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ID PMID Title PublicationDate abstract
23703358 Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis 2013 Sep This study aims to investigate the use of biological disease-modifying antirheumatic drugs (bDMARDs) as monotherapy in patients with rheumatoid arthritis (RA) in "real world" clinical settings and to compare tumor necrosis factor (TNF) inhibitors and tocilizumab monotherapy in terms of efficacy and patient and clinician satisfaction with treatment. This study made use of a retrospective, cohort-19 based study including included data from 254 patients (TNF inhibitors n = 128; tocilizumab n = 126) managed in 30 centers throughout Germany. Efficacy of monotherapy and patient and physician overall satisfaction with treatment were assessed at baseline, 3, and 6 months of monotherapy using a range of measures including Disease Activity Score 28 joint (DAS28), swollen joint count (SJC) and tender joint count (TJC), and visual analogue scales (VAS). Between 18 and 41 % of patients treated with bDMARDs received the agent as monotherapy. Intolerance to DMARDs, contraindications for combination therapy, and comorbidities were the most common reasons for introduction of bDMARD monotherapy. Mean DAS28 (erythrocyte sedimentation rate, ESR) was significantly lower at 3 and 6 months following tocilizumab vs. TNF inhibitors (p ≤ 0.001). Joint counts improved from baseline to month 6 in both groups (SJC -5.1 vs. -3.7 and TJC -5.6 vs. -5.1, for tocilizumab and TNF inhibitors, respectively). Patient as well as physician satisfaction (VAS 100 mm scale) was significantly higher for tocilizumab vs. TNF inhibitors (75.3 vs. 66.8; p = 0.001 and 74.9 vs. 67.1, p = 0.003, respectively). Significantly more patients remained on tocilizumab monotherapy vs. TNF-inhibitor monotherapy (89.7 vs. 75.8 %; p < 0.01). Monotherapy with bDMARDs is common in routine clinical practice. Tocilizumab monotherapy appeared to be superior over TNF-inhibitor monotherapy with respect to DAS28 and drug adherence.
25756476 TNF-inhibitor induced lupus in a patient treated with adalimumab for rheumatoid arthritis. 2014 Dec 13 Anti-tumor necrosis factor induced lupus (ATIL) is a rare side effect reported in patients treated with anti-tumor necrosis factor medications such as infliximab, etanercept and adalimumab. Of the three, this condition has been least commonly reported secondary to adalimumab. In this report, we present a case of ATIL in a patient treated for rheumatoid arthritis (RA) with adalimumab. This report will increase physician awareness of the warning signs, diagnostic options and potential complications of ATIL. In this patient, adalimumab was discontinued and treatment was started, leading to improvement in the patient's status.
24923411 Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kin 2014 Jun 12 INTRODUCTION: Acid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS). METHODS: Experiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay. RESULTS: Acidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS. CONCLUSIONS: Decreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage.
25046458 Cutaneous erosions: a herald for impending pancytopenia in methotrexate toxicity. 2014 Jul 15 Psoriatic plaque erosion is a rare toxic side effect of low-dose methotrexate (LDMTX) that has been reported during the treatment of psoriasis and described as a herald for impending pancytopenia. Fatalities from this have rarely been reported. Even rarer is methotrexate (MTX)-induced erosions of clinically normal skin in patients without a history of psoriasis. We report 3 rare presentations of MTX-induced cutaneous erosions, 2 fatalities occurring with MTX-induced psoriatic plaque erosions, and the sixth reported case of MTX-induced erosions with no prior history of psoriasis. Each were elderly patients on proton pump inhibitors with a history of chronic non-steroidal anti-inflammatory drug (NSAID) use. They all presented with acute onset of erosions after a recent change in their MTX dose. Pancytopenia followed in each case. Physicians' awareness of the sequelae in MTX-induced cutaneous erosions is imperative so MTX can be discontinued and treatment instituted to prevent fatal bone marrow suppression.
