The Contribution of Drugs and Helicobacter pylori to Gastric Mucosa Changes in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

BACKGROUND: The nature and rate of gastric mucosal (GM) damage in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) remain to be among the unsolved problems. OBJECTIVE: To define the role of H. pylori and drugs in the development of GM damages in SLE and APS. METHODS: A study was conducted on 85 patients with SLE and APS. All the patients underwent esophagogastroduodenoscopy with targeted biopsy of the mucosa of the gastric body and antrum. The presence of H. pylori in the gastric biopsy specimens was determined using polymerase chain reaction. RESULTS: Endoscopic examination revealed that the patients with SLE and APS on admission had the following GM changes: antral gastritis (82.4%), erosions (24.7%), hemorrhages (8.2%), and pangastritis (8.2%). SLE and APS patients showed no direct correlation between the found GM damages and the presence of H. pylori. The use of glucocorticoid, low-dose acetylsalicylic acid, nonsteroidal anti-inflammatory drug, and anticoagulant in SLE and APS patients is accompanied by GM damage. CONCLUSION: There was no evidence of the role of H. pylori in GM damage in the SLE and APS patients. More frequent detection of H. pylori was observed in anticoagulants or low-dose acetylsalicylic acid users than in glucocorticoids and nonsteroidal anti-inflammatory drugs ones.

Maintenance of remission with combination etanercept-DMARD therapy versus DMARDs alone in active rheumatoid arthritis: results of an international treat-to-target study conducted in regions with limited biologic access.

In this transglobal, randomized, double-blind, placebo-controlled, treat-to-target study, the maintenance of efficacy was compared between biologic-and biologic-free-disease-modifying antirheumatic drug (DMARD) combination regimens after low disease activity (LDA) was achieved with biologic DMARD induction therapy. Patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy received open-label etanercept 50 mg subcutaneously once weekly plus methotrexate with or without other conventional synthetic (cs) DMARDs for 24 weeks. Patients achieving LDA [disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) <3.2] at week 24 were randomized to receive etanercept-methotrexate combination therapy or placebo-methotrexate combination therapy, with or without other csDMARDs, for 28 weeks. In the open-label period, 72% of patients achieved DAS28-ESR LDA at week 24. Patients enrolled in the double-blind period had long-standing rheumatoid arthritis and high disease activity at baseline (mean duration, 8.1 years; DAS28-ESR, 6.4). In the etanercept and placebo combination groups, 44% versus 17% achieved DAS28-ESR LDA and 34 versus 13% achieved DAS28-ESR remission at week 52 (p < 0.001). Adverse events were reported in 37 and 43%, serious adverse events in 0 and 4%, and serious infections in 0 and 2% in these groups, respectively, in the double-blind period. After induction of response with etanercept combination therapy following a treat-to-target approach in patients with long-standing rheumatoid arthritis and high disease activity at baseline, the etanercept combination regimen was significantly more effective in maintaining LDA and remission than a biologic-free regimen. ClinicalTrials.gov identifier. NCT01578850.

The Effects of Rituximab on Lipids, Arterial Stiffness and Carotid Intima-Media Thickness in Rheumatoid Arthritis.

The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (СVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI - reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD.

Cardiovascular effects of methotrexate in rheumatoid arthritis revisited.

Cardiovascular events such as myocardial infarction (MI) and stroke due to enhanced inflammatory atherosclerosis account for increased premature mortality in rheumatoid arthritis (RA). Accumulated evidence suggests that accelerated atherosclerosis and related cardiovascular comorbidities in RA are confounded not only by traditional risk factors (TRF) but also by a number of immune and inflammatory pathways. Since chronic inflammation and autoimmune disorders play a key role in atherosclerosis and related cardiovascular complications in RA, effective suppression of systemic inflammation can be viewed as a strategy for cardiovascular therapy and prevention in this disease. This article overviews some mechanisms of action of methotrexate on TRF, clinical and subclinical manifestations of RA-induced atherosclerosis, and related cardiovascular morbidity and mortality.

