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ID PMID Title PublicationDate abstract
26456224 Update on the 2012 Brazilian Society of Rheumatology Guidelines for the treatment of rheum 2015 Nov In 2014, tofacitinib, a target-specific, synthetic disease modifying anti rheumatic drug (DMARD) and a selective inhibitor of Janus kinase (JAK) was approved for use in Brazil. This position paper aims to update the recommendations of the Brazilian Society of Rheumatology (SBR) on the treatment of rheumatoid arthritis (RA) in Brazil, specifically regarding the use of target-specific synthetic DMARDs. The method of this recommendation consisted of a literature review of scientific papers held on the Medline database. After this review, a text was produced, answering questions in Pico structure, considering efficacy and safety issues of tofacitinib use for RA treatment in different scenarios (such as first-line treatment after failure with methotrexate [MTX] or other conventional synthetic DMARDs after failure with biological therapy). Based on existing evidence, and considering the available data on efficacy, safety and cost of medications available to treat the disease in Brazil, the RA Commission of SBR, after a process of discussion and voting on proposals, established the following position on the use of tofacitinib for treatment of RA in Brazil: "Tofacitinib, alone or in combination with MTX, is an alternative for RA patients with moderate or high activity after failure of at least two different synthetic DMARDs and one biological DMARD." The level of agreement with this recommendation was 7.5. This position may be reviewed in the coming years, in the face of a greater experience with the use of this medication.
27282428 Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoria 2016 Aug INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta. OBJECTIVE: The objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting. METHODS: Pregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up. RESULTS: Out of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up. CONCLUSIONS: The pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.
25532946 Safety of disease-modifying antirheumatic drugs and biologic agents for rheumatoid arthrit 2015 Apr OBJECTIVE: The aim of this study was to describe the incidence rate (IR) of adverse drug reactions (ADRs) in daily clinical practice, related to disease-modifying antirheumatic drugs (DMARDs) and biologic agents (BA) in rheumatoid arthritis (RA) patients, and to analyze factors causing discontinuation due to ADRs. METHODS: This was a prospective observational study (October 2010 to October 2011). RA patients who were attended in our hospital taking DMARDs or BA during the study period were included. ADRs were injuries related to these drugs and registered with a software system in routine visits. ADRs could be mild (lowering dosage), moderate (drug discontinuation), or severe (hospital admission). The IR of ADR per 100 patient-years was estimated using survival techniques. Cox regression models (HR; 95% confidence interval) were used to explore factors associated with discontinuation due to ADRs. RESULTS: In total, 1202 patients were analyzed, with 158 ADRs (IR = 15.2). Of all ADRs, 80.4% required drug discontinuation (IR = 12.2). Age, less disease and therapy duration, taking corticoids, and combined therapy versus monotherapy (HR = 3; 95% CI: 2.0-4.4) were the factors independently associated to discontinuation due to ADRs. We did not find statistical differences between the different monotherapy regimens. Regarding combinations, Methotrexate + BA had the lowest risk of discontinuation compared to the rest (HR = 0.24; 95% CI: 0.09-0.6). CONCLUSIONS: We have estimated the incidence of ADRs related to DMARDs/BA in real-life conditions. We confirm the role of combined therapy in the development of discontinuations due to ADRs, except for BA + MTX, which did not show an increase of toxicity compared to monotherapy. This combination seems to be safer than others.
26107769 Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interf 2015 INTRODUCTION: Proof of concept for local gene therapy for the treatment of arthritis with immunomodulatory cytokine interferon beta (IFN-β) has shown promising results in animal models of rheumatoid arthritis (RA). For the treatment of RA patients, we engineered a recombinant adeno-associated serotype 5 vector (rAAV5) encoding human (h)IFN-β under control of a nuclear factor κB promoter (ART-I02). METHODS: The potency of ART-I02 in vitro as well as biodistribution in vivo in arthritic animals was evaluated to characterize the vector prior to clinical application. ART-I02 expression and bioactivity after transduction was evaluated in fibroblast-like synoviocytes (FLS) from different species. Biodistribution of the vector after local injection was assessed in a rat adjuvant arthritis model through qPCR analysis of vector DNA. In vivo imaging was used to investigate transgene expression and kinetics in a mouse collagen induced arthritis model. RESULTS: Transduction of RA FLS in vitro with ART-I02 resulted in high expression levels of bioactive hIFN-β. Transduction of FLS from rhesus monkeys, rodents and rabbits with ART-I02 showed high transgene expression, and hIFN-β proved bioactive in FLS from rhesus monkeys. Transgene expression and bioactivity in RA FLS were unaltered in the presence of methotrexate. In vivo, vector biodistribution analysis in rats after intra-articular injection of ART-I02 demonstrated that the majority of vector DNA remained in the joint (>93%). In vivo imaging in mice confirmed local expression of rAAV5 in the knee joint region and demonstrated rapid detectable and sustained expression up until 7 weeks. CONCLUSIONS: These data show that hIFN-β produced by RA FLS transduced with ART-I02 is bioactive and that intra-articular delivery of rAAV5 drives expression of a therapeutic transgene in the joint, with only limited biodistribution of vector DNA to other tissues, supporting progress towards a phase 1 clinical trial for the local treatment of arthritis in patients with RA.
