Therapy In Rheumatoid Arthritis Patients Research Articles

Procollagen III amino terminal propeptide (PIIINP): A non invasive marker of methotrexate induced liver fibrosis in Rheumatoid arthritis patients

Abstract Background Rheumatoid Arthritis (RA) is a common autoimmune disease with a complex pathogenesis involving multiple genetic and environmental factors. The management of RA rests on several principles. Drug treatment, which comprises disease-modifying antirheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs and glucocorticoids (GCs), as well as non-pharmacological measures, such as physical, occupational and psychological therapeutic approaches, together may lead to therapeutic success. However, the mainstay of RA treatment is the application of DMARDs. Methotrexate is an antifolate and antimetabolite; it’s one of the DMARDs. Long term therapy with methotrexate has been associated with development of fatty liver and hepatic fibrosis. Liver biopsy is the standard method for diagnosing liver fibrosis, but it may be associated with significant morbidity and mortality of up to 0.33% thereby limiting its use. So the use of noninvasive markers of hepatic fibrosis such as serial platelet counts, FIB 4 score, ALT/AST ratio and recently serum PIIINP become mandatory. Objectives to evaluate the reliability of PIIINP in the screening for hepatic fibrosis induced by long term methotrexate therapy in rheumatoid arthritis patients compared with FIB 4 score and ALT/AST ratio. Patients and Methods This case study included 90 RA patients categorized into 60 RA patients on MTX therapy (group I), 30 RA patients on other medications (group II). All participants were subjected to full history taking, thorough rheumatological examination and lab investigations including complete blood count (CBC), ESR, CRP, AST, ALT, RF and measurement of serum PIINP levels, DAS and FIB-4 score were calculated. Results Patients in group I showed significant increase in serum PIIINP compared to patients in group II. There was significant negative correlation between disease duration, Platelets count and serum PIIINP levels in patients of both groups. There was significant negative correlation between folic acid intake and serum PIIINP levels of group I. There was significant positive correlation between Mean Corpuscular Volume, AST, ALT, AST/ALT ratio, FIB-4 score and serum PIIINP levels in patients of both groups. There was significant positive correlation between MTX dose and duration and levels of serum PIIINP in patients of group I. Conclusion Serum PIIINP levels could be used as non invasive marker for screening for hepatic fibrosis induced by long term MTX therapy in RA patients.

Circulating IFN-γ producing CD4+ T cells and IL-17A producing CD4+ T cells, HLA-shared epitope and ACPA may characterize the clinical response to therapy in rheumatoid arthritis patients

This study analyzed the association between peripheral distributions of helper T cell subsets, HLA shared-epitope (SE), anti-cyclic citrullinated peptide antibody (ACPA) and clinical response to therapy in rheumatoid arthritis (RA) patients. Frequencies of IFN-γ-producing CD4+T (Th1) and IL-17A-producing CD4+T (Th17) cells were determined by flow cytometry in 167 patients (114 cases with good-response (GR) and 53 poor-response (PR) based on DAS28). HLA-DRB1 alleles for patients and 150 healthy controls were determined by PCR-SSP. We observed that 65.2% of RA patients were SE+, 63.4%ACPA+, 43.7%SE+ACPA+ and 14.9% were SE−ACPA−. Higher significantly proportions of Th1 and Th17 cells were found in RA patients than controls (P < 0.05) as well as in the SE+ or ACPA+RA patients compared to SE− and ACPA− patients. Increased frequencies of both Th subsets were found in SE+ACPA+ versus SE−ACPA− patients (P < 0.001) and in the PR versus GR group (P < 0.001). We showed significant differences for Th cells frequencies between SE+ and SE− patients in both groups, and between ACPA+ and ACPA− cases in the PR group. Our findings suggest a close link between Th1 and Th17 cells proportions and HLA-SE/ACPA in the RA patients and remarkably in the PR group which could be indicative for the importance of immune monitoring for evaluation of response to therapy.

Manual Therapy (Postisometric Relaxation and Joint Mobilization) in Knee Pain and Function Experienced by Patients with Rheumatoid Arthritis: A Randomized Clinical Pilot Study.

