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ID PMID Title PublicationDate abstract
29664818 Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Chang 2018 Jun PURPOSE: This study reports the effect of disease-modifying therapies for rheumatoid arthritis (RA) on systolic and diastolic blood pressure (SBP, DBP) over 6 months and incident hypertension over 3 years in a large administrative database. METHODS: We used administrative Veterans Affairs databases to define unique dispensing episodes of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, tumor necrosis factor inhibitors, and prednisone among patients with RA. Changes in SBP and DBP in the 6 months before disease-modifying antirheumatic drug initiation were compared with changes observed in the 6 months after initiation. The risk of incident hypertension within 3 years (new diagnosis code for hypertension and prescription for antihypertensive) was also assessed. Multivariable models and propensity analyses assessed the impact of confounding by indication. RESULTS: A total of 37,900 treatment courses in 21,216 unique patients contributed data. Overall, there were no changes in SBP or DBP in 6 months prior to disease-modifying antirheumatic drug initiation (all P > 0.62). In contrast, there was a decline in SBP (β = -1.08 [-1.32 to -0.85]; P < 0.0001) and DBP (β = -0.48 [-0.62 to -0.33]; P < 0.0001) over the 6 months following initiation. The greatest decline was observed among methotrexate and hydroxychloroquine users. Methotrexate users were 9% more likely to have optimal blood pressure (BP) after 6 months of treatment. Patients treated with leflunomide had increases in BP and a greater risk of incident hypertension compared with patients treated with methotrexate (hazard ratio, 1.53 [1.21-1.91]; P < 0.001). CONCLUSIONS: Blood pressure may improve with treatment of RA, particularly with methotrexate or hydroxychloroquine. Leflunomide use, in contrast, is associated with increases in BP and a greater risk of incident hypertension.
29879987 Discriminating phenotypic signatures identified for tocilizumab, adalimumab, and tofacitin 2018 Jun 7 BACKGROUND: Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity. METHODS: TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 μg/ml; TOF1, 1.1 μM; TOF2, 0.12 µM; MTX, 10 μM. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents. RESULTS: Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually. CONCLUSIONS: These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX. Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.
27900440 Role of methotrexate chronotherapy in collagen-induced rheumatoid arthritis in rats. 2018 Apr AIM: To explore the circadian rhythm of serum interleukin (IL)-6 in collagen-induced arthritis (CIA) rats and compare the safety and effectiveness of methotrexate (MTX) administered traditionally and via chronotherapy. METHODS: CIA rat models were immunized with bovine type II collagen. Serum IL-6 levels in normal and CIA rats were measured at 2, 6, 10, 14, 18, or 22 h after the light was turned on (HALO). MTX was administered to 6 HALO/18 HALO experimental groups of Wistar rats once daily according to the IL-6 rhythm. The control groups (positive, negative, and normal) were given MTX or an equal volume of phosphate buffered saline (PBS) once a week simultaneously. Arthritis score, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP) levels in the serum were measured by enzyme-linked immunosorbent assay (ELISA). Histological changes in the ankle joint were analyzed. RESULTS: After 6 weeks of treatment, arthritis scores in the experimental group were lower than in the control group. The expression of TNF-α, IL-6, and CRP was lower in the 18 HALO group than in the control or 6 HALO groups. Histopathology scores in the experimental groups were lower than in the control group (p < 0.05). CONCLUSION: The plasma IL-6 levels in CIA rats were higher than in normal rats and showed significant circadian rhythm. Daily administration of MTX is more potent than weekly administration. The therapeutic index of rheumatoid arthritis (RA) may be improved with MTX therapy based on the IL-6 circadian rhythm.
29798700 Long-term deterioration of interstitial lung disease in patients with rheumatoid arthritis 2019 May OBJECTIVE: To examine the deterioration of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) treated with abatacept over the long-term. METHODS: We examined 131 patients with RA who had been treated with abatacept for more than 1 year. All patients underwent high-resolution computed tomographic (HRCT) scanning of the chest before administration of abatacept, and we examined deterioration of ILD over a follow-up period after administration of abatacept was initiated. RESULTS: Eleven patients (8.4%) showed deterioration of ILD over a mean follow-up period of 47.8 months. The factors related to ILD deterioration were use of methotrexate (MTX) [odds ratio 12.75, 95% confidence interval (CI) 1.09-148.77], and change in Krebs von-den Lungen-6 (odds ratio 1.00, 95% CI 1.00-1.01), according to multivariate logistic regression analysis. CONCLUSION: MTX in patients with RA treated with abatacept was a risk factor for deterioration of ILD. Discontinuation of MTX should be considered one of treatment reduction to prevent the deterioration of ILD.
