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ID PMID Title PublicationDate abstract
27317338 Collagen-induced arthritis and imiquimod-induced psoriasis develop independently of interl 2016 Jun 18 BACKGROUND: Interleukin (IL)-33 is a dual cytokine with both an alarmin role and a T helper 2 cell (Th2)-like inducing effect. It is involved in the pathogenesis of rheumatoid arthritis (RA) and its models; we recently demonstrated that exogenous IL-33 could inhibit collagen-induced arthritis (CIA) in C57BL/6 mice. However, its pathophysiological role in RA is unclear. Indeed, mice deficient in the IL-33 receptor ST2 show reduced susceptibility to arthritis, and the disease is not modified in IL-33-deficient mice. We examined the immune response in wild-type (WT) and IL-33-deficient mice with CIA. To further understand the role of endogenous IL-33 in inflammatory diseases, we studied its role in a skin psoriasis model. Mice on a C57BL/6 background were deficient in IL-33 but expressed lacZ under the IL-33 promoter. Therefore, IL-33 promotor activity could be analyzed by lacZ detection and IL-33 gene expression was analyzed by X-Gal staining in various mice compartments. Frequencies of CD4(+)FoxP3(+) regulatory T cells (Tregs) and Th1 and Th17 cells were evaluated by flow cytometry in WT and IL-33(-/-) mice. Bone resorption was studied by evaluating osteoclast activity on a synthetic mineral matrix. Psoriasis-like dermatitis was induced by application of imiquimod to the skin of mice. RESULTS: Severity of CIA was similar in IL-33(-/-) and WT littermates. Joints of IL-33(-/-) mice with CIA showed IL-33 promotor activity. In mice with CIA, frequencies of Tregs, Th1 and Th17 in the spleen or lymph nodes did not differ between the genotypes; osteoclast activity was higher but not significantly in IL-33(-/-) than WT mice. Psoriasis development did not differ between the genotypes. CONCLUSIONS: Despite its expression in the synovium of arthritic mice and normal keratinocytes, IL-33 is not required for CIA development in arthritis or psoriasis. Its absence does not induce a T cell shift toward Th1, Th17 or Treg subpopulations. Altogether, these data and our previous ones, showing that exogenous IL-33 can almost completely inhibit CIA development, suggest that this cytokine is not crucial for development of chronic inflammation. Studies of RA patients are needed to determine whether treatment targeting the IL-33/ST2 axis would be effective.
25406356 The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT 2015 Jun OBJECTIVE: Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. METHODS: The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. RESULTS: STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. CONCLUSION: The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.
26606742 Brief Report: Patterns and Secular Trends in Use of Immunomodulatory Agents During Pregnan 2016 May OBJECTIVE: To describe patterns and secular trends in the use of immunomodulatory agents in pregnant women with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). METHODS: We identified a cohort of women with SLE, RA, PsA, or AS enrolled in public (Medicaid, 2001-2010) or private (Optum Clinformatics, 2004-2012) health insurance, and we included women filling prescriptions for immunomodulatory agents (including steroids, nonbiologic disease-modifying agents, and biologic agents) in the 3-month period immediately prior to their pregnancies. The proportion of women continuing or discontinuing individual agents during pregnancy was reported. Annual prescription fill rates, estimated after accounting for patient characteristics and random variability from year to year in mixed-effects regression models, were used to conduct time trends analysis. RESULTS: We included 2,645 women being treated with immunomodulatory agents prior to pregnancy. More women with PsA or AS stopped filling prescriptions for immunomodulatory agents during pregnancy (61%) than women with SLE (26%) or women with RA (34.5%). From the first to the third trimester, the proportions of women filling prescriptions for immunomodulatory agents decreased across all indications. Overall, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). The rates (reported per 100 deliveries in our cohort) for steroid prescription fills during pregnancy decreased significantly from 54.4 in 2001 to 42.4 in 2012, while rates for biologic agents increased from 5.1 in 2001 to 16.6 in 2012 (P < 0.001 for both trends). CONCLUSION: Steroids and hydroxychloroquine remain the most widely prescribed treatment options in pregnancy, but the use of biologic agents is becoming increasingly common.