25344930 Automatic identification of methotrexate-induced liver toxicity in patients with rheumatoi 2015 Apr OBJECTIVES: To improve the accuracy of mining structured and unstructured components of the electronic medical record (EMR) by adding temporal features to automatically identify patients with rheumatoid arthritis (RA) with methotrexate-induced liver transaminase abnormalities. MATERIALS AND METHODS: Codified information and a string-matching algorithm were applied to a RA cohort of 5903 patients from Partners HealthCare to select 1130 patients with potential liver toxicity. Supervised machine learning was applied as our key method. For features, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) was used to extract standard vocabulary from relevant sections of the unstructured clinical narrative. Temporal features were further extracted to assess the temporal relevance of event mentions with regard to the date of transaminase abnormality. All features were encapsulated in a 3-month-long episode for classification. Results were summarized at patient level in a training set (N=480 patients) and evaluated against a test set (N=120 patients). RESULTS: The system achieved positive predictive value (PPV) 0.756, sensitivity 0.919, F1 score 0.829 on the test set, which was significantly better than the best baseline system (PPV 0.590, sensitivity 0.703, F1 score 0.642). Our innovations, which included framing the phenotype problem as an episode-level classification task, and adding temporal information, all proved highly effective. CONCLUSIONS: Automated methotrexate-induced liver toxicity phenotype discovery for patients with RA based on structured and unstructured information in the EMR shows accurate results. Our work demonstrates that adding temporal features significantly improved classification results.
25593074 Infliximab, methotrexate and their combination for the treatment of rheumatoid arthritis: 2015 Mar We performed a systematic review to evaluate the efficacy and safety of infliximab + methotrexate (IFX + MTX) regimens versus MTX alone or in combination with other disease-modifying anti-rheumatic drugs (DMARDs). We searched through major databases, the grey literature and did a manual search. Two independent reviewers conducted the selection, data extraction and analysis of the quality of the studies. Meta-analysis was conducted using Review Manager(®) 5.1 software. Nine trials were included. The mean modified Jadad score was 4.4, but only one study showed low risk of bias. IFX + MTX regimen presented better responses in clinical outcomes of ACR and DAS28 by up to 54 weeks, and of radiographic progression by up to 104 weeks. Withdrawals due to lack of efficacy was lower in the IFX + MTX group. No significant difference in adverse events was observed. The IFX + MTX combination is more effective than treatment with MTX alone or DMARDs combination. This regimen presented good tolerability in patients previously treated with DMARDs, not treated with MTX or with insufficient responses to MTX. The efficacy of IFX + MTX is noted primarily during initial periods of treatment. High doses of IFX were as effective as the standard dose, but with possible higher risk of serious infections. Therefore, we advise clinicians to use the standard dose of IFX 3 mg/kg every 8 weeks.
26581205 Efficacy and safety of combination therapy for preventing bone damage in rheumatoid arthri 2016 Jan The main outcomes of the therapies for rheumatoid arthritis (RA) must be preventing, or at least lessening, the development of structural damage. Biological disease-modifying anti-rheumatic drugs (bDMARDs), targeting tumour necrosis factor-α (TNF-α) or other key steps (IL-1, IL-6, T cells, B cells) in the pathogenesis of RA, have given clues to be effective and safe as treatments for RA, being capable of improving disease activity, ameliorating functional ability and halting joint damage. A large body of evidence, stemming from randomized clinical trials, observational studies, and registries, has shown that the beneficial effects of the bDMARDs become optimal when combined with synthetic (s)-DMARDs, mainly methotrexate (MTX). Despite combination therapy is advocated by the international guidelines for the management of RA, data from the daily standard of care indicate that almost one third of RA patients are treated with bDMARDs as monotherapy. Many reasons may be taken into account to explain this gap from official recommendations, among which the fact that in real-life settings, the assessment of clinical outcomes is exclusively based on clinical indices, disregarding the evolution of bone damage. Furthermore, some bDMARDs have been launched in the market with the official approval to be used as monotherapy. But even for the latter, there is no conclusive proof that monotherapy regimen is comparable to co-therapy with MTX in preventing articular damage. In conclusion, the most recent published data show that combination therapy with bDMARDs and MTX represents the best therapeutic option for the treatment of RA since it can stop or at least slow the progression of disabling structural damage.
