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ID PMID Title PublicationDate abstract
26608346 Visual Assessment of Chest Computed Tomography Findings in Anti-cyclic Citrullinated Pepti 2016 Feb INTRODUCTION: We aimed to evaluate the association between specific anti-cyclic citrullinated peptide antibody (ACCPA) and pulmonary abnormalities in rheumatoid arthritis (RA) subjects. METHODS: Computed tomography (CT) images of 83 subjects with RA were evaluated in a blind fashion. Enrolled subjects underwent autoantibody testing to determinate titer of ACCPA and rheumatoid factor, and pulmonary function testing. Visual CT assessment included lobar analysis for extent of semi-quantitative total interstitial lung disease score (ILDS) and each airway abnormality score (bronchiectasis, bronchial wall thickening, centrilobular nodules, and expiratory air trapping). Correlation tests, and simple and multiple regression analyses were performed to determine the relationship between the visual CT abnormalities, physiologic parameters, and autoantibody titers. RESULTS: ACCPA-positive subjects had a greater extent and higher prevalence of small airway abnormalities including centrilobular nodules and air trapping compared to ACCPA-negative subjects (all p < 0.05). Bronchiectasis and bronchial wall thickening correlated with the ratio of forced expiratory volume in 1 s and forced vital capacity (FVC) (r = -0.236 and r = -0.329, all p < 0.05), and ILDS correlated with FVC and the diffusing capacity of the lung for carbon monoxide (r = -0.218 and r = -0.366, all p < 0.05). Bronchial wall thickening and air trapping correlated with ACCPA titers (r = 0.235 and r = 0.264, all p < 0.05). Air trapping and bronchial wall thickening were significantly associated with ACCPA titers. CONCLUSION: In ACCPA (+) RA, visual CT assessment of large and small airways beyond RA-ILD, which is attributable to RA-related autoimmunity, can provide valuable information regarding airway abnormalities, regardless of the patients' physiologic airflow limitations.
27609750 Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: 2016 Dec BACKGROUND: Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. METHODS: We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between -600 and -250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. RESULTS: In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected. CONCLUSIONS: RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.
26104678 Reactivity of rat bone marrow-derived macrophages to neurotransmitter stimulation in the c 2015 Jun 24 INTRODUCTION: Numerous observations indicate that rheumatoid arthritis (RA) has a bone marrow component. In parallel, local synovial changes depend on neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze whether collagen II-induced arthritis (CIA) has an impact on number, adhesion, apoptosis, and proliferation of the macrophage subset of bone marrow cells and how alterations in neurotransmitter microenvironment affect these properties. METHODS: Bone marrow-derived macrophages (BMMs) were isolated from Dark Agouti rats at different stages of CIA, and number, adhesion, caspase 3/7 activity, and proliferation were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA), and vasoactive intestinal peptide (VIP). RESULTS: Opposed to enhanced CD11b(+) (cluster of differentiation 11b-positive) and EMR1(+) (epidermal growth factor-like module-containing mucin-like hormone receptor-like 1-positive) cells, characterizing the macrophage subset, in native bone marrow of rats with acute inflammatory arthritis, we found decreased numbers of CIA macrophages after enrichment and culture in comparison with healthy (control) animals. Adhesion studies revealed significantly reduced attachment to plastic in acute arthritis and collagen type I and fibronectin in chronic arthritis. Additionally, we found a strong reduction in proliferation of BMMs at CIA onset and in the chronic phase of CIA. Apoptosis remained unaffected. Neurotransmitter stimulation profoundly affected proliferation, adhesion, and apoptosis of BMMs from CIA and control rats, depending on disease time point. Cultured BMMs from CIA and control animals expressed neurotransmitter receptors for ACh, VIP and NA, but the expression profile seemed not to be affected by CIA. CONCLUSIONS: Induction of CIA distinctly inhibits proliferation of BMMs in low- and non-inflammatory phases and reduces attachment to plastic at the acute inflammatory arthritis stage and adhesion to collagen I and fibronectin at the chronic stage. Influence of neurotransmitter stimulation on adhesion, apoptosis, and proliferation is altered by CIA depending on disease stage. We suggest an altered reactivity of BMMs to neurotransmitter stimulation caused by CIA and maybe also by aging.