25908282 [Postoperative complications and revision surgery following primary total knee arthroplast 2015 Feb OBJECTIVE: To determine the postoperative complications of primary total knee arthroplasty (TKA) within 30 postoperative days, and the different causes for revision surgery during follow-up. METHODS: Between January 2001 and December 2012, a total of 1 920 patients underwent 2 779 primary TKA with fixed bearing platform in Peking Union Medical College Hospital, with 323 for male and 1 607 for female. The revision surgery at index time and the hemophiliac arthropathy were excluded for this study. The average age was (66 ± 9) years (from 25 to 86 years).Osteoarthritis accounted for 1 720 cases (89.58%), rheumatoid arthritis for 168 cases (8.75%), ankylosing spondylitis for 12 cases (0.63%), secondary arthritis for 20 cases (1.04%). The postoperative complications with 30 postoperative days and revision surgery during follow-up were recorded. RESULTS: Follow-up was concluded at December 2013. Totally, 1 854 patients (2 693 knees) were successfully followed-up.Forty-one patients experienced systemic complication within 30 postoperative days, with the rate of 2.21%. The most common reasons of systemic complication were the respiratory complication and cardiovascular complication in origin, with the rate of 0.49% (9/1 854) and 0.38% (7/1 854) respectively. The average rate of deep venous thrombosis in this group was 3.02% (56/1 854). The local complication rate within 30 days was 1.29% in this group. Totally 59 knees experienced the revision surgeries during average 67 months follow-up. The most common causes for revision surgery in relative values were septic loosening, with the rate of 1.19% (32 in 2 693 knees), followed by postoperative stiffness, with the rate of 0.37% (10 in 2 693 knees). CONCLUSIONS: The most common reasons of systemic complication with 30 postoperative days after primary TKA procedure are the respiratory complication and cardiovascular complication in origin. The most common reason for revision surgery during mid-term follow-up for primary TKA is septic loosening.
25997746 Cost-effectiveness of abatacept, rituximab, and TNFi treatment after previous failure with 2015 May 22 INTRODUCTION: For patients with rheumatoid arthritis (RA) whose treatment with a tumour necrosis factor inhibitor (TNFi) is failing, several biological treatment options are available. Often, another TNFi or a biological with another mode of action is prescribed. The objective of this study was to compare the effectiveness and cost-effectiveness of three biologic treatments with different modes of action in patients with RA whose TNFi therapy is failing. METHODS: We conducted a pragmatic, 1-year randomised trial in a multicentre setting. Patients with active RA despite previous TNFi treatment were randomised to receive abatacept, rituximab or a different TNFi. The primary outcome (Disease Activity Score in 28 joints) and the secondary outcomes (Health Assessment Questionnaire Disability Index and 36-item Short Form Health Survey scores) were analysed using linear mixed models. Cost-effectiveness was analysed on the basis of incremental net monetary benefit, which was based on quality-adjusted life-years (calculated using EQ-5D scores), and all medication expenditures consumed in 1 year. All analyses were also corrected for possible confounders. RESULTS: Of 144 randomised patients, 5 were excluded and 139 started taking abatacept (43 patients), rituximab (46 patients) or a different TNFi (50 patients). There were no significant differences between the three groups with respect to multiple measures of RA outcomes. However, our analysis revealed that rituximab therapy is significantly more cost-effective than both abatacept and TNFi over a willingness-to-pay range of 0 to 80,000 euros. CONCLUSIONS: All three treatment options were similarly effective; however, when costs were factored into the treatment decision, rituximab was the best option available to patients whose first TNFi treatment failed. However, generalization of these costs to other countries should be undertaken carefully. TRIAL REGISTRATION: Netherlands Trial Register number NTR1605. Registered 24 December 2008.