25744928 [A case of methotrexate-associated lymphoproliferative disorder diagnosed by liver biopsy] 2015 Jan In 1998, a 68-year-old woman was diagnosed with rheumatoid arthritis. She was treated with prednisolone, nonsteroidal anti-inflammatory drugs, methotrexate (MTX), and biological drugs. Retroperitoneal lymph node swelling and hepatosplenomegaly appeared but spontaneously disappeared after drug withdrawal. Anorexia and general fatigue occurred in March 2012. She was admitted to our hospital with retroperitoneal, periaortic, and mediastinal lymph node swelling and was found to have multiple liver tumors. Based on the results of aspiration biopsy of a liver tumor, she was diagnosed with malignant lymphoma (Hodgkin lymphoma). She died from liver failure and disseminated intravascular coagulation before chemotherapy. We present this case of MTX-associated lymphoproliferative disorder, which caused formation of a liver tumor.
27473088 Measuring transaminases in patients with rheumatoid arthritis on weekly methotrexate: does 2016 Dec The change in transaminase levels over a single week during therapy with methotrexate (MTX) has not been investigated or reported to date. In clinical practice, it is common to observe abnormal transaminase levels upon routine blood work for toxicity monitoring. Many have suggested that such lab abnormalities can sometimes be attributed to sampling blood for toxicity monitoring proximately following MTX dosing. The aim of our study was to evaluate changes in transaminase levels (AST/ALT) over 1 week after MTX administration in rheumatoid arthritis (RA) patients. In this small proof of concept study, we evaluated 13 patients with RA taking stable doses of methotrexate and background medications (e.g., NSAIDs and prednisone), but no other disease-modifying anti-rheumatic drugs (DMARDs). All patients were on a stable dose of folic acid. Patients received their usual doses of MTX administered at a specified time, and then sequential blood samples were obtained over the course of 7 days. Peripheral blood was obtained at each time point to measure serum transaminases. We did not observe any significant change in sequential transaminases over 1 week in relationship to MTX administration. It is possible that MTX therapy alone does not lead to significant weekly transaminase variations, contrary to our clinical expectations. The addition of other medications (i.e., NSAIDs) to stable MTX regimen may result in transaminase abnormalities.
25943001 Factors associated with the initiation of biologic disease-modifying antirheumatic drugs i 2015 May BACKGROUND: Rheumatoid arthritis (RA) is a progressive autoimmune disorder of joints that is associated with high health care costs, yet guidance is lacking on how early to initiate biologic disease-modifying antirheumatic drugs (DMARDs), a class of medications that is the major cost driver in RA management. Few studies have examined the factors associated with the transition from nonbiologic DMARDs, the first-line therapy for RA, to biologic DMARDs in RA patients.  OBJECTIVE: To examine patient sociodemographics, medication use patterns, and clinical characteristics associated with initiation of biologic DMARDs.   METHODS: This was a retrospective study using the Texas Medicaid prescription and medical claims database from July 1, 2003-December 31, 2010. Adults (aged 18-63 years) with an RA diagnosis (ICD-9-CM code 714.xx), no nonbiologic DMARD or biologic DMARD use during the 6-month pre-index period, and a minimum of 2 prescription claims for the same nonbiologic DMARD during the post-index period were included in the study. The index date was defined as the date when the first nonbiologic DMARD claim was made. Predictors of initiation of biologic DMARDs were age, gender, race, adherence (proportion of days covered), persistence to nonbiologic DMARDs, comorbidity (Charlson Comorbidity Index [CCI]), pain medication use, glucocorticoid use, and rheumatologist visit. Logistic regression was used to examine the factors associated with the initiation of biologic DMARDs.   