24930648 Clinical features of pulmonary aspergillosis associated with interstitial pneumonia. 2014 OBJECTIVE: We retrospectively investigated the clinical features of pulmonary aspergillosis associated with interstitial pneumonia. METHODS: We reviewed the medical records of all patients treated for interstitial pneumonia with or without pulmonary aspergillosis at our institution between April 2006 and August 2012 and evaluated the clinical features as well as risk and prognostic factors for pulmonary aspergillosis associated with interstitial pneumonia. RESULTS: Among 539 patients with interstitial pneumonia, 15 who suffered from pulmonary aspergillosis were identified. The median age was 69.2±7.0 years, and fourteen patients were men. The subtypes of pulmonary aspergillosis were chronic pulmonary aspergillosis (n=14) and invasive pulmonary aspergillosis (n=1). The forms of interstitial pneumonia included idiopathic pulmonary fibrosis (n=9), rheumatoid arthritis-related interstitial pneumonia (n=4) and pleuroparenchymal fibroelastosis (n=2). The underlying conditions were emphysema (n=9) and a history of oral corticosteroid and/or immunosuppressive use (n=4). Home oxygen therapy (HOT) was administered in 11 patients. Following the diagnosis of pulmonary aspergillosis, all patients were treated with antifungal drugs. Ten patients (66.6%) died. A comparison of the interstitial pneumonia patients with and without pulmonary aspergillosis showed that the presence of emphysema, use of HOT and death were significantly associated with pulmonary aspergillosis. CONCLUSION: Pulmonary aspergillosis is one of the major complications of interstitial pneumonia and its prognosis is poor. Therefore, providing careful monitoring and proper treatment is extremely important.
24431398 Effectiveness of TNF inhibitor switch in RA: results from the national Swedish register. 2015 May BACKGROUND: Switching to a second tumour necrosis factor inhibitor (TNFi) after discontinuation of a first in rheumatoid arthritis (RA) is a common strategy. The reason for the switch from the first TNFi could potentially influence the response to therapy. Data on direct comparisons between TNFi after switching are limited. METHODS: The national Swedish register was used. RA patients who switched to a second TNFi (infliximab, etanercept or adalimumab) after failure of a TNFi as first-ever biologic were identified. Effectiveness of treatment was compared across the three drugs according to the first TNFi used, the reason for discontinuing and the drug survival. Drug survival across TNFi used as second biologic was compared. RESULTS: Half of all patients starting infliximab, adalimumab or etanercept during the period 2005-2012 discontinued treatment for various reasons. Of these patients, a third switched within 2 months to a second TNFi (infliximab, etanercept or adalimumab). Around 35% of all patients achieved low disease activity or remission at 6 months. Regarding the switching strategy, best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as second TNFi was associated with longer drug survival compared with infliximab. CONCLUSIONS: Switching to a second TNFi after the failure of the first may lead to good clinical results. The inter-drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi, suggesting that these differences are not solely due to channelling bias.
23335701 [Anticitrulin antibody and the extra-articular manifestations in rheumatoid arthritis]. 2013 A large proportion of rheumatoid arthritis (RA) patients develop extra-articular manifestations (EAM), which are associated with morbidity and early mortality. Anti cyclic citrullinated peptide (ACCP) antibody has proven to be highly specific for the diagnosis of RA, associated with severe joint damage and may have some role in the pathogenesis of EAM. The aim of this study was to determine the relationship between ACCP antibody and the presence of EAM in RA patients. Seventy four RA patients (ACR 1987) with EAM, > 18 years, more than 6 months duration were included, and an EAM free control, matched by sex and age, for each patient. Demographic, clinical and laboratory variables were compared using t-test, chi-square or Mann-Whitney test. Multivariate analysis was performed: p = 0.05. Patients with EAM presented a greater value of ACCP antibody (116 vs. 34, p < 0.01) and rheumatoid factor (108 vs. 34.5, p < 0.01). Independent association with current smoking habit (p = 0.02, OR = 3.78, 95%: 1.17-12.2), RF positive (p = 0.04, OR 3.23, CI 95%: 1.04 to 11.8) and ACCP antibody positive (p = 0.04, OR 3.23, 95% CI: 1.04-10) was found. The patients with xerostomia (109 vs. 34, p = 0.04), xerophthalmia (150 vs. 34, p < 0.01), subcutaneous nodules (141 vs. 34, p < 0.01) and pulmonary fibrosis (158 vs. 34, p = 0.04) had a higher degree of the ACCP antibody, than controls. In conclusion, ACCP antibody positive, RF positive and smoking were independent risk factors for the development of MEXA.