27074807 Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for a 2016 Aug OBJECTIVES: Autophagy may represent a functional processing event that creates a substrate for autoreactivity. In particular, autophagy may play a role in the pathogenesis of RA, since autophagy is a key cellular event involved in the generation of citrullinated peptides, with consequent breakage of tolerance. Thus, in RA, autophagy may be the common feature in several situations (including smoking, joint injury and infection) that may drive the adaptive responses to citrullinated self-proteins. The aim of this study was the analysis, in vitro, of the role of autophagy in the generation of citrullinated peptides and, in vivo, of the relationship between autophagy and the production of anti-CCP antibodies (Abs). METHODS: For autophagy induction, fibroblast-like synoviocytes, primary fibroblasts and monocytes were stimulated with tunicamycin or rapamycin. Peptidyl arginine deiminase activity was tested by enzyme-linked immunosorbent assay, and protein citrullination was evaluated by western blotting. The main citrullinated RA candidate antigens, vimentin, α-enolase and filaggrin, were demonstrated by immunoprecipitation. The relationship between autophagy and anti-CCP Abs was analysed in 30 early-active RA patients. RESULTS: Our results demonstrated in vitro a role for autophagy in the citrullination process. Cells treated with tunicamycin or rapamycin showed peptidyl arginine deiminase 4 activation, with consequent protein citrullination. Immunoblotting and immunoprecipitation experiments, using specific Abs, identified the main citrullinated proteins: vimentin, α-enolase and filaggrin. In vivo, a significant association between levels of autophagy and anti-CCP Abs was observed in treatment-naïve early-active RA patients. CONCLUSION: These findings support the view that the processing of proteins in autophagy generates citrullinated peptides recognized by the immune system in RA.
26713667 A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relev 2016 May OBJECTIVE: Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. METHODS: Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) β-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. RESULTS: A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII(311-325) bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCRβ repertoire of Cit-CII(311-325) -stimulated PBMCs. CONCLUSION: These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII(311-325) to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.
27840083 Cobrotoxin extracted from Naja atra venom relieves arthritis symptoms through anti-inflamm 2016 Dec 24 ETHNOPHARMACOLOGICAL RELEVANCE: The Naja atra (Chinese cobra), primarily distributing in the low or medium altitude areas of southern China and Taiwan, was considered as a medicine in traditional Chinese medicine and used to treat pain, inflammation and arthritis. AIM OF THE STUDY: To study the anti-inflammatory and anti-arthritic activities of cobrotoxin (CTX), an active component of the venom from Naja atra. MATERIALS AND METHODS: Adjuvant-induced arthritis (AA) rats were used as the animal model of rheumatoid arthritis. The anti-arthritic effects of CTX were evaluated through the arthritis score, paw edema and histopathology changes of joints. The anti-inflammation effects were assayed by the level of IL-6, TNF-α, IL-1β and the number of inflammatory cells in peripheral blood, as well as the proliferation of fibroblast-like synoviocytes (FLS). The immune level was valued by the proliferation of T cells and the level of CD4 and CD8. RESULTS: CTX alleviated the disease development of AA rats according to the ameliorating arthritis score, paw edema and histopathology character. At the meanwhile, CTX decreased the levels of IL-6, TNF-α, IL-1β and the numbers of inflammatory cells in peripheral blood. CTX also suppressed the abnormal increasing of CD4+ T cells/ CD8+ T cells ratio, and could significantly inhibit T cell proliferation. Consistent with its effects on inhibiting granuloma's formation, CTX inhibited the proliferation of the cultured FLSs. Further studies on inflammatory signaling in FLSs revealed that CTX could inhibit the NF-κB signaling pathway. CONCLUSIONS: CTX has beneficial effects on rheumatoid arthritis by its immune regulation effects and anti-inflammation effects. The inhibition of NF-κB pathway partly contributes to the anti-inflammatory properties of CTX.