RESULTS: A total of 2,714 patients were included. After controlling for patient characteristics, logistic regression showed, that compared with methotrexate (MTX) users, sulfasalazine (SSZ) and hydroxychloroquine (HCQ) users were less likely to initiate biologic DMARDs by 69.0% (OR = 0.310, 95% CI = 0.221-0.434, P  less than  0.0001) and 79.9% (OR = 0.201, 95% CI = 0.152-0.265, P  less than  0.0001), respectively. Nonbiologic DMARD dual therapy users were 39.1% less likely to initiate biologic DMARDs compared with nonbiologic DMARD monotherapy users (OR = 0.609, 95% CI = 0.463-0.803, P = 0.0004). With each year increase in age, patients were 1.6% less likely to start biologic DMARDs (OR = 0.984, 95% CI = 0.975-0.993, P = 0.0006). Compared with glucocorticoid users, glucocorticoid nonusers were 53.8% less likely to start on biologic DMARDs (OR = 0.462, 95% CI = 0.372-0.573, P  less than  0.0001). Patients with CCI scores of ≥ 3 were approximately 1.6 times more likely to initiate biologic DMARDs than those with CCI scores of 1 (OR = 1.618, 95% CI = 1.228-2.132, P = 0.0006).  CONCLUSIONS: Younger age, CCI scores ≥3, glucocorticoid use, MTX users (vs. SSZ and HCQ users), and nonbiologic DMARD monotherapy users (vs. dual therapy users) were significantly associated with higher likelihood to initiate biologic DMARDs. Recognizing these potential factors that drive the initiation of biologic DMARDs in this patient population, health care providers and Texas Medicaid should take measures to achieve optimal therapy for RA patients through thorough RA medication evaluation, well-structured RA monitoring programs, and patient education.
27775461 Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethaso 2017 Sep OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.
24818633 Intensive combination treatment regimens, including prednisolone, are effective in treatin 2015 Jun BACKGROUND: Recently, we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy (methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day) compared with the original COBRA therapy (methotrexate 7.5 mg/week, sulfasalazine 2 g/day, with initial prednisolone 60 mg/day) after 26 weeks in patients with early active rheumatoid arthritis (RA). OBJECTIVE: To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity (DAS44), functional outcome (Health Assessment Questionnaire (HAQ)) and radiographic progression (Sharp/van der Heijde score (SHS)), and to assess the effect of adding etanercept. METHODS: An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA, following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39. RESULTS: Both groups showed major improvements in DAS44 after 52 weeks: mean (SD) -2.41 (1.2) in the COBRA and -2.02 (1.0) in the COBRA-light group (p=ns). In both groups, functional ability improved and radiological progression of joints was minimal. At least one adverse event was reported in 96% of the patients in both groups. In total, 25 serious adverse events occurred: 9 vs 16 in COBRA and COBRA-light, respectively. Treatment actually instituted was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 67 of these (62%) actually received it. CONCLUSIONS: Intensive COBRA or COBRA-light therapy has major, comparably favourable effects on disease activity, functional ability and radiological outcome after 1 year in patients with early RA. Protocolised addition of etanercept was often not implemented by treating rheumatologists, and patients receiving it appeared to have limited added benefit, probably because of low disease activity levels at its initiation. TRIAL REGISTRATION NUMBER: ISRCTN55552928.
29932627 Effects and safety of Sinomenine in treatment of rheumatoid arthritis contrast to methotre 2016 Oct OBJECTIVE: To systematically evaluate the curative clinical efficacy and safety of sinomenine (SIN) in treatment of rheumatoid arthritis (RA) in comparison to methotrexate (MTX). METHODS: We searched the China National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, Pubmed and Cochrane Library electronically up to August 31, 2015, without language limitation. Only randomized controlled trials (RCTs) were included. Software Review Manager 5.3 was used for Meta-analysis. RESULTS: A total of 16 eligible studies within 1500 RA patients were included. The meta-analysis indicated that on basis of MTX, SIN was more effective in total effective rate (P < 0.000 01). Besides, SIN alone versus MTX also showed advantages in RA therapy (P = 0.04) Taken together, adverse events occurred less frequently in combination of SIN and MTX than MTX alone (P < 0.0001), especially in digestive system (P < 0.000 01),while occurred more in dermato mucosal system with SIN treatment versus MTX (P = 0.02), and were similar for both remedies in nervous system (P = 0.12) and hematological system (P = 0.25). CONCLUTION: Compared to MTX, SIN had better clinical efficacy and relatively fewer adverse events in treatment of RA, especially when it was used together with MTX. Due to the poor methodological quality, well-designed, multiple-center RCTs are still required to further confirm the findings.