26726793 Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP 2016 Oct OBJECTIVES: The mechanism by which methotrexate (MTX) improves glucose homeostasis in patients with rheumatoid (RA) and psoriatic arthritis (PsA) remains undetermined. Animal studies indicate a role for intracellular accumulation of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5'-monophosphate (ZMP) but this has not been directly demonstrated in humans. We explored whether accumulation of ZMP is associated with improvements in glucose homeostasis during MTX therapy. METHOD: MTX-naïve, non-diabetic RA (n = 16) and PsA (n = 10) patients received uninterrupted MTX treatment for 6 months. To evaluate whether ZMP accumulated during MTX therapy, we measured the concentration of ZMP in erythrocytes and the concentration of its dephosphorylated derivative 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) in urine using liquid chromatography mass spectrometry (LC-MS/MS). To assess glucose homeostasis, we determined the concentration of glycated haemoglobin (HbA1c) and homeostasis model assessment of insulin resistance [HOMA-IR: fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5]. RESULTS: Erythrocyte ZMP and urinary AICAR concentrations did not increase during 6 months of MTX therapy. HbA1c concentration was reduced from 5.80 ± 0.29% at baseline to 5.51 ± 0.32% at 6 months (p < 0.001), while HOMA-IR remained unaltered. Reduction in HbA1c concentration was not associated with increased ZMP or AICAR concentrations. CONCLUSIONS: MTX therapy probably does not produce a chronic increase in erythrocyte ZMP or urinary AICAR concentrations. Collectively, our data do not support the hypothesis that MTX improves glucose homeostasis through chronic accumulation of ZMP.
27974664 Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infect 2016 Dec 14 A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anticitrullinated protein antibodies and rheumatoid factor. The effect of human lymphocyte antigen-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients who were exposed to Aa These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA.
25736830 Estimation of toxic elements in the samples of different cigarettes and their effect on th 2015 Apr Cigarette smoking interferes with the metal homeostasis of the human body, which plays a crucial role for maintaining the health. A significant flux of heavy metals, among other toxins, reaches the lungs through smoking. In the present study, the relationship between toxic element (TE) exposure via cigarette smoking and rheumatoid arthritis incidence in population living in Dublin, Ireland, is investigated. The trace {zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se)} and toxic elements arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) were determined in biological (scalp hair and blood) samples of patients diagnosed with rheumatoid arthritis, who are smokers living in Dublin, Ireland. These results were compared with age- and sex-matched healthy, nonsmoker controls. The different brands of cigarette (filler tobacco, filter, and ash) consumed by the studied population were also analyzed for As, Cd, Hg, and Pb. The concentrations of trace and TEs in biological samples and different components of cigarette were measured by inductively coupled plasma mass spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference materials. The recovery of all the studied elements was found to be in the range of 96.4-99.8% in certified reference materials. The filler tobacco of different branded cigarettes contains Hg, As, Cd, and Pb concentrations in the ranges of 9.55-12.4 ng, 0.432-0.727 μg, 1.70-2.12 μg, and 0.378-1.16 μg/cigarette, respectively. The results of this study showed that the mean values of As, Cd, Hg, and Pb were significantly higher in scalp hair and blood samples of rheumatoid arthritis patients as compare to healthy controls, while Zn, Cu, Mn, and Se concentrations were found to be lower in rheumatoid arthritis patients, the difference was significant in the case of smoker patients (p<0.001). The levels of four toxic elements were 2-3-folds higher in scalp hair and blood samples of nonrheumatoid arthritis smoker subjects as compared to nonsmoker controls. The high exposure of toxic metals as a result of cigarette smoking may be synergistic with risk factors associated with rheumatoid arthritis.