26017630 Bronchiectasis is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumat 2015 Sep OBJECTIVE: To examine the potential of chronic severe bacterial infection to generate rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), by studying patients with bronchiectasis (BR) alone and BR patients with rheumatoid arthritis (BR/RA). METHODS: We studied 122 patients with BR alone, 50 patients with BR/RA, and 50 RA patients without lung disease, as well as 87 patients with asthma and 79 healthy subjects as controls. RF levels were measured using an automated analyzer, and cyclic citrullinated peptide 2 (CCP-2) was used to detect ACPAs. The fine specificities of citrullinated α-enolase peptide 1 (CEP-1), Cit-vimentin, and Cit-fibrinogen to their arginine-containing control peptides (arginine-containing α-enolase peptide 1 [REP-1], vimentin, and fibrinogen) were measured by enzyme-linked immunosorbent assay. RESULTS: Among the BR patients and control subjects, 39% and 42%, respectively, were ever-smokers. The frequency of RF positivity in serum was increased in BR patients compared with controls (25% versus 10%), as were the frequencies of antibodies to CCP-2 (5% versus 0%), CEP-1 (7% versus 4%), Cit-vimentin (7% versus 4%), and Cit-fibrinogen (12% versus 4%), although only the differences for RF and Cit-fibrinogen were significant (P < 0.05). We observed a corresponding increase in the frequency of antibodies to the arginine-containing control peptides in BR patients compared with controls (for REP-1, 19% versus 4% [P < 0.01]; for vimentin, 16% versus 4% [P < 0.05]), demonstrating that the ACPA response in patients with BR is not citrulline specific. The lack of citrulline specificity was further confirmed by absorption studies. In BR/RA patients, all ACPA responses were highly citrulline specific. CONCLUSION: Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that the ACPA response is not citrulline specific during the early stages of tolerance breakdown but becomes more specific in patients with BR in whom BR/RA develops.
25529994 Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteocla 2015 Feb Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound - celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteoclast differentiation and functions in RANKL-induced osteoclast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (CT). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp-9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP+ multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen-activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction.
26336855 Variation at interleukin-6 receptor gene is associated to joint damage in rheumatoid arthr 2015 Sep 4 INTRODUCTION: Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA. METHODS: IL6R gene tagging SNPs (n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase. RESULTS: In the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA (P = 0.0058, P corrected = 0.026), and a moderate association with SNP rs4453032 (P = 0.02, P corrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage (P = 0.0037, P corrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA (P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association (P = 0.0058, meta-analysis P = 6.64 e-5). CONCLUSIONS: Genetic variation at IL6R gene is associated with joint damage in RA.
26189371 Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis. 2017 Feb Fibroblast-like synoviocytes (FLSs) contribute to synovial hyperplasia in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell proliferation. The objective of this study was to investigate the role of Smo in RA synoviocyte proliferation. FLSs were isolated from RA synovium. Shh signaling was studied using a Smo antagonist (GDC-0449) and small interfering RNA (siRNA) targeting the Smo gene in FLSs. Cell proliferation was quantified by using kit-8 assay and cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell cycle-related genes and proteins were detected by real-time PCR and western blot. FLSs treated with GDC-0449 or Smo-siRNA showed significantly decreased proliferation compared to controls (P < 0.05). Incubation with GDC-0449 or transfection with Smo-siRNA resulted in a significant increase of G(1) phase cells compared to controls (P < 0.05). Cell cycle arrest was validated by the significant increase in cyclin D1 and E1 mRNA expression, decrease in cyclin-dependent kinase p21 mRNA expression in Smo-siRNA transfected cells (P < 0.05). Protein expression of cyclin D1 was also downregulated after Smo gene knockdown (P < 0.05). The results suggest that Shh signaling plays an important role in RA-FLSs proliferation in a Smo-dependent manner and may contribute to synovial hyperplasia. Targeting Shh signaling may help control joint damage in patients with RA.
26117510 Retention on anti-tumour necrosis factor therapy: the Waikato experience. 2015 May 29 AIM: To investigate the retention on anti-TNF agents used in a real-world setting, and determine the factors predicting retention on drug. METHOD: Patients starting anti-TNF therapy were recorded prospectively on the departmental database. Medical records of all patients commenced on anti-TNF therapy between 2006 and 2013 at the Rheumatology Department, Waikato Hospital, Hamilton, were retrospectively reviewed to obtain details of their course on biologic therapy. RESULTS: 183 patients were identified. 139 (76.5%) were commenced on adalimumab. The predominant indication was rheumatoid arthritis (52.5%). 60 patients (32.8%) discontinued their initial anti-TNF agent. Of these, 31.7% were due to primary failure, 36.7% due to secondary failure and 25% due to adverse events. At 5 years, retention on agents was: adalimumab (77.2%), etanercept (69.6%) and infliximab (16.7%). Retention on adalimumab was significantly higher than infliximab (p<0.001), but did not differ between adalimumab and etanercept, or etanercept and infliximab. CONCLUSION: In a real-world setting, retention on infliximab was significantly lower than adalimumab.
