable etiology of her hypertriglyceridemia with subsequent AP after ruling out other secondary causes. Hereditary hypertriglyceridemia, given her family history, likely contributed to her chronically elevated TG’s.TCZ has been reported to increase TG levels mainly through an increase in VLDL-TG content. TCZ was found to reduce hepatic LDLr expression thus reducing hepatic clearance of TGs and LPL mediated lipolysis of TG-rich lipoproteins (2). Despite the association of TCZ with increased lipid levels, it has a favorable impact on lipid metabolism via improved functionality of HDL-C and no impact in the atherogenic index; patients also experience a favorable response to statin treatment (3). In observational studies, TCZ shows a favorable effect on myocardial infarction compared to other biologic agents for RA, attributed partly to a decrease in lipoprotein(a) levels. Nonetheless, it should be used in caution in those with high cardiovascular risk, especially dyslipidemia (4).1. Flaig T, Douros A. Tocilizumab-induced pancreatitis:case report and review of data from the FDA Adverse Event Reporting System. Journal of Clinical Pharmacy and Therapeutics 2016,41:718-721.2. Strang A, Bisoendial R. Atherosclerosis 229(2013):174-181.3. Garcıa-Gomez C, Martın-Martınez M. Lipoprotein(a) concentrations in rheumatoid arthritis on biologic therapy:Results from the CARdiovascular inrheuMAtology study project. Journal of Clinical Lipidology (2017) 11:749-756.4. CastagnéB, Viprey M. Cardiovascular safety of tocilizumab: A systematic review and network meta-analysis. PLoS ONE 14(8):e0220178.

Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

Angiogenesis and synoviocyte hyperplasia, called ‘pannus,’ are pathologic hallmarks of rheumatoid arthritis (RA). To determine the clinical significance of angiogenic cytokines in RA, the levels of pro-angiogenic cytokines, including VEGF, placenta growth factor (PlGF), and IL-6, were measured in the synovial fluid (SF, n = 54) and sera of RA patients (n = 157) using ELISA. Patients (n = 103) with disease activity score 28 (DAS28) > 3.2, which indicates moderate to high RA activity, underwent follow-up blood sampling at 6 months after treatment with conventional disease-modifying anti-rheumatic drugs (c-DMARD) or biologic DMARD (b-DMARD) including an anti-TNFα antibody, an anti-IL-6 antibody, and abatacept. Ultrasonography (US) was performed on affected joints to define the synovitis severity at the time of sampling. Consequently, in the SF of RA patients, PlGF and IL-6 levels correlated well with synovitis severity determined by US. In RA sera, VEGF and IL-6 levels were elevated in proportion to synovitis severity, correlating with conventional markers for disease activity, including ESR, CRP, and DAS28. In c-DMARD users (n = 53), serially monitored levels of serum VEGF, IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) all decreased in good and moderate responders but not in nonresponders. In b-DMARD users (n = 49), only serum VEGF well represented the treatment response, while CRP nonspecifically decreased irrespective of the treatment outcome. By multivariable analysis, serum ΔVEGF, but not ΔESR or ΔCRP, was an independent factor associated with good and moderate responses to DMARD. In summary, the angiogenic cytokines PlGF and VEGF represent the synovitis severity of RA assessed by US. In patients receiving b-DMARD, serum VEGF may be more valuable than CRP in reflecting the treatment response.

Golimumab as the First-, Second-, or at Least Third-Line Biologic Agent in Patients with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis: Post Hoc Analysis of a Noninterventional Study in Germany.