Objectives The purpose of this study was to evaluate the impact of manual therapy on the management of rheumatoid arthritis (RA) patients with knee pain. Materials and Methods This was a small, randomized clinical pilot study. Subjects were 46 patients with diagnosed RA, randomly assigned to the manual therapy group (postisometric relaxation and joint mobilization) or control group (standard exercise). Subjects in each group had 10 sessions of interventions, once a day with one day break after the sixth day. Outcomes included the pain intensity of knee, Knee Society Score, Oxford Knee Score, and Health Assessment Questionnaire. Results There were no statistically significant differences between groups, except for the pain intensity of the knee. Conclusions This study suggests that manual therapy (postisometric relaxation and joint mobilization) may have clinical benefits for treating knee pain and function in rheumatoid patients. Further extended studies are expected to determine the effectiveness of manual therapy in RA patients with knee pain.

&lt;p&gt;Efficacy and Safety of Umbilical Cord Mesenchymal Stem Cell Therapy for Rheumatoid Arthritis Patients: A Prospective Phase I/II Study&lt;/p&gt;

BackgroundThe traditional anti-inflammation disease-modifying anti-rheumatic drugs (DMARDs) have limited therapeutic effects in rheumatoid arthritis (RA) patients. We previously reported the safety and efficacy of umbilical cord mesenchymal stem cell (UC-MSC) treatment in RA patients that were observed for up to 8 months after UC-MSC infusion. The aim of this study is to assess the long-term efficacy and safety of UC-MSC along with DMARDs for the treatment of RA.Methods64 RA patients aged 18–64 years were recruited in the study. During the treatment, patients were treated with 40 mL UC-MSC suspension product (2 × 107 cells/20 mL) via intravenous injection immediately after the infusion of 100 mL saline. The serological markers tests were used to assess safety and the 28-joint disease activity score (DAS28) and the Health Assessment Questionnaire (HAQ) to assess efficacy.Results1 year and 3 years after UC-MSC cells treatment, the blood routine, liver and kidney function and immunoglobulin examination showed no abnormalities, which were all in the normal range. The ESR, CRP, RF of 1 year and 3 years after treatment and anti-CCP of 3 years after treatment were detected to be lower than that of pretreatment, which showed significant change (P < 0.05). Health index (HAQ) and joint function index (DAS28) decreased 1 year and 3 years after treatment than before treatment (P < 0.05).ConclusionUC-MSC cells plus DMARDs therapy can be a safe, effective and feasible therapeutic option for RA patients.

Clinical effectiveness and safety of additional administration of tacrolimus in rheumatoid arthritis patients with an inadequate response to abatacept: A retrospective cohort study.

Abatacept (ABT) demonstrates good clinical efficacy and retention in rheumatoid arthritis (RA) patients. However, no rescue treatment option against inadequate response to ABT exists. Since tacrolimus (TAC) and ABT suppress T lymphocytes via different mechanisms and a combination of these agents could potentially be effective, this study aimed to examine the efficacy and safety of add-on TAC therapy in RA patients with inadequate response to ABT. Of 550 patients treated with ABT and registered in a Japanese multicenter registry, 25 consecutive patients who underwent add-on TAC therapy and were followed for longer than 24weeks were included in this study. Mean patient age was 67.0years, disease duration was 16.2years, and duration of ABT treatment was 1.2years at the initiation of add-on TAC therapy. Mean TAC dose was 1.2mg/d at baseline and 1.6mg/d at week 24. Mean Disease Activity Score of 28 joints - erythrocyte sedimentation rate was significantly improved at week 24 (3.35) relative to baseline (4.97). The proportion of patients who achieved low disease activity or remission was 40.0%, and the European League Against Rheumatism moderate or good response was 72.0%. ABT retention rate was 92.0% at week 24, as calculated by Kaplan-Meier analysis. Only one patient discontinued add-on TAC therapy due to an adverse event (itching sensation). This is the first report describing the efficacy and safety profile of add-on TAC therapy with a focus on RA patients with inadequate response to ABT. Our findings suggest that add-on TAC therapy is a worthwhile complementary treatment option in daily clinical practice.