29774784 Moderate alcohol consumption is associated with increased radiological progression in wome 2018 Nov OBJECTIVE: We conducted this study to determine whether alcohol consumption influences radiological progression in early rheumatoid arthritis (RA). METHOD: Patients fulfilling the European League Against Rheumatism/American College of Rheumatology 2010 criteria in the early arthritis cohort ESPOIR (Étude et Suivi des Polyarthrites Indifférenciées Récentes) were included in this study. Alcohol consumption was collected at baseline and at each visit. We classified alcohol consumption into three groups: abstinent (0 g/day), moderate (≤ 20 g/day for women, ≤ 30 g/day for men), and abuse (> 20 g/day for women, > 30 g/day for men). The primary outcome was the occurrence of radiological progression, defined as an increase ≥ 5 points in the total Sharp/van der Heijde score. We investigated whether alcohol consumption is predictive of radiological progression at 1, 3, and 5 years by univariate and multivariate analysis adjusted for age, baseline erosion, rheumatoid factor, anti-citrullinated peptide antibody, smoking status, body mass index, and treatment with leflunomide or methotrexate and biologics. RESULTS: The study included 596 patients. When considering the influence of gender on the interaction between alcohol consumption and radiological progression, we showed a deleterious effect of moderate consumption in women [odds ratio (OR) = 1.73, 95% confidence interval (CI) 1.01; 2.96, p = 0.045] and a trend towards a protective effect of moderate consumption in men (OR = 0.50, 95% CI 0.21; 1.16, p = 0.106) in multivariate analysis. CONCLUSION: Our data suggest a deleterious effect of moderate consumption of alcohol on radiological progression in women, but not in men, with early RA.
30280369 Chronic lung disease in U.S. Veterans with rheumatoid arthritis and the impact on survival 2018 Nov Assess the impact of chronic lung diseases (CLD) on survival in rheumatoid arthritis (RA). Among participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a prospective cohort of U.S. Veterans with RA, we identified CLD and cardiovascular disease (CVD) using administrative and registry data. Demographics, smoking status, RA characteristics including Disease Activity Score in 28 joints (DAS28), and disease-modifying anti-rheumatic drug (DMARD) use were obtained from registry data, which were linked to the National Death Index to obtain vital status. We evaluated associations of CLD with survival using the multivariable Cox regression models. Among a large (n = 2053), male-predominant (91%) RA cohort, 554 (27%) had CLD at enrollment. Mortality risk was increased 1.51-fold (95% CI 1.26-1.81) in RA patients with CLD after multivariable adjustment, a risk that was similar to that observed with CVD (HR CLD alone 1.46 [1.03-2.06]; CVD alone 1.62 [1.35-1.94]). Survival was significantly reduced in those with interstitial lung disease (ILD) as well as other forms of CLD. Mortality risk with methotrexate and biologic use was not different in those with CLD compared to those without (p interaction ≥ 0.15) using multiple exposure definitions and propensity score adjustment. Mortality risk is significantly increased in RA patients with CLD. This risk is attributable not only to ILD but also to other chronic lung conditions and does not appear to be substantially greater in those receiving methotrexate or biologic therapies. Comorbid lung disease should be targeted as a means of improving long-term outcomes in RA.
29278006 Relationship between disease activity and patient-reported outcomes in rheumatoid arthriti 2018 Nov OBJECTIVE: To examine patient-reported outcomes (PROs) in patients with different rheumatoid arthritis (RA) disease activity levels and identify residual symptoms. METHODS: Post hoc analyses of overall and Japanese data from two randomized controlled trials including RA patients with previous inadequate responses to methotrexate (NCT01710358) or no/minimal previous disease-modifying antirheumatic drug treatment (NCT01711359) (sponsor: Eli Lilly and Company). Week 24 assessments were disease activity (Simplified Disease Activity Index, Disease Activity Score/Disease Activity Score 28 joints-erythrocyte sedimentation rate) and PROs (pain visual analog scale [VAS], morning joint stiffness [MJS], Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, and Medical Outcomes Study Short Form 36 Health Survey Physical and Mental Component Scores). RESULTS: Patients achieving remission/low disease activity (LDA) at Week 24 had larger/significant improvements from baseline in pain, MJS, disability, fatigue, and physical and emotional quality of life versus patients with high/moderate disease activity. Some patients achieving remission and LDA, reported residual pain (pain VAS >10 mm): 20.8-39.3% and 48.7-70.0% (overall study populations), 16.0-34.5% and 47.1-62.0% (Japanese patients). Residual MJS and fatigue were also reported. CONCLUSION: Remission/LDA were associated with improvements in PROs in overall and Japanese patient populations; however, some patients achieving remission had residual symptoms, including pain.