24951881 Teaching methotrexate self-injection with a web-based video maintains patient care while r 2015 Jan The aim of the study was to compare standard nurse-led methotrexate self-injection patient education to a web-based methotrexate self-injection education video in conjunction with standard teaching on patient self-confidence for self-injection, as well as patient satisfaction, patient knowledge and teaching time. Consecutive rheumatology patients seen for methotrexate self-injection education were enrolled. Prior to education, patient self-confidence for self-injection, age, gender and education were recorded. Patients were randomized 1:1 to standard teaching or the intervention: a 12-min methotrexate self-injection education video followed by further in-person nurse education. Patients recorded their post-education confidence for self-injection, satisfaction with the teaching process and answered four specific questions testing knowledge on methotrexate self-injection. The time spent providing direct education to the patient was recorded. Twenty-nine patients participated in this study: 15 had standard (C) teaching and 14 were in the intervention group (I). Average age, gender and education level were similar in both groups. Both groups were satisfied with the quality of teaching. There was no difference in pre-confidence (C = 5.5/10 vs. I = 4.7/10, p = 0.44) or post-confidence (C = 8.8, I = 8.8, p = 0.93) between the groups. There was a trend toward improved patient knowledge in the video group versus the standard group (C = 4.7/6, I = 5.5/6, p = 0.15). Nurse teaching time was less in the video group (C = 60 min, I = 44 min, p = 0.012), with men requiring longer education time than women across all groups. An education video may be a good supplement to standard in-person nurse teaching for methotrexate self-injection. It equals the standard teaching practise with regard to patient satisfaction, confidence and knowledge while decreasing teaching time by 25 %.
27438197 Infliximab in patients with psoriasis and other inflammatory diseases: evaluation of adver 2016 May BACKGROUND: Psoriasis is immune-mediated chronic inflammatory disease with preference for skin and joints. The skin involvement occurs by hyperproliferation and abnormal differentiation of keratinocytes. It is associated with comorbidities, mainly related to the clinical manifestations of the metabolic syndrome. Increased TNF-alpha expression (TNF-α) is related to its pathophysiology. Infliximab is an intravenous drug that acts neutralizing the biological activity of TNF-α and prevents the binding of the molecule to the target cell receptor, inhibiting cell proliferation of psoriasis and other diseases mediated by TNF-α. A lot of infusion reactions have been described in the literature. OBJECTIVE: To evaluate the adverse effects of intravenous treatment with infliximab, analyzing patients with psoriasis compared to those with other chronic inflammatory diseases (rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and ulcerative colitis). METHOD: Analysis of medical records and adverse events of 168 patients undergoing infliximab infusion for psoriasis and chronic inflammatory diseases treatment. RESULTS: 168 patients who have used infliximab were evaluated, 24 had psoriasis and 144 had chronic inflammatory diseases. Only 2 (8.3%) patients with psoriasis showed adverse events requiring treatment discontinuation, and just 6 (4.2%) female patients with chronic inflammatory diseases experienced adverse events. CONCLUSION: Infliximab is a safe drug, with a low percentage of adverse events and there were more adverse events in women with chronic inflammatory diseases and in patients who received more infliximab infusions.
25870331 Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective anal 2015 Aug 1 BACKGROUND: Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. METHODS: We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. RESULTS: The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. CONCLUSIONS: In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.
25769495 Tumour necrosis factor inhibitors versus combination intensive therapy with conventional d 2015 Mar 13 OBJECTIVE: To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. DESIGN: Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. SETTING: 24 rheumatology clinics in England. PARTICIPANTS: Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. INTERVENTIONS: Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. PRIMARY OUTCOME: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. SECONDARY OUTCOMES: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. RESULTS: 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was -0.14, and the 95% confidence interval (-0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12. CONCLUSIONS: In patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.