The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients

The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients

Evaluation of rituximab therapy in real clinical practice (according to the OREL registry of patients with rheumatoid arthritis

Objective:to analyze therapy with rituximab (RTM) in real clinical practice according to the data available in OREL registry of patients with active rheumatoid arthritis (RA).Subjects and methods. The analysis included 349 patients. All the patients received RTM: 340 – the original drug (MabThera®) and 9 – the biosimilar Acellbia®. 263 patients (75.4%) received RTM in combination with disease-modifying anti-rheumatic drugs (DMARDs) and 86 (24.6%) – RTM as monotherapy.Results and discussion. Of the 349 patients included in the analysis, 272 (77.9%) patients received RTM as the first biologic agent (BA) (263 patients were treated with the original drug and 9 – with the biosimilar) and 77 (22.1%) patients had previously used the BA. The majority of patients (n=205 (58.7%)) received three or more; 109 (31.2%) patients – one, and 35 (10%) – two RTM courses of RTM therapy. RTM caused a significant reduction in disease activity just after the first therapy course and in the levels of acute-phase reactants (C-reactive protein (CRP) and ESR); after the fifth therapy course, median CRP concentration decreased by 1.4 times and amounted to 7 [1.2; 17.9] mg/l and that of ESR reduced by 1.8 times and was 10 [5; 20] mm/hr (p&lt;0.05).Conclusion.The analysis of RTM therapy in RA patients in real clinical practice demonstrated that in most cases RTM was given as the first BA, in combination with DMARDs, the main agent of which was methotrexate. The use of RTM was accompanied by a significant reduction in disease activity and in the serum levels of acute-phase reactants and autoantibodies.

Comparative evaluation of denosumab efficacy of in patients with rheumatoid arthritis and postmenopausal osteoporosis: results of 1-year study in clinical practice

Objective: to assess bone mineral density (BMD) changes in rheumatoid arthritis (RA) patients with osteoporosis (OP) and in women with postmenopausal OP during therapy with denosumab (DSB) for 1 yearSubjects and methods. 121 women were included: the main group – 69 patients with RA (mean age – 60±7 years), 34 (49.3%) from them received glucocorticoids (GC). Comparison group comprised 52 women with primary OP (mean age – 62±10 years). Measurement of BMD using dual-energy X-ray absorptiometry (DXA) was performed in the lumbar spine (LI–IV), femoral neck (FN), proximal femur as a whole (PF) and distal forearm (DF). DSB was administered subcutaneously at a dose of 60 mg 1 time in 6 months.Results and discussion. In patients with RA, the average increase of BMD for 12 months of treatment was: in LI–IV – 4.6%, in FN-2.8%, in PF-3.0% and in DF-0.7%, and in the comparison group – 5.2; 2.1; 2.9 and 0.9%, respectively. There were no significant differences of BMD changes between the groups. Efficacy of DSB therapy in RA patients with OP did not depend on RA activity, duration of GC therapy and cumulative dose of GC. Adverse events that did not lead to the withdrawal of the drug were noted in 3% of the study participants. There were no fractures during the observation.Conclusion. The efficacy treatment with DSB for 1 year in RA patients with OP and in women with postmenopausal OP is comparable. The use of GC did not have a negative impact on DSB effect.

Occult HBV infection may negatively impact on drug survival in patients with rheumatoid arthritis on treatment with a first biologic drug. An appraisal from the Biologic Apulian Registry (BIOPURE).

We performed a retrospective analysis to evaluate the survival on first line biologic drug of rheumatoid arthritis (RA) patients with potential occult HBV infection (pOBI). We analysed longitudinal data of 486 consecutive RA patients starting a first biological drug in a time frame from 1st January 2008 to 31st December 2014. Demographic and disease related characteristics were collected at baseline and at the last observation visit. Baseline serological markers of HBV infection and causes of treatment discontinuation were also recorded. Primary endpoint was the influence of pOBI on drug survival, estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of drug discontinuation, adjusted for disease characteristics, biological drug class and HBcAb status were computed by Cox-regression models. The retention rate was significantly lower in pOBI positive patients (58.2%) when compared to pOBI negative ones (67.8%) and this data was confirmed also when only discontinuation due to ineffectiveness was considered (pOBI positive 66.4% vs pOBI negative 75.3%, long rank 7.93, p=0.005). Cox regression models showed a significant association between HBcAb-neg (HR 0.58, 0.41-0.84), higher ESR-DAS28 at baseline (HR 1.07, 1.03-1.11) or RF/ACPA-neg (HR 1.46, 1.04-2.06) and drug discontinuation. Occult HBV infection seems to influence negatively the effectiveness of biological therapies in RA patients.