28963634 Intra-articular methotrexate versus corticosteroid injections in medium-sized joints of rh 2018 Feb The effects of intra-articular methotrexate (I/A MTX) in knee synovitis in rheumatoid arthritis have been previously evaluated. I/A MTX has not been studied in other joints. Ultrasonography (US) has been little studied in monitoring the effect of I/A MTX. The aim of the study is to test the efficacy of I/A MTX in suppression of persistent synovitis in medium-sized joints (ankle, wrist, and elbow) in rheumatoid arthritis patients. Patients were divided into two groups: group 1 (methotrexate group): 56 patients in which 84 joints (32 ankles, 28 wrists, and 24 elbows) were injected intra-articularly by 10 mg of methotrexate in the targeted joint on a weekly basis for 8 weeks and group 2 (steroid group): 44 patients in which 70 joints (26 ankles, 24 wrists, and 20 elbows) were injected once by Triamcinolone acetonide 40 mg. Clinical, ultrasonographic, and power Doppler US (PDUS) evaluation was done before the first injection (W0), after 2 months (W8), and after 5 months (W20). Synovial thickness and the intra-articular power Doppler signal were graded on a semiquantitative scale from 0 to 3 during the US examination. Clinical parameters improved significantly in both groups between baselines and 2 months. In both groups, gray-scale US and power Doppler US showed that synovial thickness and intra-articular power signals were reduced significantly between W0 and W8. The improvement of clinical parameters continued in the methotrexate group up to W20, but in the corticosteroid group, clinical parameters at W20 were similar to clinical parameters at W0. In the methotrexate group, there was an insignificant increase in synovial thickness between W8 and W20 while there was a significant increase in power Doppler signals between W8 and W20, p < 0.05. In the corticosteroid group, there was a significant increase in both synovial thickening and power Doppler signals between W8 and W20, p < 0.001. In the MTX group, all patients at week 0 showed that the Doppler signal in grades 2 and 3 is 100%; at 8 weeks, most of the patients showed that the power Doppler in grade 0 is 76%; and at week 20, most of the patients showed that the power Doppler signal in grade 0 is 28% and in grade 1 is 47%, while in grades 2 and 3 is 23.6%, so there is an improvement compared to the baseline of treatment. Repeated I/A MTX resulted in a decrease in the degree of synovitis of medium-sized joints in RA patients both clinically and by power Doppler US.
30211216 Effects of Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Response to Per 2018 Rheumatoid arthritis (RA) and periodontitis are common chronic inflammatory diseases and periodontitis is known to be more common and more severe in patients with RA. Based on a paucity of studies about the relationship between common conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and periodontitis, this prospective study aimed to evaluate the adjunctive effect of csDMARDs on response to nonsurgical periodontal treatment in patients with RA. Thirty-two patients with RA (RA group) and 32 systemically healthy patients (control group) with periodontitis were included in this study. The RA group patients were treated with csDMARDs, such as methotrexate, hydroxychloroquine, and sulfasalazine. Conventional nonsurgical periodontal treatment with scaling and root planing was performed in both groups. The extent and severity of periodontitis were evaluated by plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) at baseline and 4 weeks after periodontal treatment. There was no statistically significant difference of periodontal parameters between the RA and control groups at baseline. Four weeks after scaling and root planing, PD reduction, and CAL gain were higher in the RA group treated with csDMARDs compared to the control group, and the difference was statistically significant (P = 0.006 and 0.003, respectively). A post hoc analysis of the RA group showed no statistically significant difference on the response to nonsurgical periodontal treatment in multiple csDMARDs therapy and addition of NSAIDs and/or steroids to csDMARDs. In patients with RA, csDMARDs showed beneficial effect on periodontal clinical parameters following the nonsurgical periodontal treatment.
30148435 Methotrexate did not improve endothelial function in rheumatoid arthritis: a study in rats 2019 Jan OBJECTIVES: Rheumatoid arthritis is associated with an increased cardiovascular risk, secondary to endothelial dysfunction. There is accumulating evidence that methotrexate reduces cardiovascular risk in rheumatoid arthritis, but the mechanisms involved are still unknown. In this study, we aimed to determine the effect of methotrexate on endothelial function and traditional cardiovascular risk factors in the adjuvant-induced arthritis (AIA) rat model. METHODS: On the first signs of arthritis, methotrexate (1 mg/kg/week, s.c.) or saline (Vehicle) was administered to AIA for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine in the presence or not of inhibitors of nitric oxide synthase, cyclooxygenase-2, arginase, EDHF and superoxide anions production. Arthritis and radiological scores, blood pressure and blood levels of cytokines, triglycerides, cholesterol, homocysteine and BMP-4 were measured. RESULTS: Although methotrexate significantly reduced the arthritis score, it had no effect on Ach-induced relaxation. As regards mechanisms, methotrexate increased nitric oxide synthase activity and reduced the superoxide anions production but did not change arginase, cyclooxygenase-2 and EDHF pathways. Methotrexate did not change the radiological score or blood pressure, lipid, glucose and homocysteine levels. By contrast, methotrexate significantly reduced plasma IL-1β and TNF-α levels and increased serum BMP-4 level. CONCLUSIONS: Despite a reduction of clinical and biological inflammation, methotrexate did not improve endothelial function in AIA rats. Overall data suggest that mechanisms other than the ED reduction are likely involved, and remain to be elucidated to better understand the cardiovascular benefits of methotrexate in rheumatoid arthritis.
30081197 Methotrexate mechanism in treatment of rheumatoid arthritis. 2019 May Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.
30136633 Biologic treatment in comparison to methotrexate has positive effect on trabecular bone sc 2019 Apr INTRODUCTION: Biologic treatment may influence activity of rheumatoid arthritis (RA), as well as areal bone mineral density (aBMD). Decreased aBMD explains the fracture risk in RA patients only partially. The trabecular bone score (TBS), novel texture parameter reflects degradation of trabecular bone and therefore could be used as a further parameter to predict the risk of fragility fracture. OBJECTIVE: To compare the effects of biological disease-modifying antirheumatic drugs (bDMARDs) and conventional synthetic (cs) DMARDs (methotrexate) on aBMD and TBS in patients suffering from active RA. METHODS: A 12 month prospective trial was performed in 105 active RA patients. The cohort was divided into two groups: group 1 (n = 84, mean age 54 yrs) treated with bDMARDs and group 2 (n = 21, mean age 53 yrs) treated with csDMARDs. The mean daily dose of prednisone at baseline was 6.2 and 6.6 mg (NS) between group 1 and 2, respectively. Patients with anti-osteoporotic treatment were not included. All patients received calcium (600 mg) and cholecalciferol (800IU). Lumbar spine (LS) and FN aBMD (by DXA, Hologic) were measured at baseline and after 1 year of treatment. TBS was generated using TBS Insight software (Medimaps, Switzerland). RESULTS: Treatment with bDMARDS led to decrease in mean prednisone dose and to increase of 1.7% (p < 0.05) in TBS and OC levels of 26% (p < 0.001) but not on aBMD and CTX after treatment. The greatest TBS increase (2.7%, p < 0.05) was observed in premenopausal females within group 1. No effect of csDMARDS on measured parameters was observed. CONCLUSION: Treatment of patients suffering from active RA with bDMARDs in comparison to csDMARDS led to increase of TBS, with greater increment of TBS in premenopausal women, despite no change in aBMD.
29985080 Predictive value of a multi-biomarker disease activity score for clinical remission and ra 2019 Jan OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial. METHOD: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year. RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003). CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.
27455886 Oral Methotrexate in split dose weekly versus oral or parenteral Methotrexate once weekly 2018 May OBJECTIVE: To investigate whether methotrexate (MTX) administered orally to rheumatoid arthritis (RA) patients in split doses at 2-3 days' interval, would result in equal or better efficacy, tolerability and compliance, without increasing toxicity compared to single weekly dose given orally or parenterally. MATERIALS AND METHODS: One hundred and thirty-five patients fulfilling the American College of Rheumatology (ACR) 2010 criteria for RA, on 7.5 mg of MTX weekly orally, with the Simplified Disease Activity Index (SDAI) > 11 were enrolled for a 24-week period. Patients were randomly divided into three groups and were given MTX: Group 1 7.5 mg twice or thrice weekly orally, Group 2 15 mg or 22.5 mg in a single dose weekly orally and Group 3 15 mg or 22.5 mg in a single dose weekly as an intramuscular injection. The primary outcomes were low disease activity (LDA) and mean change in SDAI at week 24, whereas secondary outcomes included remission, adverse events and compliance. RESULTS: At week 24, adherence to treatment was maximum in Group 1, 69% (P = 0.09). In intention-to-treat analysis at 24 weeks, Group 1, 49%, Group 2, 36% and Group 3, 47% achieved LDA (P = 0.4). There was significant difference in mean change in SDAI at week 24 from baseline (P = 0.008) among the groups. Group 3 patients were more uncomfortable with the mode of administration of MTX (P = 0.003). There was no significant difference in adverse events. CONCLUSION: Oral split doses of MTX are better than an oral single dose and similar to parenteral MTX in terms of efficacy.
29853822 Disease Characteristics and Change in Arthritis Activity according to Treatment in Hepatit 2018 Jun 4 BACKGROUND: Rheumatoid arthritis (RA) treatment may differ according to hepatitis B state and consequently may bring about different arthritis outcomes. However, whether hepatitis B affects treatment outcome remains unclear. We investigated differences in change in arthritis activity between RA patients according to concomitant hepatitis B virus infection. METHODS: A retrospective medical chart review was performed by two rheumatologic fellows using single center data, from January 2000 to March 2015. Among RA patients older than 18 years, patients with comorbidities that could affect RA treatment aside from hepatitis B were excluded. Using 1:3 propensity score matching, 40 hepatitis B virus surface antigen (HBsAg)-positive patients and 112 HBsAg-negative patients were included in the study. Data were collected longitudinally using standardized electronic forms. The longitudinal relationship between HBsAg-positivity and RA activity was analyzed using generalized estimating equations. RESULTS: RA activity showed time-dependent improvement. Reductions of swollen joint count over time were significantly larger in the HBsAg-negative group. However, changes in disease activity score in 28 joints with three variables (DAS28-3), tender joint count, erythrocyte sedimentation rate and C-reactive protein level did not differ between the groups. There were no differences in alanine aminotransferase level. HBsAg-positive patients were less likely to receive methotrexate (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19; P < 0.001) and more likely to receive sulfasalazine (OR, 3.67; 95% CI, 1.94-6.95; P < 0.001). CONCLUSION: RA medication use varied according to HBsAg-positivity. However, improvement in RA activity was not significantly affected by concomitant hepatitis B infection.
29321415 Cerebral Toxoplasmosis Diagnosed by Nested-polymerase Chain Reaction in a Patient with Rhe 2018 May 15 A 65-year-old woman with rheumatoid arthritis (RA) visited our hospital because of right facial sensory hypoesthesia. Cerebral toxoplasmosis was suspected on brain magnetic resonance imaging. We discontinued methotrexate for RA and started a sulfamethoxazole/trimethoprim (ST) mixture. Although ST treatment was interrupted because of adverse reactions, her prognosis was favorable. The Toxoplasma 18S rDNA gene was detected by nested-polymerase chain reaction (PCR) from blood and cerebrospinal fluid. Detecting the Toxoplasma 18S rDNA gene by nested-PCR is useful for the diagnosis and safer than a brain biopsy. In addition, the discontinuation of immunosuppressants may be recommended in patients compromised by those immunosuppressants.
29461286 Recent advances in the treatment of rheumatoid arthritis. 2018 May PURPOSE OF REVIEW: Therapies for rheumatoid arthritis (RA) continue to expand rapidly. The purpose of this review is to discuss novel treatment options, including biosimilars, that are available, as well as to highlight promising agents in development. The purpose is also to discuss new emerging safety signals associated with these drugs and to discuss strategies in tapering therapy. RECENT FINDINGS: There are several novel RA therapies. These include the interleukin-6 (IL-6) receptor blocker sarilumab, which was approved in 2017. In aggregate, the sarilumab studies show that it is effective in RA, including patients with incomplete responses to methotrexate and anti-tumor necrosis factor inhibitor, and showing superior efficacy when used in higher dose (200 mg every 2 weeks) to standard-dose adalilumab. Other drugs that are currently being studied include the IL-6 cytokine blocker sarikumab, the small targeted molecule filgotinib, and many new biosimilars. Baracitinib failed to achieve approval by the Food and Drug Administration primarily over perceived safety concerns. The two biosimilar drugs currently approved are CT-P13 and SB2, which are based on the reference product infliximab. Although this review summarizes trials examining biologic tapering, additional data are needed to guide clinicians in regards to treatment de-escalation in RA. SUMMARY: With the greatly expanded armamentarium of RA treatment options available, it is important for clinicians to understand the data regarding drug efficacy and safety. With remission increasingly attainable, effective drug tapering strategies are needed. Although tapering trials do exist, more studies will be needed to help guide clinical practice.
29336711 Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular end 2018 Jul OBJECTIVE: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). METHOD: Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses. RESULTS: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. CONCLUSION: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.
29770539 Hepatitis B virus reactivation in patients with rheumatoid arthritis: Analysis of the Nati 2018 Nov This study aimed to determine the incidence and risk factors for hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) undergoing immunosuppressive therapy. The National Database of Japan, in which insurance claim data have been comprehensively accumulated, was utilized. The subjects were 76 641 RA patients who were plausibly initiated on immunosuppressive therapy from April 2013 to March 2014. Laboratory tests of the hepatitis B surface antigen, anti-hepatitis B virus surface antibody, and anti-hepatitis B virus core antibody were performed in 28.23%, 12.52% and 14.63% of patients, respectively, when the therapy was initiated. We found that HBV reactivation and fulminant hepatitis occurred in both the patients with and without HBV DNA monitoring, indicating insufficient monitoring in Japan during the study. The cumulative incidence of HBV reactivation over 24 months was 1.57% (95% confidence interval [CI] = 1.28%-1.92%) in the monitoring group, which consisted of those with resolved HBV infection. Glucocorticoid administration was a potent risk factor for HBV reactivation (hazard ratio [HR]  = 1.70, 95% CI = 1.26-2.29, P = .001 in all subjects, and HR = 1.82, 95% CI = 1.18-2.81, P = .007 in the nonmonitoring group), although it was not statistically significant in the monitoring group (HR = 1.49, 95% CI = 0.99-2.26 and P = .057). No significant risk difference was observed between single administration of methotrexate and biological drugs.
29802817 Prophylactic and therapeutic activity of alkaline phosphatase in arthritic rats: single-ag 2018 Sep Alkaline phosphatase (AP) is a gate-keeper of innate immune system responses by detoxifying inflammation triggering moieties released from endogenous and external sources. We examined whether AP's broad mechanism of action constitutes a safe therapeutic, either as single agent or combined with methotrexate (MTX), for chronic inflammatory disorders, for example, rheumatoid arthritis (RA). A rat model for RA was used with repeated intra-articular methylated bovine serum albumin (mBSA) injections in 1 knee ("arthritic" knee), with the contralateral knee serving as internal control. AP (200 µg, subcut) was administered before mBSA injections (prophylactic setting) or after arthritis induction (therapeutic setting) or combined with MTX (0.3 mg/kg or 1 mg/kg; intraperitoneally). As end point of treatment outcome, macrophage infiltration in knees, liver, and spleen was assessed by immunohistochemistry (ED1 and ED2 expression), immunofluoresence (macrophage marker folate receptor-β [FRβ]), and [(18)F]fluoro-polyethylene glycol-folate positron emission tomography (PET) (macrophage imaging) and ex vivo tissue distribution. Single-agent AP treatment and combinations with MTX were well tolerated. Both prophylactic and therapeutic AP markedly reduced synovial macrophage infiltration in arthritic knees (ED1: 3.5- to 4-fold; ED2: 3.5- to 6-fold), comparable with MTX treatment. AP-MTX combinations slightly improved on single agent effects. PET monitoring and ex vivo tissue distribution studies corroborated the impact of AP, MTX, and AP-MTX on reducing synovial macrophage infiltration. Beyond localized articular effects, AP also revealed systemic anti-inflammatory effects by a 2-fold reduction of ED1, ED2, and FRβ(+) macrophages in liver and spleen of arthritic rats. Collectively, single-agent AP and AP combined with MTX elicited local and systemic anti-arthritic activity in arthritic rats.