23819333 [The magnitude of fatigue and its association with depression, pain, and inflammatory acti 2013 AIM: To analyze the rate of clinically significant fatigue and to search for its predictors in patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation included 95 patients with a valid RA diagnosis. The majority of the patients were women (87.4%); mean age was 46.7 +/- 1.2 years; mean disease duration was 135.5 +/- 11.6 months. The authors evaluated RA activity by the Disease Activity Score (DAS28), magnitude of fatigue by the Fatigue Severity Scale (FSS), that of pain by the Brief Pain Inventory, and functional status and quality of life by the Health Assessment Questionnaire and EQ-5D. A psychiatrist diagnosed mental disorders in accordance with ICD-10 and using the psychiatric and psychological scales and procedures. RESULTS: 80% of the patients felt clinically significant fatigue (FSS scores of > or = 4). Multivariate analysis yielded a prognostic model that made it possible to state that clinically significant fatigue was primarily associated with the magnitude of depression by the Hospital Anxiety and Depression Scale, the presence of a depressive episode, the duration of anxiety and depressive spectrum, the magnitude of pain (Ritchie index), DAS28, and the presence of osteoporosis. CONCLUSION: The presence and magnitude of depression along with the magnitude of pain are an important factor that influences the formation of fatigue in RA, which gives rise to evident functional failure and a low quality of life. Combination therapy for RA may be effective when mental disorders, mainly the anxiety and depressive spectrum, are timely diagnosed.
24907157 The reliability of a novel magnetic resonance imaging-based tool for the evaluation of for 2014 Nov OBJECTIVE: The aim of this study was to determine the reliability of an MRI-based score that evaluates forefoot bursae (FFBs) in patients with RA. METHODS: Items for inclusion, grading criteria and MRI sequences were determined iteratively. The score was evaluated in 30 patients with established RA. Reader agreement was evaluated using the percentage of exact/close agreement, Bland-Altman plots, kappa and intraclass correlation coefficient analyses. RESULTS: The FFB score assesses nine forefoot regions and contains four items: presence, shape, enhancement and magnetic resonance characteristics. The FFB score showed moderate to good intra- and interreader agreement (κ range = 0.5-0.9 and 0.47-0.87, respectively). CONCLUSION: The FFB score is adequately reliable in the evaluation of bursa-like lesions of the forefoot in patients with RA.
24503329 Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m anti-CD4-mAb fragme 2014 Apr PURPOSE: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99m labelled murine anti-human CD4 IgG1-Fab fragment ([(99m)Tc]-anti-CD4-Fab, [(99m)Tc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. METHODS: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24h after application of 550 ± 150 MBq [(99m)Tc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. RESULTS: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. CONCLUSION: Scintigraphy with [(99m)Tc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [(99m)Tc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake.
23793310 Effect of fibromyalgia on bone mineral density in patients with fibromylagia and rheumatoi 2013 Apr OBJECTIVES: Fibromyalgia (FM) may t cause a decrease in bone mineral density (BMD) because of decreased mobility. The condition is relatively frequent in rheumatoid arthritis (RA) and RA patients with FM have more disability than those without FM. We evaluated the effect of FM on BMD and investigated the effect of FM on BMD in RA patients. MATERIALS AND METHODS: We included age-matched 56 FM, 52 RA patients, and 37 healthy females as controls. Twenty three of all RA subjects met 1990 ACR FM criteria. Patients using the antiresorptive drugs, those on hormone replacement therapy, patients with thyroid or parathyroid dysfunction were excluded. Self-reported pain and fatigue severity, functional items of FM impact questionnaire were questioned in FM and RA patients. In all subjects, BMD of the lumbar spine and femur neck were determined by dual X-ray absorptiometry, and T-scores were recorded. RESULTS: Self-reported pain and fatigue scores in FM subjects were significantly higher than in RA patients (P<0.001). The mean lumbar spine and femur neck BMD and their T-scores in RA patients were significantly lower than in FM and control groups (P values<0.01). There was no difference in BMD between FM subjects and the control group. BMD in RA patients with and without FM were similar (P>0.05). There was a significant negative correlation between self-reported pain score and lumbar spine BMD in FM subjects (r=-0.41, P=0.006). CONCLUSIONS: In spite of functional disability, FM does not cause a decrease in BMD. The presence of FM in RA patients does not result in a change in BMD.