Role of optical coherence tomography in the early detection of macular thinning in rheumatoid arthritis patients with chloroquine retinopathy.

Background:Chloroquine and hydroxychloroquine are drugs that are primarily used for the treatment of malaria and are also recommended for treating connective tissue disorders, autoimmune diseases, and some dermatological and inflammatory diseases. Treatment with these drugs has potential risk for the development of retinopathy, clinically characterized by bilateral pigment changes in the macula, as one serious ocular complication. The aim of this research was to evaluate the parafoveal and perifoveal macular retinal thickness, as central foveal thickness in adult patients with rheumatoid arthritis (RA) on chloroquine therapy using optical coherence tomography (OCT).Materials and Methods:In this cross-sectional study, 56 RA patients (56 eyes) were included and examined. All patients were treated with chloroquine (tablets resochin or delagil) at a dose of 250 mg/day without treatment with steroids and other immunosuppressive drugs. Patients were divided into two groups, namely, Group I patients - no visible changes in the macula (26 patients) and Group II patients- with visible changes in the macula (30 patients). The central fovea thickness and parafoveal and perifoveal retinal thickness in all quadrants were measured by OCT and compared in both groups.Results:There are a significantly higher number of eyes without thinning of the macula in Group I patients than in Group II (P < 0.001) patients. There are a higher number of patients with recorded parafoveal thinning in Group II patients, especially in the inferior, nasal, and temporal sectors, respectively (P < 0.05).Conclusion:Maculopathy is the main side effect of chloroquine therapy in RA patients that can be detected by OCT in the early stages of the macular involvement.

Adherence to etanercept therapy in rheumatoid arthritis patients during 3 years of follow-up.

ObjectivesTo determine the percentage non-adherence to etanercept in patients with rheumatoid arthritis during three years of follow-up.MethodsDuring study visits in this prospective cohort study, blood samples were taken to determine serum etanercept concentrations using ELISA and patients were asked if they had missed an etanercept dose, at which date and for what reason. Non-adherence was defined as serum etanercept concentration <0.1 μg/mL and no valid reason to miss the prescribed etanercept dose.ResultsIn total, 292 consecutive patients treated with etanercept were included. Most patients had a valid reason to miss their etanercept dose (25/37). In total 12 out of 292 patients (4.1%, 95% confidence interval 2.2–7.2) were non-adherent during the 3 year period. In a small percentage of patients (3.4%, 95% confidence interval 0.8–10.4) who failed to respond to etanercept therapy, according to their rheumatologist, this was associated with inadequate exposure to etanercept and thus non-adherence.ConclusionIn this study, adherence to etanercept therapy was measured using serum etanercept concentration. In most patients an absent etanercept concentration was due to a medical reason. Furthermore, the majority of patients were adherent to etanercept therapy and had adequate drug exposure. In total, only 12 out of 292 patients (4.1%) were non-adherent during 3 years of follow-up. These findings highlight that only a small minority of patients are non-adherent to etanercept treatment, especially compared to adherence rates of other drugs. However, physicians should be aware that in patients failing to respond to treatment, non-adherence is a possible cause.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

The role of concomitant methotrexate dosage and maintenance over time in the therapy of rheumatoid arthritis patients treated with adalimumab or etanercept: retrospective analysis of a local registry.

ObjectiveTo evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi).Patients and methodsThe study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan–Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time.ResultsA total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p=0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p=0.031).ConclusionIn a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.

Is current smoking status and its relationship to anti-cyclic citrullinated peptide antibodies a predictor of worse response to biological therapies in rheumatoid arthritis patients?