27744121 S-propargyl-cysteine attenuates inflammatory response in rheumatoid arthritis by modulatin 2016 Dec Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H(2)S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H(2)S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)-9 in interleukin (IL)-1β-induced human rheumatoid fibroblast-like synoviocytes MH7A. In addition, SPRC blocked IL-1β-mediated migration and invasion of MH7A cells. As expected, the protective effects of SPRC were partially abrogated by DL-propargylglycine (PAG, a H(2)S biosynthesis inhibitor). In vivo study also demonstrated that SPRC treatment markedly ameliorated the severity of RA in adjuvant-induced arthritis rats, and this effect was associated with the inhibition of inflammatory response. We further identified that SPRC remarkably induced heme oxygenase-1 expression associated with the degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); this effect was attributed to the sulfhydrylation of the cysteine residue of Keap1. Our data demonstrated for the first time that SPRC, an endogenous H(2)S modulator, exerted anti-inflammatory properties in RA by upregulating the Nrf2-antioxidant response element (ARE) signaling pathway.
24889405 T cell ALL presenting as seropositive rheumatoid arthritis: case report and review of the 2015 Sep We present the case of a 61-year-old female with an acute onset of polyarthritis involving the wrists, hands, knees, and ankles. Associated systemic symptoms included fever, weight loss, and lymphadenopathy. Serologic workup revealed positive rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP) antibodies. Radiograph imaging of her bilateral hands and wrists showed erosive joint disease and lymph node, and bone marrow biopsy confirmed a diagnosis of T cell lymphoblastic leukemia. Our case demonstrates a unique clinical phenotype of paraneoplastic arthritis and is only the second reported case of RF, anti-CCP-positive arthritis related to a hematological malignancy. We review the only three published cases of seropositive paraneoplastic arthritis. In each case, systemic symptoms or a poor response to steroid treatment triggered additional workup. These cases highlight the importance of careful clinical assessment and vigilance to rule out secondary causes of inflammatory arthritis, even in patients with seropositive erosive arthritis.
26306497 Regulatory B cells mediate tolerance to apoptotic self in health: implications for disease 2015 Oct B cells are able to regulate immune responses through the secretion of IL-10 and other inhibitory cytokines, though no transcription factor that can define 'regulatory B cells' as a separate lineage has yet been found. Instead it is likely that this function arises as a result of the immune context in which B cells find themselves and the stimuli they perceive. However, some B cells found within the B1a and the marginal zone subsets have a greater propensity to produce IL-10 than others. What are the natural stimuli for these cells to induce immune regulation? We discuss the role that the recognition of autoantigens exposed by apoptotic cells plays in stimulating IL-10 production in mouse and human studies. This mechanism involves the recognition and uptake of self-antigens by autoreactive BCRs, for delivery to endocytic compartments, where apoptosis-derived DNA binds to TLR9, driving IL-10 production. These 'natural' regulatory B cells represent a way of maintaining tolerance to self. We discuss how this may operate in inflammatory lesions where there is an excess of apoptotic leukocytes and how this impacts on our understanding of autoimmune disease.