IntroductionWhile golimumab (GLM) has demonstrated efficacy in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in several randomized clinical trials with biologic-naïve patients, observational data from biologic-experienced patients are sparse. We aimed to assess the effectiveness of GLM used as the first-, second-, or at least third-line biologic agent in RA, PsA, and AS patients in a real-world setting.MethodsPost hoc analysis of the noninterventional, prospective, 24-month GO-NICE study of RA, PsA, and AS patients who initiated GLM 50 mg subcutaneously once monthly in a real-world setting in Germany.ResultsIn 1454 patients with RA, PsA, or AS, GLM was administered as the first-line (n = 305, 286, 292, respectively), second-line (n = 104, 136, 130, respectively), or at least third-line (n = 64, 79, 58, respectively) biologic agent. In RA patients (n = 473), the time since first diagnosis was 9.7, 10.1, and 14.3 years, respectively. The DAS28 score at BL was 5.0, 4.9, and 5.1 in patients using GLM as a first-, second-, and third-line biologic agent, respectively, and dropped significantly in all groups. After 3 months of treatment, 27.5%, 19.5%, and 14.5% of patients were in remission; the corresponding values after 24 months were 45.3%, 50.0%, and 33.3%, respectively. In PsA patients (n = 501), time since fist diagnosis was 12.4, 13.7, and 13.8 years, respectively. Based on PsARC, a response was achieved at 24 months in the first-, second-, and third-line use of GLM in 76.4%, 51.0%, and 50.0% of the patients. In AS patients (n = 480), the time since first diagnosis was 9.4, 9.8, and 12.4 years in patients using GLM as the first-, second-, and at least third-line biologic agent, respectively. After 24 months of treatment, the mean BASDAI scores decreased significantly (p < 0.001 vs. BL) to 2.1, 2.9, and 2.9 in the patients using GLM as the first-, second-, and at least third-line treatment, respectively.ConclusionsGolimumab is an effective treatment in patients with RA, PsA, and AS, irrespective of any pretreatment with biologic agents.Study RegistrationClinicalTrials.gov NCT01313858.

Glucocorticoid-trials in rheumatoid arthritis mostly study representative real-world patients: A systematic review and meta-analysis

ObjectiveRandomized controlled trials (RCTs) are considered the gold standard in clinical research due to credible causality. Their results, however, may not be generalizable to real-world populations. While glucocorticoids (GCs) remain a mainstay of rheumatoid arthritis (RA) treatment, it is unclear whether the results of GC-RCTs are generalizable to current real-world RA patients. MethodsMEDLINE was searched for RCTs and, as comparators, cohort studies (CSs) in RA evaluating systemic GCs. Random-effects meta-analyses were performed for descriptive baseline characteristics (including general demographics, comorbidities, and disease activity) that have been shown to be able to modify the benefit-risk-ratio of various RA therapeutics. These meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared. Further sensitivity analyses were performed stratifying by disease duration. Results56 RCTs (7053 participants) and 10 CSs (14,688 participants) were included. 12 characteristics were reported frequently enough to allow for comparative analysis. In 10/12 characteristics (83%), RCT estimates did not appear to differ from CS estimates. However, RCT participants were younger (-4.7 years [95% CI -7.2 to -2.1]; p < 0.001) and had higher erythrocyte sedimentation rates (11.8 mm/h [5.7 to 17.8]; p < 0.001) than CS participants. Comorbidities could not be assessed due to insufficient reporting. ConclusionOur findings suggest that evidence from GC trials in RA is of acceptable generalizability to current real-world patients – especially compared to findings from biologic agents in RA. However, RCT participants were younger than real-world patients, potentially limiting the generalizability of trial results to elderly patients. Systematic review registrationPROSPERO (CRD42019134675)

Methotrexate and its mechanisms of action in inflammatory arthritis.

Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.

Health Care Resource Utilization and Costs Associated With Switching Biologics in Rheumatoid Arthritis