27608800 Possible relationship between certolizumab pegol and arrhythmias: report of two cases. 2016 Sep 9 It is still unknown whether there is an association between the use of certolizumab pegol (CZP) in rheumatic patients and the onset of cardiac arrhythmias. We describe the cases of two patients with rheumatoid arthritis (RA) treated with CZP as the first-line biological drug and methotrexate (MTX), who developed an arrhythmic event. The first was a 60-year-old, hypertensive male smoker, the second a 66-year-old dyslipidemic female non-smoker. Both were diagnosed as having RA in 2010, and started treatment with MTX plus CZP. The first patient developed undatable atrial fibrillation, which was resistant to pharmacological treatment and electrical cardioversion. The second patient developed an atrial flutter, which was treated with a betablocker. In both cases, we set a cautious interval between two consecutive administrations of CZP and, in the first case, also reduced the dose of MTX without any worsening of RA activity. Although many studies have shown that tumor necrosis factor (TNF)-alpha plays a pathogenetic role in inducing an arrhythmogenic substrate that is apparently rescued by anti-TNF drugs, there is still a lack of conclusive data. We suggest caution in any patient developing a cardiac event (including rhythm disorders) during treatment with a conventional or biological disease-modifying anti-rheumatic drug.
26927756 Immune responses to Mycobacterial heat shock protein 70 accompany self-reactivity to human 2016 Mar 1 Rheumatoid arthritis (RA) is an autoimmune disease, and a member of human heat shock protein (HSP) 70 protein family, Binding Immunoglobulin Protein (BiP), has been identified as an important autoantigen for T and B cells. We herein focused on Mycobacterial (Myc) HSPs and immune responses to MycHSPs in RA patients. Serum titers of antibodies against MycHSP70 were significantly elevated in RA patients and correlated with serum anti-BiP antibody titers. A MycHSP70-derived HLA-DR4 major epitope was identified using the proliferative capacity of RA PBMCs as an indicator. The major epitope, MycHSP70287-306, was located at the corresponding position in the major epitope for human BiP336-355, and a strong correlation was found between the proliferation of PBMCs in response to MycHSP70287-306 and BiP336-355. The immunization of HLA-DR4 transgenic mice with MycHSP70 induced the proliferation of T cells and development of anti-BiP antibodies. In contrast, the oral administration of MycHSP70287-306 resulted in the amelioration of collagen-induced arthritis, serum antibody responses, and T cell proliferation. In conclusion, immune responses to MycHSP70 were associated with adaptive immunity against BiP in RA, and could be an important mechanism underlying the development of autoimmunity.
27320937 [Retrospective investigation of side effects and prognoses of moderate-dose trimethoprim-s 2016 Trimethoprim-sulfamethoxazole (TMP/SMX) treatment for pneumocystis pneumonia (PCP) in patients with autoimmune diseases who developed PCP was conducted in a retrospective study of the following: dosage, frequency of side effects and persistence rate of TMP/SMX and prognosis of patients. Seven patients (two males and five females, mean age: 72 years) were hospitalized between April 1, 2013 and August 31, 2015, and their underlying diseases were rheumatoid arthritis (six patients) and microscopic polyangiitis (one patient). Moderate-dose TMP/SMX (TMP equivalent to TMP/SMX, average: 9.6 mg/kg/day, range: 5.1-12.5 mg/kg/day) was used for PCP treatment. As a result, patients experienced the following side effects: hyponatremia in five patients (71.4%), exanthema in four patients (57.1%), and thrombocytopenia in two patients (28.6%). Elevated creatinine level, increased blood pressure, malaise, and hyperkalemia were experienced by each patient. Six patients (85.7%) discontinued TMP/SMX treatment due to side effects, but once they had recovered, desensitization to TMP/SMX was used to treat them. Eventually, four patients were successfully treated with TMP/SMX (final persistence rate, 57.1%). Their prognoses were good, and no patients died for at least 60 days after admission. Moderate-dose TMP/SMX treatment for PCP in patients with autoimmune diseases who developed PCP may have therapeutic effects equal to high-dose TMP/SMX treatment, and therefore collecting more case studies is expected.