22589380 Detection, scoring and volume assessment of bone erosions by ultrasonography in rheumatoid 2013 Apr OBJECTIVES: To determine the accuracy of ultrasonography (US) for bone erosion detection in different areas of rheumatoid arthritis (RA) metacarpophalangeal (MCP) joints with multislice CT as the reference method. Second, to establish the necessary bone volume loss on CT for US to reliably detect it as an erosion, and finally to compare two semiquantitative US-erosion scoring methods. METHODS: The 2nd-5th MCP joints of 49 patients with RA were examined by CT and US, and evaluated for the presence of bone erosion in each MCP joint quadrant. On CT, erosion volume was scored according to the OMERACT-RAMRIS score (bone volume loss in 10% increments of original bone volume). US erosions were scored 0-3 according to the Szkudlarek and Scoring by UltraSound Structural erosion (ScUSSe) systems, respectively. RESULTS: Seven hundred and eighty-four MCP joint quadrants were examined. Erosions were detected by CT in 259 quadrants and by US in 142 quadrants. Sensitivity/specificity/accuracy of US was overall 44%/95%/78% compared with 71%/95%/90% in areas with good US accessibility (radial 2nd MCP, ulnar 5th MCP and all dorsal/palmar aspects). US detected 95% of erosions with bone volume loss >20%. In US accessible areas, 63% of erosions with 1-10% bone volume loss and 94% of erosions with >10% bone loss were detected. The two US scoring systems agreed well on large erosions, whereas the smallest erosions (Szkudlarek grade 1, of which 86% were confirmed by CT) were not scored by ScUSSe. CONCLUSION: In accessible areas, US was highly accurate for detection and semiquantitative assessment of RA bone erosion. Even the smallest erosions, only detected in one plane, were generally confirmed by CT.
24039666 Imbalance between HAT and HDAC activities in the PBMCs of patients with ankylosing spondyl 2013 OBJECTIVE: Acetylation or deacetylation of histone proteins may modulate cytokine gene transcription such as TNF alpha (TNF). We evaluated the balance between histone deacetytlase (HDAC) and histone acetyltransferase (HAT) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) compared to healthy controls (HC) and determined the influence of HDAC inhibitors (trichostatin A -TSA- or Sirtinol -Sirt-) on these enzymatic activities and on the PBMC production of TNF. METHODS: 52 patients with RA, 21 with AS and 38 HC were evaluated. HAT and HDAC activities were measured on nuclear extracts from PBMC using colorimetric assays. Enzymatic activities were determined prior to and after ex vivo treatment of PBMC by TSA or Sirt. TNF levels were evaluated in PBMC culture supernatants in the absence or presence of TSA or Sirt. RESULTS: HAT and HDAC activities were significantly reduced in AS, while these activities reached similar levels in RA and HC. Ex vivo treatment of PBMC by HDACi tended to decrease HDAC expression in HC, but Sirt significantly reduced HAT in RA. TNF production by PBMC was significantly down-regulated by Sirt in HC and AS patients. CONCLUSION: HAT and HDAC were disturbed in AS while no major changes were found in RA. HDACi may modulate HDAC and HAT PBMC expression, especially Sirt in RA. Sirtinol was able to down regulate TNF production by PBMC in HC and AS. An imbalance between HAT and HDAC activities might provide the rationale for the development of HDACi in the therapeutic approach to inflammatory rheumatic diseases.