Objective: To assess the association between smoking, anti-cyclic citrullinated peptide (anti-CCP) antibody status, and clinical efficacy of biological therapies in rheumatoid arthritis (RA) patients.Method: This retrospective clinical practice setting study included 1349 RA patients from the METEOR database (aged >18 years). We collected data on sociodemographics, smoking status (smoker, <10, 10–19, and >20 cigarettes/day; ex-smoker; non-smoker), baseline disease activity parameters and anti-CCP, previous disease-modifying anti-rheumatic drugs (DMARDs), biological therapy, combined therapy (steroids and DMARDs), and follow-up disease activity. Clinical efficacy was assessed by European League Against Rheumatism (EULAR) good/moderate response rates for all aggregated biological therapies, based on both smoking and anti-CCP status.Results: The non-smoking RA patients were more often female at biological therapy initiation than the ex-smokers and smokers (91.1% vs 60.4% and 67.9%, respectively, p < 0.001), and ex-smokers were older than non-smokers and smokers (mean ± sd 56.5 ± 11.1, 53.5 ± 13.3 and 51.3 ± 11.0 years old, respectively; p < 0.001). In total, 845 (62.6%) were non-smokers, 214 (15.9%) ex-smokers, and 290 (21.5%) smokers [daily cigarettes smoked: 148 (11%) <11; 61 (4.5%) 11–20; and 81 (6%) >20]. Anti CCP-antibody status was similar in both groups. Non-smokers showed higher baseline DAS28 than ex-smokers and smokers (5.0 ± 1.5 vs 4.7 ± 1.4 and 4.7 ± 1.4, respectively; p < 0.001) and used more baseline steroids and DMARDs. A higher EULAR response rate was observed in non-smokers than in ex-smokers and smokers (73% vs 65% and 64.1%, respectively; p = 0.004). Drug survival was higher in non-smokers compared to ex-smokers and smokers [57.7 months (46.4–53.8), 38.6 (30.3–46.8), and 50.1 (41.8–58.4); p < 0.001, respectively].Conclusion: In daily clinical practice, non-smokers respond better than smokers to biological therapy, but this does not result in better drug survival.

Timing and Impact of Decisions to Adjust Disease-Modifying Antirheumatic Drug Therapy for Rheumatoid Arthritis Patients With Active Disease.

Guidelines recommend that rheumatoid arthritis (RA) patients with moderate-to-high disease activity (MHDAS) adjust disease-modifying antirheumatic drug (DMARD) therapy at least every 3 months until reaching low disease activity or remission (LDAS). We examined how quickly RA patients with MHDAS adjust DMARD therapy in clinical practice, and whether those who adjust DMARDs within 90 days in response to MHDAS reach LDAS sooner. We identified RA patients with MHDAS in the University of Pittsburgh Rheumatoid Arthritis Comparative Effectiveness Research registry, and conducted a competing risks regression on time to DMARD therapy adjustment and a Cox regression on time to LDAS. We identified 538 eligible subjects with 943.5 patient-years of followup. Sixty percent of patients with persistent MHDAS adjusted DMARDs within 90 days. Among all subjects, median times to DMARD adjustment and LDAS were 154 (interquartile range [IQR] 1-706) days and 301 (IQR 140-706) days, respectively. Being elderly (subdistribution hazard ratio [SHR] 0.61, P = 0.02), lower baseline disease activity (SHR 0.72, P < 0.01), longer duration of RA (SHR 0.98, P < 0.01), and biologic use (SHR 0.71, P < 0.01) were significantly associated with longer times to therapy adjustment. African American race (hazard ratio [HR] 0.63, P = 0.01), higher baseline disease activity (HR 0.75, P < 0.01), and not adjusting DMARD therapy within 90 days (HR 0.76, P = 0.01) were associated with longer times to LDAS. Adjusting DMARDs within 90 days was associated with shorter times to LDAS, but many patients with persistent MHDAS waited >90 days to adjust DMARDs. Interventions are needed to address the timeliness of DMARD adjustments for RA patients with MHDAS.

Application of Genetic-Engineering Biological Therapy in Rheumatoid Arthritis Patients in the Republic of Kazakhstan

The purpose of this paper is to conduct a clinical-laboratory and radiological evaluation of the combined administration of infliximab and methotrexate to rheumatoid arthritis patients. The research is based on a retrospective analysis of medical records of inpatients, who underwent treatment at the S.D. Asfendiyarov Kazakh National Medical University Department of Ambulatory-Out-Patient Therapy and the city rheumatologic centre (CRC) of Almaty. The main group was injected with infliximab and methotrexate, while the control group – with methotrexate as background therapy. The groups were comparable in terms of age-related, gender, and clinical-laboratory indicators. The research used DAS28 and its standard components and the Larsen index. It was established that the aggregate clinical-laboratory effectiveness of the combined background therapy is determined by a significantly greater reduction of the DAS28 (p&lt;0.05), and a high probability of transition from the average and high to the low level of disease activity (OR – 4.90 [2.47-9.75]), compared to monotherapy. The study proved the significant effect of infliximab and methotrexate on radiological signs of osseous lesion – erosion count (p&lt;0.05) and Larsen index (p&lt;0.05), and the high probability of prevention of osteochondral progression, compared to a mono-component background therapy (OR – 2.66 [1.42-5.01]). The combined administration of infliximab and methotrexate for rheumatoid arthritis patients has greater clinical-laboratory and radiological effectiveness, compared to background monotherapy.