PurposeAlthough biologics are effective in managing rheumatoid arthritis (RA), many patients experience at least one biologic switch during treatment. A switch in biologic treatment can occur for medical or nonmedical reasons. Changes to treatment regimens, even in patients previously stable on therapy, can have clinical and cost implications. This study examined health care resource use and costs incurred with switching from an anti–tumor necrosis factor (TNF) medication in a population of patients with RA. MethodsA retrospective analysis of patients with RA identified in Truven Commercial Claims and Encounters database (January 1, 2009, to December 13, 2013) was conducted. Patients were required to show evidence of new initiation of treatment with a biologic medication (index date) and continuous eligibility from 6 months before to 12 months after index. Patients were segmented into a continuous biologic group and a biologic switch group, the latter being further divided into switch from anti-TNF to anti-TNF (A-A subgroup) and switch from anti-TNF to a treatment with other mechanism of action (A-O subgroup). Means (SD) and medians of resource use and cost outcomes were calculated over the 12-month postindex period; multivariate models controlling for demographics, biologic switch, and preindex health, resource use, and costs were constructed. FindingsThe total sample comprised 18,070 patients, with 16,643 qualifying for the continuous group and 1427 qualifying for the overall switch group. The overall switch group was more likely to utilize physician office, emergency department, and pharmacy services compared to the continuous group. Consequently, the overall switch group incurred greater total health care costs compared to the continuous group ($41,482 vs $36,557 per patient per annum; p < 0.05). Within the switch group, the A-O subgroup had significantly greater outpatient, medical, and total health care expenditures compared to those in the A-A subgroup. Regression analyses revealed that increased baseline utilization and costs, worse health, and older age were associated with increased utilization and costs over the follow-up period. Switching of biologics was associated with an approximate increase of US $4000 per patient per annum in total health care costs. ImplicationsThese findings suggest that switching biologic agents in patients with RA may be accompanied by increased total health care costs. Efforts to optimize patient response to initial biologic therapy and to reduce unnecessary switching, such as for nonmedical reasons, may help to mitigate these costs.

Concomitant methotrexate has little effect on clinical outcomes of abatacept in rheumatoid arthritis: a propensity score matching analysis.

To compare the clinical outcomes of abatacept between rheumatoid arthritis patients with and without concomitant methotrexate (MTX) treatment in daily clinical practice. A retrospective cohort study was performed using data from a multicentre registry. A total of 176 consecutive rheumatoid arthritis patients treated with abatacept were included. The propensity score based on multiple baseline characteristic variables was calculated, and 41 of 86 patients treated without MTX (MTX(-)) and 41 of 90 patients treated with concomitant MTX (MTX(+)) were statistically extracted and analysed. Clinical outcomes were evaluated and compared between the two groups over a 52-week period. Baseline characteristics were statistically comparable. No significant differences were observed in the following clinical outcomes from baseline throughout the 52-week period: drug retention rate (MTX(-)/MTX(+) 79.1%/80.5%), mean change in disease activity score based on 28 joints (DAS28-CRP) from baseline (- 1.35/- 1.54), low disease activity rate (48.8%/43.9%), clinical remission rate (31.7%/36.6%), moderate European League Against Rheumatism (EULAR) response rate (68.3%/68.3%), and good EULAR response rate (36.6%/41.1%) at 52weeks. In rheumatoid arthritis patients with similar background characteristics undergoing abatacept treatment, concomitant MTX does not seem to affect clinical outcomes. Abatacept would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX. • This is the first study to directly compare the clinical efficacy and safety of abatacept between patients with and without concomitant methotrexate (MTX) treatment in 'real-world' settings using the propensity score matching method. • There were no significant differences in clinical outcomes of abatacept between patients with and without concomitant MTX treatment. • We used data from a large Japanese multicentre registry for biologics in rheumatoid arthritis, thereby decreasing selection bias based on the personal preferences of physicians.

Prediction of infection risk in rheumatoid arthritis patients treated with biologics: are we any closer to risk stratification?

Purpose of reviewThere are currently several available biologics for rheumatoid arthritis (RA) with similar efficacy in most trials. A major consideration therefore in choosing a biologic, continues to be safety concerns such as infection. Considerable advances have been made in the understanding of biologic safety on a population level; however, how close are we to stratifying risk for individual patients? This review discusses evidence published in the last year, with reference to key previous literature.Recent findingsComparative safety of biologics has been studied in observational cohorts, with a possible increased risk of serious infection in tocilizumab-treated patients compared with etanercept. Rheumatoid arthritis patients on biologics are often on concomitant medications such as steroids and opioids, and the advances in relation to infection are summarized. Pharmacological biomarkers and optimizing existing risk prediction scores may allow better future risk stratification.SummaryImproved quantification of personalized benefit:harms would allow better-informed decisions, reduction of infection-associated morbidity as well as direct/indirect costs associated with biologics. Although advances have been made to better understand and predict risk, future studies are likely to require a range of novel data sources and methodologies for the goal of precision medicine to be truly realized.