24898359 The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arth 2014 OBJECTIVES: To determine the differences in a proliferation-inducing ligand (APRIL) between seropositive and seronegative rheumatoid arthritis (RA) patients and further investigate the possible pathogenesis of the two subtypes of RA. METHOD: Concentrations of APRIL in sera (18 seropositive RA patients, 16 seronegative RA patients, and 10 healthy controls) and synovial fluid (SF) (eight seropositive RA patients, two seronegative RA patients, and 10 controls) were detected by enzyme-linked immunosorbent assay (ELISA). Infiltration of plasma cells, macrophages, and APRIL-positive cells in the synovium [14 seropositives, eight seronegatives, and 10 osteoarthritis (OA) controls] was detected by immunohistochemistry. Correlations between serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 28-joint Disease Activity Score (DAS28), and sera/SF levels of APRIL and synovial cell infiltration were analysed. RESULTS: The mean serum APRIL level of seropositive RA patients was significantly higher than that of seronegative patients (26.1 ± 31.2 vs. 8.0 ± 10.2 ng/mL, p = 0.03). The level of APRIL in the SF of seropositive RA patients was comparable to that of seronegative patients [47.9 ± 54.4 vs. 32.82 (6.52-59.12) ng/mL, p > 0.05]. The SF APRIL level of RA patients was higher than that of patients with other inflammatory arthritis. Dramatically increased infiltration of APRIL-positive cells in the RA synovium was observed compared with the OA group (seropositive RA vs. OA, p < 0.001; seronegative RA vs. OA, p = 0.001). The infiltration of both plasma cells and macrophages was more in seropositive RA than in OA (p = 0.013 and p = 0.003, respectively). CONCLUSIONS: The serum APRIL levels of seropositive RA patients are significantly higher than those of seronegative RA patients. APRIL may participate in the formation of seropositive RA.
22652412 Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis. 2013 Feb Circulating IgG anti-cyclic citrullinated peptide antibodies (CCP) are highly specific for rheumatoid arthritis (RA) and prognostic of poor outcome. Serum IgA anti-CCP occurs in a subset of IgG-positive cases and relates to still more aggressive disease. Mucosal IgA-class antibodies, however, are generally associated with anti-inflammatory actions and systemic tolerance induction. In the present study, unstimulated salivary samples from 63 patients with established RA and 20 healthy persons were analysed by enzyme-linked immunoassay for the presence of IgA anti-CCP antibodies. To ensure antigen specificity, IgA-reactivity with the corresponding uncitrullinated antigen, cyclic arginine peptide (CAP), was analysed and anti-CCP/anti-CAP ratios calculated. Retrospective data regarding disease activity and radiological outcome were achieved via medical records. Salivary IgA anti-CCP was found in 14/63 (22%) patients and one (5%) control (positive test=anti-CCP/anti-CAP ratio>1.5). Salivary IgA reactivity was dose-dependently inhibited by pre-incubation with soluble CCP to a degree strongly correlating with anti-CCP/anti-CAP ratio. In salivary IgA anti-CCP positive patients, joint erosions within 6 years of diagnosis was significantly lower (p=0.043), and at the time for diagnosis there was a trend towards lower erythrocyte sedimentation rate (p=0.071) and C-reactive protein (p=0.085). Contrasting to circulating IgG and IgA anti-CCP, our results imply that salivary IgA antibodies may be associated with a less severe outcome of RA. Hypothetically, this relates to an anti-inflammatory and protective immunomodulating role of secretory IgA-class autoantibodies against citrullinated antigens presented at mucosal surfaces.