26386673 Significantly impaired shoulder function in the first years of rheumatoid arthritis: a con 2015 Sep 20 INTRODUCTION: Patients with rheumatoid arthritis (RA) risk impaired shoulder function due to the inflammatory process. The knowledge of shoulder function in the early years of the disease is limited. The aim was to compare shoulder function and activity limitation related to the shoulder-arm-hand in women with RA in early disease course compared to age-matched healthy women. METHOD: This controlled cross-sectional study included 103 women with rheumatoid arthritis and a reference group of 103 age-matched healthy women. The mean age was 47.1 (SD 10.0) years, the mean disease duration was 20.3 (SD 8.5) months and the mean DAS28 score was 3.8 (SD 1.4) among the patients. Participants were provided with self-reported questionnaires quantifying activity limitations. Shoulder function was assessed by isometric strength of the shoulder, shoulder-arm movement and shoulder pain. Hand-grip force was assessed and examination was made of tender and swollen joints among the patients. RESULTS: Patients showed significantly (p < 0.0001) impaired shoulder muscle strength, shoulder-arm movement, and shoulder pain compared to the reference group. Patients shoulder muscle strength was approximately 65% of the results observed in the reference group. Activity limitations related to the shoulder-arm-hand (DASH) were significantly (p < 0.0001) higher in the patient group compared to the reference group and indicates limitations in daily activities for the patients. CONCLUSION: Patients with RA were found to have significantly impaired shoulder function already 1.5 years after disease onset compared to age-matched subjects. Reduced shoulder muscle strength was found to be associated with activity limitations (DASH) implying that screening of the shoulder function, emphasising the shoulder muscle strength, should be initiated from disease onset.
26107717 Putative IL-10 Low Producer Genotypes Are Associated with a Favourable Etanercept Response 2015 Outcome predictors of biologic therapeutic drugs like TNF inhibitors are of interest since side effects like serious infections or malignancy cannot be completely ruled out. Response rates are heterogeneous. The present study addressed the question whether in patients with rheumatoid arthritis (RA) interleukin-10 (IL-10) promoter genotypes with potential relevance for IL-10 production capacity are associated with response to long-term treatment with etanercept. Caucasian RA patients that, according to the EULAR criteria, responded well (n = 25), moderately (n = 17) or not (n = 8) to etanercept therapy (median 36 months, range 4-52), and 160 matched controls were genotyped for the IL-10 promoter SNPs -2849 G>A (rs6703630), -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872). Haplotypes were reconstructed via mathematic model and tested for associations with disease susceptibility and therapy response. We identified the four predominant haplotypes AGCC, GATA, GGCC, and GACC in almost equal distribution. Patients that responded well carried the putative IL-10 low producer allele -2849 A or the haplotypes AGCC and GATA (RR 2.1 and 4.0, respectively; 95% CI 1.1-4.0 and 1.1-14.8), whereas an unfavourable response was associated with carriage of the putative high producer haplotype GGCC (RR 1.9, 95% CI 1.1-3.3). No significant associations of alleles or haplotypes with disease susceptibility were observed. In RA, a low IL-10 production which is genetically determined rather by haplotypes than by SNPs may favour the response to etanercept treatment. Iatrogenic blockade of TNF may reveal proinflammatory effects of its endogeneous antagonist IL-10. Further studies are needed to correlate these genetic findings to direct cytokine measurements.
27715362 Cellular Infiltrate in Rheumatoid Arthritis-associated Paracentral Corneal Ulceration. 2017 Dec PURPOSE: To investigate an immunopathogenesis of central and paracentral corneal ulceration associated with rheumatoid arthritis. METHODS: Sparse infiltrating cells in the ulcer area were identified by immunohistochemistry applied to archived formalin fixed, paraffin embedded tissues that had been recovered from patients undergoing penetrating keratoplasty necessitated by rheumatoid-associated central or paracentral corneal ulceration. RESULTS: Clinically, the ulcers presented as non-infiltrated lesions with a modicum of other ocular inflammation. Sparse T-lymphocytes were consistently identified in the subepithelial areas adjacent to the ulcer, with some neutrophils and macrophages in the stroma. B-lymphocytes were not detected. MHC Class II antigens reactivity was noted on some infiltrating cells and on corneal endothelium of two specimens. CONCLUSIONS: Immunohistochemistry of archival tissue facilitated detection and identification of sparse infiltrate in this infrequent corneal melting. Selective, consistent finding of T-lymphocyte infiltration in the ulcer area supports an immunopathogenesis of this clinical entity.