TYMS polymorphisms and responsiveness to or toxicity of methotrexate in rheumatoid arthritis.

The aim of this study was to investigate whether the thymidylate synthase (TYMS) 2R/3R and 6 bpI/D polymorphisms can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). We conducted ameta-analysis of studies on the association between the TYMS 2R/3R and 6 bpI/D polymorphisms and non-responsiveness to or toxicity of MTX in RA patients. Atotal of 11studies involving 1613patients were considered. Meta-analysis showed no association between the TYMS 2R/3R 3R allele and non-responsiveness to MTX therapy (odds ratio [OR] = 1.087, confidence interval [CI] = 0.682-1.731, p = 0.726). The meta-analysis indicated that there was no association between the TYMS 6 bpI/DD allele and non-responsiveness to MTX therapy (OR = 0.688, 95% CI = 0.281-1.683, p = 0.413). Meta-analysis revealed that the TYMS 2R/3R polymorphism was not associated with MTX toxicity, except for in aco-dominant model, and the TYMS 6 bpI/D polymorphism was not associated with MTX toxicity in all genetic models. This meta-analysis demonstrates that the TYMS 2R/3R and 6 bpI/D polymorphisms may not be associated with non-responsiveness to or toxicity of MTX therapy in RA patients.

Analiza povezanosti 174G/C interleukin 6 polimorfizma i terapeutskog odgovora na metotreksat u reumatoidnom artritisu

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with IL-6 as a main mediator of systemic and localized inflammation. The most often used drug for the treatment of RA is methotrexate (MTX). Aim: To explore if there is an association between the 174G/C polymorphism in IL6 gene and response to methotrexate therapy in RA patients. Materials and Methods: Study has included 131 RA patients treated and followed at the Institute of Rheumatology in Belgrade. Clinical response to the MTX therapy was conducted following the EULAR response criteria. Each patient's DNA was isolated by salting-out method. For each patient IL6 174G/C polymorphism genotype was determined by allele specific PCR method. For statistical analyses we have used SPSS program version 17.0. Results: According to EULAR response criteria 103 (78.6 %) patients were responders 12(9.2 %) good and 91 (69.5 %) moderate response) and 28 (21.4 %) were non responders. Among all patients in 47 (35.9 %) we have detected GG genotype, in 69 (52.7 %) GC genotype and in 15 (11.5 %) CC genotype. We have observed no association between genotypes or alleles and response to MTX therapy. Conclusion: No association of -174G/C IL-6 polymorphism and therapeutic response to MTX in RA patients in Serbian population was observed.

Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan

Objectives: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs).Methods: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs.Results: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24.Conclusions: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

Optimization of biological therapy in rheumatoid arthritis patients: outcomes from the CREATE registry after 2 years of follow-up.

Dose optimization was 20-50% of the standard dose. Outcome measurement were effectiveness (percentage of patients who continued to meet criteria for clinical remission) and efficiency (dose reduction and mean savings). Sixty-eight patients with RA were optimized, with initial mean DAS28 of 2.2±0.7. After 2years of follow-up, the mean DAS28 was 2.4±0.7, a non-statistically significant difference. Twenty-eight patients (41.2%) continued in clinical remission with dose optimization after 2years. Mean survival time was 14.2months (95% CI 12.0-16.5). Of the 40 patients who needed to return to a standard dose, 57.5% managed to achieve remission again at 2years. Mean dose reduction at 2years was 21.17%, reaching a mean saving of €5576±5099 per patient. In actual clinical practice, over 40% of patients with established RA who had been in sustained clinical remission managed to continue in remission 2years after receiving optimized doses. The savings achieved was about 21% of the actual direct health costs for patients in the CREATE registry.