26936262 Inadequate response or intolerability to oral methotrexate: Is it optimal to switch to sub 2016 May Methotrexate (MTX) is considered an anchor drug in the treatment of rheumatoid arthritis. It is also the first-line therapy in a multitude of rheumatologic conditions. Low-dose oral MTX is the preliminary modality of treatment for rheumatoid arthritis due to its affordability, favorable outcomes, and limited risks. However, patients refractory to low-dose MTX therapy may require larger doses of oral MTX. Several studies in the past have demonstrated variability in bioavailability of oral MTX at high doses. This warrants a subsequent switch to parenteral MTX. Widely used among the parenteral preparations of MTX is subcutaneous (SC) MTX. SC MTX provides dependable efficacy, predictable bioavailability, sustained clinical outcomes, and minimal GI adverse effects. It is useful either singularly or in combination therapy regimens. Although SC MTX and intramuscular MTX have similar pharmacokinetics, SC MTX may be preferred by most patients. Development of prefilled syringes and auto-injectors have enabled self-administration of the medication providing the patients with a sense of independence and improved general well-being. Hence, SC MTX can prove to be more efficacious in patients refractory to oral MTX therapy or in patients experiencing severe gastrointestinal adverse effects.
27974925 New pharmacological strategies in rheumatic diseases. 2016 Jul Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. Abbreviations: ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor.
26815184 [Effect of 10-hydroxycamptotbecine on the expression of VEGF in rheumatoid arthritis synov 2015 Sep 15 OBJECTIVE: To study the effect of 10-Hydroxycamptotbecine (10-HCPT) on the expression of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: RASFs were isolated form synovial tissue of RA patients and cultured in vitro. 10-HCPT (3.0×10(-6) mol/L, 3.0×10(-5) mol/L) and Methotrexate (MTX) (2.0×10(-6) mol/L, 2.0×10(-5) mol/L) with different concentrations were used to treat RASFs for 48 hours, and RASFs without 10-HCPT and MTX treatment were served as the control group. The level of VEGF in the supernatant of RASFs culture was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with control group, high and low dose 10-HCPT groups showed significant values on the effect of inhibiting the expression of VEGF in RASFs. Compared with low-dose MTX group, both high and low dose 10-HCPT groups showed significant difference (P<0.05); compared with high-dose MTX group, the high-dose 10-HCPT group had significant difference (P<0.05). CONCLUSION: Compared with MTX, 10-HCPT showed significant effect on inhibiting the expression of VEGF in RASFs.
27114561 Effect of adalimumab on the work-related outcomes scores in patients with early rheumatoid 2016 Aug OBJECTIVES: To evaluate the effects of adalimumab plus MTX (ADA + MTX) vs MTX monotherapy on work-related outcomes in early RA patients with elevated risk of employment loss. METHODS: A post hoc analysis at weeks 26 and 24 from the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PRevention Of Work Disability (PROWD) trials, respectively, was conducted in MTX-naïve RA patients randomized to ADA + MTX or placebo (PBO) + MTX. Work instability was assessed using the RA-Work Instability Scale (RA-WIS) and work productivity was measured with the Work Productivity and Activity Impairment Questionnaire. Employed patients with a baseline RA-WIS score ⩾10, indicating medium to high risk for job loss, were included (OPTIMA, n = 320; PROWD, n = 124). RESULTS: Patients receiving ADA + MTX in OPTIMA had significantly greater improvements in RA-WIS compared with PBO + MTX (mean change -7.22 vs -5.23, respectively). Significantly higher percentages of patients in the ADA + MTX group experienced improvements in one or more risk category (58 vs 47%) and ⩾5 (55 vs 43%), ⩾7 (47 vs 35%) and ⩾9 (42% vs 26%) points in their RA-WIS score. These trends were seen in PROWD but were not significant. In OPTIMA, patients receiving ADA + MTX showed significant changes in percentage points from baseline vs PBO + MTX in activity impairment, presenteeism and overall work impairment (-32.0 vs -23.7, -24.6 vs -17.1, -27.3 vs -18.3, respectively). CONCLUSIONS: Among early RA patients with elevated risk of employment loss, ADA + MTX therapy was associated with a significant reduction in work instability vs PBO + MTX. Significantly greater percentages of patients receiving ADA + MTX therapy achieved clinically meaningful improvements in their RA-WIS scores.
27165179 Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patient 2017 Jan OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.