27192568 Co-stimulatory and Co-inhibitory Pathways in Autoimmunity. 2016 May 17 The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. Although co-stimulation is essential for boosting and shaping the initial response following signaling through the antigen receptor, inhibitory pathways are also critical for modulating the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance and thus to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (systemic lupus erythematosus and rheumatoid arthritis) and two organ-specific (multiple sclerosis and type 1 diabetes) emblematic autoimmune diseases. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.
24963082 Total wrist arthroplasty: a systematic review of the evidence from the last 5 years. 2015 Jun We reviewed evidence on total wrist replacement from the last 5 years. Eight articles met a minimum set standard. The results of 405 prostheses were available, including seven different manufacturers. The mean follow up was 2.3-7.3 years with an average age of 52-63. Rheumatoid arthritis was the indication in 42% of patients. Motec demonstrated the best post-operative DASH scores. Only Maestro achieved a defined functional range of motion post-operatively. Universal 2 displayed the highest survival rates (100% at 3-5 years), while Elos had the lowest (57% at 5 years). Biaxial had the highest complication rates (68.7%), while Remotion had the lowest (11%). Wrist arthroplasty preserves some range of motion. Functional scores improved and were maintained over the mid- to long-term. Complication rates were higher than wrist fusion, with reports of radiological loosening and osteolysis. The evidence does not support the widespread use of arthroplasty over arthrodesis, and careful patient selection is essential.
25715256 Effect of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor on disease activity in 2015 Feb HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid-lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk. However, whether they have an effect on RA disease activity is controversial. This study aimed to investigate the effect of statins on disease activity in RA patients. A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases. Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included. The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP. The Jadad score was used for quality assessment. The inverse variance method was used to analyze continuous outcomes. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used. For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis. Publication bias was assessed using Egger test. A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP. The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was -0.55 (95% CI [-0.83, -0.26], P = 0.0002), with an I2 value of 68%. Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD -0.73, P = 0.01) than patients with moderate or low disease activity (SMD -0.38, P = 0.03). Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not significant (P > 0.05). This meta-analysis suggested that statin therapy might be effective in the reduction of RA disease activity measured by DAS28, TJC, SJC, as well as ESR and CRP.
26054042 Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-inter 2015 Dec This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- ∞ ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18%-19%, respectively, after sirukumab administration. Caffeine AUC0-∞ was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA.
26101866 Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with "Explosive" Imm 2015 Jun 19 Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin's lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.
26676809 The association between serious infection and disease outcome in patients with rheumatoid 2016 Jan The purpose of this study was to study the association between the past history of serious infection (SI) that required hospitalization and the current disease status of rheumatoid arthritis (RA), including disease activity, physical disability, and radiological joint destruction. The history of hospitalized infection was retrospectively analyzed in a cohort of 370 RA patients. The patients were divided into three groups based on the number of SI events (SI = 0, SI = 1, SI ≥ 2). Disease activity score using 28 joints (DAS28), Health Assessment Questionnaire (HAQ), and modified total sharp score (mTSS) adjusted after disease duration or other confounding factors were compared among the three groups. Among the study patients, 7.3% (27 patients) experienced single SI (SI = 1) and 2.1% (8 patients) experienced multiple SI events (SI ≥ 2). Compared with patients with no SI (SI = 0), patients with SI (SI = 1 or SI ≥ 2) had increased pulmonary and autoimmune comorbidities and were more frequently treated with glucocorticoids. DAS28 was not different among the groups, while HAQ and mTSS increased with the number of SI. After adjustment, only mTSS adjusted after disease duration remained statistically significantly different between patients with SI = 0 and SI ≥ 2 (p = 0.030). Multiple SI events are associated with advanced physical disability and radiological joint destruction in patients with RA.
25697599 Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. 2015 The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti-interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways.
25802876 Toll-like receptor mediated modulation of T cell response by commensal intestinal microbio 2015 In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures.