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ID PMID Title PublicationDate abstract
28880684 Reduction of methotrexate and glucocorticoids use after the introduction of biological dis 2018 May OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.
28376912 Head-to-head comparison of aggressive conventional therapy and three biological treatments 2017 Apr 4 BACKGROUND: New targeted therapies and improved treatment strategies have dramatically improved the outcomes of patients with rheumatoid arthritis (RA). However, it is unknown whether different early aggressive interventions can induce stable remission or a low-active disease state that can be maintained with conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, and whether they differ in efficacy and safety. The Nordic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) study will assess and compare (1) the proportion of patients who achieve remission in a head-to-head comparison between csDMARD plus glucocorticoid therapy and three different biological DMARD (bDMARD) therapies with different modes of action and (2) two de-escalation strategies in patients who respond to first-line therapy. METHODS/DESIGN: In a pragmatic, 80-160-week, multicenter, randomized, open-label, assessor-blinded, phase 4 study, 800 patients with early RA (symptom duration less than 24 months) are randomized 1:1:1:1 to one of four different treatment arms: (1) aggressive csDMARD therapy with methotrexate + sulphasalazine + hydroxychloroquine + i.a. glucocorticoids (arm 1A) or methotrexate + prednisolone p.o. (arm 1B), (2) methotrexate + certolizumab-pegol, (3) methotrexate + abatacept, or (4) methotrexate + tocilizumab. The primary clinical endpoint is the proportion of patients reaching Clinical Disease Activity Index (CDAI) remission at week 24. Patients in stable remission over 24 consecutive weeks enter part 2 of the study earliest after 48 weeks. Patients not achieving sustained CDAI remission over 24 consecutive weeks, exit the study after 80 weeks. In part 2, patients are re-randomized to two different de-escalation strategies, either immediate or delayed (after 24 weeks) tapering, followed by cessation of study medication. All patients remain on stable doses of methotrexate. The primary clinical endpoint in part 2 is the proportion of patients in remission (CDAI ≤2.8) 24 weeks after initiating treatment de-escalation. Radiographic assessment will be performed regularly throughout the trial, and blood and urine samples will be stored in a biobank for later biomarker analyses. DISCUSSION: NORD-STAR is the first investigator-initiated, randomized, early RA trial to compare (1) csDMARD and three different bDMARD therapies head to head and (2) two different de-escalation strategies. The trial has the potential to identify which treatment strategy to apply in early RA to achieve the best possible outcomes for both patients and society. TRIAL REGISTRATION: NCT01491815 and NCT02466581 . Registered on 8 December 2011 and May 2015, respectively. EudraCT: 2011-004720-35.
28035541 Effect of Artemisia annua extract on treating active rheumatoid arthritis: A randomized co 2017 Jul OBJECTIVE: To investigate the effect and safety of the complementary use of the extract of Artemisia annua L. (EAA) on treating active rheumatoid arthritis (RA). METHODS: A randomized controlled clinical trial was performed. All the 159 participates with active RA were randomly assigned to the control group (80 cases) and EAA group (79 cases) using concealed random allocation method. In the control group, patients were medicated with leflflunomide and methotrexate for 48 weeks; and patients in the EAA group were administrated with leflflunomide, methotrexate plus EAA (30 g/d). At the time points of 0, 12, 24 and 48 weeks, the clinical outcome measures, including objective pain score, tenderness score, number of painful joints, number of swollen joints, health assessment questionnaire (HAQ) score for quality of life, levels of serum rheumatoid factor (RF), anti-cyclic citrullinated protein antibodies (CCP-Ab), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), visual analogue score for pain (VAS), and the overall effificacy were detected and recorded. RESULTS: The objective pain score, number of painful joints and ESR at 12 weeks, tenderness score and HAQ at 24 weeks, and the tenderness score, number of painfull joints, number of swollen joints, HAQ, CRP, RF and CCP-Ab at 48 weeks were signifificantly improved in the EAA group compared with the control group (P<0.01 or P<0.05). At 24 and 48 weeks, the overall effificacy of the EAA group was signifificantly higher than the control group (P<0.01). There were signifificantly higher withdrawal rate of corticosteroids within 12 weeks post-treatment and lower incidence rate of adverse effects in the EAA group compared with the control group (P<0.01 or P<0.05). CONCLUSION: EAA plus methotrexate and leflflunomide were more effective and safer than the routine use of methotrexate and leflflunomide in the treatment of active RA.
28455827 Characteristics and risk factors of lymphoproliferative disorders among patients with rheu 2017 Jun The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient's report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12-1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00-1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.
28741869 Increased baseline RUNX2, caspase 3 and p21 gene expressions in the peripheral blood of di 2017 Oct OBJECTIVE: To investigate the potential of the baseline gene expression in the whole blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis (RA) patients for predicting the response to methotrexate (MTX) treatment. METHODS: Twenty-six control subjects and 40 RA patients were examined. Clinical, immunological and radiographic parameters were assessed before and after 24 months of follow-up. The gene expressions in the whole blood were measured using real-time reverse transcription polymerase chain reaction. The protein concentrations in peripheral blood mononuclear cells were quantified using enzyme-linked immunosorbent assay. Receiver operating characteristic curve analyses were used to suggest thresholds that were associated with the prediction of the response. RESULTS: Decreases in the disease activity at the end of the study were accompanied by significant increases in joint space narrowing score (JSN). Positive correlations between the expressions of the Unc-51-like kinase 1 (ULK1) and matrix metalloproteinase 9 (MMP-9) genes with the level of C-reactive protein and MMP-9 expression with Disease Activity Score of 28 joints (DAS28) and swollen joint count were noted at baseline. The baseline tumor necrosis factor (TNF)α gene expression was positively correlated with JSN at the end of the follow-up, whereas p21, caspase 3, and runt-related transcription factor (RUNX)2 were correlated with the ΔDAS28 values. CONCLUSIONS: Our results suggest that the expressions of MMP-9 and ULK1 might be associated with disease activity. Increased baseline gene expressions of RUNX2, p21 and caspase 3 in the peripheral blood might predict better responses to MTX therapy.
28724365 Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory r 2017 Jul 19 BACKGROUND: The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. METHODS: Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. RESULTS: Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). CONCLUSIONS: Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. TRIAL REGISTRATION: The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).
29148403 Treatment patterns in rheumatoid arthritis after discontinuation of methotrexate: data fro 2018 Mar OBJECTIVES: In active rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX), guidelines support adding or switching to another conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) and/or a biologic DMARD (bDMARD). The purpose of this analysis was to describe treatment practices in routine care and to evaluate determinants of regimen selection after MTX discontinuation. METHODS: Biologic-naïve patients in the Ontario Best Practice Research Initiatives registry discontinuing MTX due to primary/secondary failure, adverse events, or patient/physician decision were included. RESULTS: Of 313 patients discontinuing MTX, 102 (32.6%) were on MTX monotherapy, 156 (49.8%) on double, and 55 (17.6%) on multiple csDMARDs. Patients on MTX monotherapy were older than patients on double or multiple csDMARDs (p=0.013), less likely to have joint erosions (p=0.009) and had lower patient global assessment (p=0.046) at MTX discontinuation. Post-MTX discontinuation, 169 (54.0%) transitioned to, or added new DMARD(s) (new csDMARD(s): 139 [44.4%]; bDMARD: 30 [9.6%]), and 144 (46.0%) opted for no new DMARD treatment. Patients on MTX monotherapy transitioning monotherapy, whereas patients on combination csDMARDs switched more to new csDMARDs and bDMARD combination therapy. Early RA (adjOR [95%CI]: 3.07 [1.40-6.72]) and treatment with multiple csDMARDs vs. MTX monotherapy (4.15 [1.35-12.8]) at MTX discontinuation were significant predictors of transitioning to or adding new csDMARD(s)/bDMARD treatment versus opting for no new DMARD treatment. CONCLUSIONS: Differences in subsequent treatment patterns exist between patients discontinuing MTX when used as monotherapy versus in combination with other csDMARDs where the former are more likely to use a subsequent monotherapy treatment.
28448195 Design characteristics of the Corrona Japan rheumatoid arthritis registry. 2018 Jan OBJECTIVES: The primary objective is to prospectively study the comparative safety and effectiveness of older and newer classes of nonbiologic DMARDs (Disease-modifying antirheumatic drugs), biologic DMARDs and targeted synthetic therapies approved for rheumatoid arthritis (RA) in a real-world patient population in Japan. METHODS: Prospective, multicenter, noninterventional, observational study across geographic distribution of both private and public institutions for patients with RA who are newly prescribed one of the following medications: (1) methotrexate; (2) anti-TNF biologic DMARDs; (3) non-TNF biologic DMARDs; and (4) approved JAK inhibitors at the time of enrollment into the registry. Target enrollment is currently 2000 subjects. Baseline and follow-up data on patient demographics, medical history, disease activity, laboratory results, comorbidities, hospitalizations, and targeted safety events are obtained via Physician and Patient Questionnaires. RESULTS: Fifty sites are anticipated to participate with 40 sites ethics committee (EC) approved at the time of submission consisting of 23% clinics, 21% private academic hospitals, 29% private mid-sized to large hospitals, 15% national academic hospitals, and 12% national hospitals. CONCLUSION: The Corrona Japan RA Registry will provide real-world evidence from both private and public institutions on the comparative effectiveness and safety of recently approved RA therapies in Japan.
28581281 A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis. 2017 Jul Rheumatoid vasculitis is a rare, but most serious extra-articular complications of long-standing, seropositive rheumatoid arthritis (RA). Vasculitis of hepatic artery is an extremely rare but severe manifestation of rheumatoid vasculitis. A 72-year-old woman who presented with polyarthralgia for 2 months was diagnosed with early RA. Since she had manifestations of livedo reticularis, and liver dysfunction which was atypical for RA patients, a percutaneous needle liver biopsy was performed revealing arteritis of a medium-sized hepatic artery. Extensive investigations did not reveal evidences of other systemic causes such as malignancy or systemic vasculitis. The patient was diagnosed with rheumatoid vasculitis involving hepatic arteries based on Bacon and Scott criteria for rheumatoid vasculitis. With high dose corticosteroid and cyclophosphamide induction and methotrexate and tacrolimus maintenance treatment, she was successfully recovered. Association of rheumatoid vasculitis at very early stages of the disease may represent an early aggressive form of RA.
28214146 Impact of anti-TNF therapy on NK cells function and on immunosurveillance against B-cell l 2017 Jun OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti-lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity. METHODS: NK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed. RESULTS: Exposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5-32.9] vs 31.3% [21.5-49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9-25.9] vs to 29.7% [22.5-43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling. CONCLUSIONS: Thus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.
28081972 Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating 2017 Feb 7 BACKGROUND: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected. METHODS: Ten patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4-6weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD. RESULTS: After vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX. CONCLUSIONS: MTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue. CLINICAL TRIAL REGISTRATION: NCT02240888.
28450312 Long-term outcome is better when a methotrexate-based treatment strategy is combined with 2017 Aug OBJECTIVES: In the second Computer-Assisted Management in Early Rheumatoid Arthritis trial, patients had started with methotrexate and 10 mg prednisone (MTX+pred) or placebo (MTX+plac). After the trial, prednisone was tapered and stopped, if possible. The objective was to compare, during the post-trial follow-up between the two former strategy groups, initiation of the first biological disease-modifying antirheumatic drug (bDMARD), radiographic outcome and onset of glucocorticoid (GC)-related comorbidities. METHODS: Data on prednisone and bDMARD use and onset of GC-related comorbidities were collected retrospectively. Sharp/van der Heijde scoring was performed. Data were analysed using Fisher's exact and Mann-Whitney U tests. RESULTS: Of 218 patients post-trial follow-up data were available. The maximum follow-up time was 11.8 years. Fewer patients initiated a first bDMARD in the former MTX+pred compared with the former MTX+plac strategy group: 31% vs 50%, p=0.003. At the 2 year post-trial follow-up, the median erosion score was significantly lower in the former MTX+pred versus former MTX+plac strategy group: 0 (range 0-0) versus 0 (0-2), p=0.002. No significant differences between the former strategy groups in the onset of GC-related comorbidities during the post-trial follow-up were found. CONCLUSION: Addition of 10 mg prednisone daily to an MTX-based treatment strategy in early rheumatoid arthritis results in a lower initiation rate of a first bDMARD and significantly better radiographic outcomes, yet does not result in more GC-related comorbidities.
27696724 Comparative Assessment of the Different American College of Rheumatology/European League A 2017 Mar OBJECTIVE: The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have defined remission using Boolean- or index-based criteria (i.e., a Simplified Disease Activity Index [SDAI] score of ≤3.3). We undertook this study to compare definitions of remission to inform choice of end points for future rheumatoid arthritis (RA) clinical trials, and we also included in our comparison the remission criterion of a score of ≤2.8 on the Clinical Disease Activity Index (CDAI). METHODS: We performed post hoc analyses on clinical remission rates using data from 2 infliximab trials (the ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset] and ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy] trials) and 1 golimumab trial (the GO-FORWARD trial). We investigated stringency of the different remission definitions, their power to discriminate between active drug and comparator, and aspects of their internal and external validity. We also investigated population determinants of discriminatory power for a particular remission end point. RESULTS: In patients with early RA (the ASPIRE trial), ACR/EULAR Boolean, CDAI, and SDAI remission rates at 6-7 months were 4-6% for methotrexate (MTX) alone versus 11-14% for infliximab plus MTX. In patients with MTX-refractory active RA (the ATTRACT and GO-FORWARD trials), remission rates were ≤1% for comparator (add-on of placebo) versus 4-6% for add-on of infliximab in the ATTRACT trial and ≤3% for comparator (add-on of placebo) versus 11-13% for add-on of golimumab in the GO-FORWARD trial. Existing remission cut points of different measures were generally comparable, with the Boolean criteria being somewhat more stringent than the SDAI and CDAI criteria. Remission rates were similar across definitions, as was average statistical power (CDAI, 55.6%; Boolean, 59.9%; SDAI, 62.6%). CONCLUSION: Remission is an ambitious primary end point for RA clinical trials, to be reserved for selected scenarios based on power considerations. The ACR/EULAR definitions are interchangeable, with slightly higher stringency of Boolean criteria over index-based criteria.
28584187 Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with mo 2017 Oct OBJECTIVES: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. METHODS: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. RESULTS: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. CONCLUSIONS: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. TRIAL REGISTRATION NUMBER: NCT01970475; Results.
28950911 Assessment of intracranial vessels in association with carotid atherosclerosis and brain v 2017 Sep 26 BACKGROUND: Stroke has been associated with rheumatoid arthritis (RA). We assessed patients with RA and healthy control subjects by transcranial Doppler (TCD), carotid ultrasonography and brain magnetic resonance imaging (MRI). METHODS: Altogether, 41 female patients with RA undergoing methotrexate (MTX) or biologic treatment and 60 age-matched control subjects underwent TCD assessment of the middle cerebral artery (MCA) and basilar artery. Pulsatility index (PI), resistivity (resistance) index (RI) and circulatory reserve capacity (CRC) were determined at rest (r) and after apnoea (a) and hyperventilation (h). The presence of carotid plaques and carotid intima-media thickness (cIMT) were also determined. Intracerebral vascular lesions were investigated by brain MRI. RESULTS: MCA PI and RI values at rest and after apnoea were significantly increased in the total and MTX-treated RA populations vs control subjects. MCA CRC was also impaired, and basilar artery PI was higher in RA. More patients with RA had carotid plaques and increased cIMT. Linear regression analysis revealed that left PI(r) and RI(r) correlated with disease duration and that left PI(r), RI(r), PI(a), PI(h) and basilar PI correlated with disease activity. Right CRC inversely correlated with 28-joint Disease Activity Score. Disease activity was an independent determinant of left PI(a) and right CRC. Compared with long-term MTX treatment alone, the use of biologics in combination with MTX was associated with less impaired cerebral circulation. Impaired cerebral circulation was also associated with measures of carotid atherosclerosis. CONCLUSIONS: To our knowledge, this is the first study to show increased distal MCA and basilar artery occlusion in RA as determined by TCD. Patients with RA also had CRC defects. We also confirmed increased carotid plaque formation and increased cIMT. Biologics may beneficially influence some parameters in the intracranial vessels.
25401225 Hepatosplenic Hodgkin lymphoma without lymphadenopathy following reversible methotrexate-a 2017 Mar Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.
29264637 Outcomes after rheumatoid arthritis patients complete their participation in a long-term o 2018 Apr To describe disease activity and disability during the first year of follow-up, from rheumatoid arthritis (RA) patients who discontinue tofacitinib after they end participation in a clinical trial. From 2008 to 2016, 36 patients were enrolled in the "Long term follow-up study with tofacitinib (and methotrexate) for RA treatment". At the end of the study, tofacitinib was discontinued and patients were proposed to enter an observational study; 35 agree and had scheduled evaluations at baseline, at 15 and 30 days of follow-up, at month 2 and 3, and thereafter every 3 months. Disease activity was evaluated as per DAS28-ESR and disability as per HAQ. During follow-up, treatment was treat-to-target oriented, only conventional DMARDs were indicated. Descriptive statistics and nonparametric test were used. The study was approved by IRB. Patients were primarily females (N = 34), had median (Q25-75) age of 52 years (45-58), and had received tofacitinib for a median of 7.9 years (6.3-8.3). The proportion of patients with remission and low disease activity decreased from day 30 of follow-up and recovered after 270 days, meanwhile patients with high disease activity increased from 0% at baseline to 6.3% at 1 year. At study entry, 20 patients had remission/low disease activity; during follow-up, 85% deteriorated after (median) 30 days; among them, 23.5% recovered their baseline status after a median of 172.5 days. The HAQ showed a similar behavior, but 66.7% recovered. A substantial proportion of RA patients deteriorated outcomes early after tofacitinib cessation; some patients recovered baseline status with traditional DMARDS.
29043871 A review of sarilumab for the treatment of rheumatoid arthritis. 2018 Jan Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting the peripheral diarthrodial joints. Sarilumab is a human monoclonal antibody against the IL-6 receptor-α. In Phase II and III clinical trials, sarilumab in the background of methotrexate showed superior clinical efficacy over placebo in RA patients with inadequate response to methotrexate or inadequate response or intolerance to TNF inhibitors. Sarilumab monotherapy also showed superior efficacy compared with adalimumab monotherapy in RA patients with inadequate response or intolerance to methotrexate. For safety, injection site reaction, neutropenia and elevation of liver enzymes and serum cholesterol were more commonly observed with sarilumab than with placebo. Overall, sarilumab is expected to serve as another useful antirheumatic drug against active RA.
28217975 Brief Report: Clinical Trials Aiming to Prevent Rheumatoid Arthritis Cannot Detect Prevent 2017 May OBJECTIVE: Prevention of rheumatoid arthritis (RA) was the aim of several trials in undifferentiated arthritis (UA), with overall negative results. As preparatory work has revealed that only ∼30% of UA patients progress to having RA, we hypothesized that inclusion of patients without imminent RA could lead to false-negative results. We undertook this study to evaluate this hypothesis by reinvestigating the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial (a 1-year course of methotrexate [MTX] versus placebo in UA) after excluding patients without a high risk of developing RA. METHODS: A validated prediction model was used to determine the risk of RA in all patients included in the PROMPT trial. Patients with a prediction score of ≥8 (positive predictive value of ≥84% for developing RA) were considered to have a high risk of developing RA. The effect of a 1-year course of MTX during 5 years of follow-up was reinvestigated in these patients. RESULTS: Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm (P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P < 0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm (P = 0.031). These beneficial effects of MTX were observed both in anti-citrullinated protein antibody (ACPA)-positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score. CONCLUSION: A 1-year course of MTX delayed and prevented RA development in high-risk UA patients. This emphasizes the importance of adequate risk prediction in trials that aim to prevent RA.
27931158 Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis i 2017 Sep OBJECTIVE: A systematic review found that an average of 27% of rheumatoid arthritis (RA) patients using tumour necrosis factor (TNF) inhibitors discontinue their treatment within 1 year. The aim of this study was to assess drug survival on TNF inhibitors among patients with RA. METHODS: Patients were identified from the National Register for Biologic Treatment in Finland (ROB-FIN), which is a longitudinal cohort study established to monitor the effectiveness and safety of biologic drugs in rheumatic diseases. Inclusion was limited to TNF-inhibitor treatments started as the patient's first, second, or third biologic treatment between 2004 and 2014. Follow-up was truncated at 36 months. The results of a time-dependent Cox proportional hazards model were reported as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of the 4200 TNF-inhibitor treatment periods identified from ROB-FIN, 3443 periods from 2687 patients met the inclusion criteria. Twenty-seven per cent of the patients discontinued their treatment within 12 months. Infliximab (HR 1.8, 95% CI 1.3-2.5) and certolizumab pegol (HR 1.7, 95% CI 1.2-2.3) had lower drug survival compared to golimumab. A similar trend was seen with adalimumab (HR 1.2, 95% CI 0.90-1.7) and etanercept (HR 1.2, 95% CI 0.87-1.6). Concomitant use of methotrexate (MTX) was associated with improved drug survival (HR 0.76, 95% CI 0.64-0.90) in comparison with TNF-inhibitor monotherapy. CONCLUSIONS: Golimumab was better in terms of drug survival than infliximab or certolizumab pegol and at least as good as adalimumab and etanercept. Concomitant use of MTX improved drug survival on TNF inhibitors.