26555431 Incidence and complications of interstitial lung disease in users of tocilizumab, rituxima 2015 Nov 11 INTRODUCTION: Interstitial lung disease (ILD) is a common extra-articular condition in rheumatoid arthritis (RA), but few studies have systematically investigated its incidence and risk factors in patients receiving anti-tumor necrosis factor-alpha (anti-TNFα) agents or alternate mechanisms of action (MOAs) (e.g., T-cell, B-cell, and interleukin-6 inhibitors). METHODS: RA patients at least 18 years old were selected from the MarketScan databases (2010-2012) if they had at least one prescription/administration of abatacept, rituximab, tocilizumab, or anti-TNF after having discontinued a different biologic agent and meeting enrollment criteria. Cox models estimated the risk of incident ILD and ILD-related hospitalization. Sensitivity analyses used an alternate ILD case definition. RESULTS: We identified 13,795 episodes of biologic exposure in 11,219 patients. Mean (standard deviation) follow-up was 0.7 (0.5) years. Patients receiving alternate MOA agents were more likely to have had recent exposure to steroids, prior exposure to a greater number of biologics, and history of ILD, anemia, chronic obstructive pulmonary disease, and other pulmonary conditions. When the sensitive definition was used, unadjusted ILD incidence rates (95% confidence interval, or CI) ranged from 4.0 (1.6-8.2, abatacept) to 12.2 (5.6-23.2, infliximab) per 1000 person-years. Being older (hazard ratio (HR) 3.5; 95% CI 2.1-6.0), being male (HR 3.1; 95% CI 1.2-8.4), and having another pulmonary condition (HR 4.8; 95% CI 1.7-13.7) were associated with increased ILD incidence in either sensitive and/or specific models. There were no significant differences by biologic class. Hospitalization rates (95% CI) when the sensitive definition was used ranged from 55.6 (6.7-200.7, tocilizumab) to 262.5 (71.5-672.2, infliximab). In Cox models, recent methotrexate exposure was associated with reduced ILD hospitalization (HR 0.16; 95% CI 0.06-0.46), whereas being male (HR 2.5; 95% CI 1.3-4.8) and having had a hospitalization for asthma (HR 3.4; 95% CI 1.2-9.8) or ILD/pneumonia (HR 2.3; 95% CI 1.1-4.7) in the 12 months prior to index were associated with increased hospitalization risk. CONCLUSIONS: There were no significant differences in the risk of ILD and its related complications between RA patients receiving anti-TNFα agents and those receiving alternate MOA agents. Further studies are needed that account for differences in baseline characteristics in order to fully evaluate the risk of ILD and its complications.
25684762 Sustained Remission in Tumor Necrosis Factor Inhibitor-treated Patients with Rheumatoid Ar 2015 May OBJECTIVE: To study frequency, possible baseline predictors, timing, and duration of sustained remission [SR; defined as 28-joint Disease Activity Score (DAS28) < 2.6 for at least 6 mos] in patients with established rheumatoid arthritis (RA) treated with different tumor necrosis factor (TNF) inhibitors [etanercept (ETN), infliximab (IFX), adalimumab (ADA)]. In addition, the aim was to compare (head-to-head) the effectiveness of individual drugs in patients receiving their first anti-TNF treatment. METHODS: All anti-TNF-treated patients with RA included in the observational South Swedish Arthritis Group register were eligible. We identified the patients' first SR periods (time between first visit after treatment initiation with DAS28 < 2.6 and subsequent visit with DAS28 ≥ 2.6). Baseline predictors of SR in biologic-naive patients were studied using multivariate regression models. Remission duration and timing of remission start was estimated with Kaplan-Meier curves. RESULTS: Of the 2416 patients included, 382 (15.8%) fulfilled the criteria for SR. Median estimated duration of SR was 5.25 years. Predictors for SR were male sex, low Health Assessment Questionnaire, low DAS28, methotrexate (MTX) treatment, and the calendar year of treatment start. OR for achieving SR within the first 12 months of treatment were 1.86 for ETN (95% CI 1.33-2.61) compared to IFX. HR for 4 years of SR were 1.32 for ETN (95% CI 1.01-1.74) and 1.84 for ADA (95% CI 1.23-2.78), with IFX as the reference drug. CONCLUSION: SR was uncommon in patients with RA treated with anti-TNF in clinical practice. However, patients remained in SR for a substantial period of time. Concomitant MTX treatment predicts remission. ETN and ADA were more likely in reaching SR.