24389749 Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to 2014 Feb The aim of this systematic review and meta-analysis is to assess the efficacy and safety of tofacitinib for the treatment of patients with acute rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drug (DMARD). Randomized controlled trials were searched in MEDLINE (1966-2013), Embase (1947-2013), the Cochrane Central Register of Controlled Trials (1948-2013), WHO International Clinical Trial Registration Platform (2004-2013), Clinical Trial.gov (1999-2013), and China Biology Medicine disc (1978-2013). The review included 10 studies involving 4,929 patients. A pooled analysis of six studies showed that tofacitinib had a superior effect over placebo (both with background therapy) at weeks 12 and 24. Also, the pooled results of three studies showed that tofacitinib monotherapy had a significantly greater effect over placebo. Compared to adalimumab, tofacitinib was found to be more efficacious as well. For safety, tofacitinib monotherapy had less serious adverse events (sAE) than placebo but not other adverse effects (oAE). In the comparison of tofacitinib and placebo both with background therapy, no difference in sAE and oAE were found. However, the quality of the evidence was quite low when evaluated using GRADE. Tofacitinib alone, or together with non-biologic DMARDs, was associated with more favorable remission in the signs and symptoms of RA than adalimumab or placebo. Also, tofacitinib monotherapy was safer than placebo with regards to reported sAE, but not oAE. However, the quality of evidence is exceedingly low; long-term, large-scale, and high-quality post-marketing research is suggested to further verify the conclusion.
23348607 Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twe 2013 Mar OBJECTIVE: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.
25518908 Safety issues and concerns of new immunomodulators in rheumatology. 2015 Mar INTRODUCTION: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab). AREAS COVERED: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments. EXPERT OPINION: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.
24666311 Safety and immunogenicity of co-administered MF59-adjuvanted 2009 pandemic and plain 2009- 2014 Jul Rheumatoid arthritis (RA) patients under immunosuppressive therapy are particularly susceptible to infections, mainly of the respiratory tract, thus vaccination may represent a strategy to reduce their incidence in this vulnerable population. In the 2009-10 influenza season, the safety and immunogenicity of co-administered non-adjuvanted seasonal and MF59-adjuvanted pandemic influenza vaccines were evaluated in this study in 30 RA patients under therapy with anti-tumour necrosis factor (TNF)-α agents or Abatacept and in 13 healthy controls (HC). Patients and HC underwent clinical and laboratory evaluation before (T0), 1 (T1) and 6 months (T2) after vaccinations. No severe adverse reactions, but a significant increase in total mild side effects in patients versus HC were observed. Both influenza vaccines fulfilled the three criteria of the Committee for Proprietary Medicinal Products (CPMP). Seroconversion rate for any viral strain in patients and HC was, respectively, 68 versus 45 for H1-A/Brisbane/59/07, 72 versus 81 for H3-A/Brisbane/10/07, 68 versus 54 for B/Brisbane/60/08 and 81 versus 54 for A/California/7/2009. A slight increase in activated interferon (IFN)-γ-, TNF-α- or interleukin (IL)-17A-secreting T cells at T1 compared to T0, followed by a reduction at T2 in both patients and HC, was registered. In conclusion, simultaneous administration of adjuvanted pandemic and non-adjuvanted seasonal influenza vaccines is safe and highly immunogenic. The largely overlapping results between patients and HC, in terms of antibody response and cytokine-producing T cells, may represent further evidence for vaccine safety and immunogenicity in RA patients on biologicals.
22451024 Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like 2013 Feb To investigate the effect of simvastatin on the migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and its cellular signal mechanisms, FLS from active RA patients were stimulated with 3 % FBS or GM-CSF in the presence or absence of simvastatin. Cells migration and invasion in vitro were measured by the Boyden chamber method. RhoA activity was assessed by a pull-down assay. Matrix metalloproteinases-2 (MMP-2) activity was evaluated by zymography. Simvastatin inhibits FBS- or GM-CSF-induced migration in a dose-dependent manner by RA FLS, and this inhibitory effect is independent of cell apoptosis. We also found that simvastatin suppressed in vitro invasion, adhesion, MMP-2 activity, cytoskeletal reorganization and RhoA activation. Furthermore, mevalonate or GGPP treatment reversed the inhibitory effect of simvastatin not only on migration and invasion in vitro but also on RhoA activation, and inhibition of RhoA by specific siRNA transfection reduced migration, adhesion and invasion of RA FLS. This study shows that simvastatin reduces RA FLS migration and invasion through the prevention of protein geranylgeranylation and RhoA activation. These findings provide a novel evidence that statin may be benefit for preventing RA arthritic destruction, and also indicate that RhoA may be a new target for the modulation of RA FLS migration and invasion.