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA. METHODS: This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety. RESULTS: 148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study--ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies. CONCLUSION: Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance. TRIAL REGISTRATION: Clinicaltrials.gov NCT01484561. Registered 30 November 2011.

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). OBJECTIVE: This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo (part A). An interim analysis after part A would determine whether the dose-finding part (part B) would be performed. METHODS: In part A, eligible methotrexate (MTX)-refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. RESULTS: The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. CONCLUSIONS: This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.

Access to biologic treatment for rheumatoid arthritis in Central and Eastern European (CEE) countries.

BACKGROUND: The aim of this study was to assess and compare patients' access to biologic anti-RA drugs in selected Central and Eastern European (CEE) countries and to analyze the determinants of differences between countries. MATERIAL/METHODS: This is a multi-country survey study, based on a combination of desk research and direct contact with national RA stakeholders. Data was collected using a pre-defined questionnaire. Affordability was measured using an affordability index, calculated comparing the index of health care expenditures to the price index, using Poland as an index of 1. RESULTS: The percentage of patients on biologic treatment in 2009 was highest in Hungary (5% RA patients on biologic treatment), followed by Slovenia (4.5%), Slovakia (3.5%), Czech Republic (2.92%), Romania (2.2%), Estonia (1.8%), and Croatia, Serbia, Poland (below 1.5%). Infliximab, etanercept, adalimumab and rituximab were included in the reimbursement system in all countries, but abatacept and tocilizumab were included only in Slovakia. In Slovenia, public payer covered 75% of the price, and 25% is covered by supplementary health insurance; in Bulgaria public payer covered 50% of etanercept and adalimumab costs, and 75% of rituximab cost. In other countries, biologic drugs are reimbursed at 100%. Affordability index for biologic drugs was the lowest in Slovenia (0.4). In each country national guidelines define which patients are eligible for biologic treatment. Disease Activity Score (DAS28) of over 5.1 and failure of 2 or more disease-modifying anti-RA drugs, including methotrexate, are commonly used criteria. CONCLUSIONS: The most important factors limiting access to biologic anti-RA treatment in the CEE region are macroeconomic conditions and restrictive treatment guidelines.

Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study.

OBJECTIVE: To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS: A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS: At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION: Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

Gastroduodenal safety and tolerability of lumiracoxib compared with Ibuprofen and celecoxib in patients with osteoarthritis.

OBJECTIVE: To compare the incidence of gastroduodenal ulcers in patients with osteoarthritis (OA) treated with therapeutic doses of the novel COX-2 selective inhibitor, lumiracoxib (COX189, Prexige), and the standard nonsteroidal antiinflammatory drug (NSAID) ibuprofen. The COX-2 selective inhibitor celecoxib was included as an active control. METHODS: In this randomized, multicenter, double-blind, parallel-group study, eligible patients were randomized to receive lumiracoxib 200 mg (n = 264) or 400 mg (n = 260) once daily (qd), ibuprofen 800 mg (n = 260) 3 times daily (tid), or celecoxib 200 mg qd (n = 258) for 13 weeks. The incidence of gastroduodenal ulcers and erosions was determined by endoscopy prior to randomization, and after 4 weeks and 13 weeks of treatment (end of study). Frequencies of adverse events were also recorded. RESULTS: The cumulative incidence of gastroduodenal ulcers >/= 3 mm in diameter was significantly lower in the lumiracoxib groups (200 mg: 4.3%; 400 mg: 4.0%) than in the ibuprofen group (15.7%; p < 0.001) and similar to the celecoxib group (3.2%). In the ibuprofen group, a significantly greater number of patients (6.0%) had > 10 gastroduodenal erosions compared with lumiracoxib 200 mg (1.2%; p < 0.01), lumiracoxib 400 mg (1.6%; p < 0.05), and celecoxib (2.4%; p < 0.05). A greater number of patients in the ibuprofen group discontinued treatment due to an adverse event compared with both lumiracoxib groups and the celecoxib group. CONCLUSION: In patients with OA, lumiracoxib 200 mg or 400 mg qd was associated with a significantly lower risk of gastroduodenal ulceration than ibuprofen 800 mg tid, and was similar to celecoxib 200 mg qd.