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ID PMID Title PublicationDate abstract
27799070 Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic suscept 2016 Nov 1 BACKGROUND: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk. RESULTS: Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells. CONCLUSIONS: Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.
26359812 Hyperspectral imaging for detection of arthritis: feasibility and prospects. 2015 Sep Rheumatoid arthritis (RA) is a disease that frequently leads to joint destruction. It has a high incidence rate worldwide, and the disease significantly reduces patients’ quality of life. Detecting and treating inflammatory arthritis before structural damage to the joint has occurred is known to be essential for preventing patient disability and pain. Existing diagnostic technologies are expensive, time consuming, and require trained personnel to collect and interpret data. Optical techniques might be a fast, noninvasive alternative. Hyperspectral imaging (HSI) is a noncontact optical technique which provides both spectral and spatial information in one measurement. In this study, the feasibility of HSI in arthritis diagnostics was explored by numerical simulations and optimal imaging parameters were identified. Hyperspectral reflectance and transmission images of RA and normal human joint models were simulated using the Monte Carlo method. The spectral range was 600 to 1100 nm. Characteristic spatial patterns for RA joints and two spectral windows with transmission were identified. The study demonstrated that transmittance images of human joints could be used as one parameter for discrimination between arthritic and unaffected joints. The presented work shows that HSI is a promising imaging modality for the diagnostics and follow-up monitoring of arthritis in small joints.
27718235 The soluble cytoplasmic tail of CD45 (ct-CD45) in human plasma contributes to keep T cells 2017 Jan The cytoplasmic tail of CD45 (ct-CD45) is proteolytically cleaved and released upon activation of human phagocytes. It acts on T cells as an inhibitory, cytokine-like factor in vitro. Here, we show that ct-CD45 is abundant in human peripheral blood plasma from healthy adults compared with plasma derived from umbilical cord blood and plasma from patients with rheumatoid arthritis or systemic lupus erythematosus. Plasma depleted of ct-CD45 enhanced T-cell proliferation, while addition of exogenous ct-CD45 protein inhibited proliferation and reduced cytokine production of human T lymphocytes in response to TCR signaling. Inhibition of T-cell proliferation by ct-CD45 was overcome by costimulation via CD28. T-cell activation in the presence of ct-CD45 was associated with an upregulation of the quiescence factors Schlafen family member 12 (SLFN12) and Krueppel-like factor 2 (KLF2) as well as of the cyclin-dependent kinase (CDK) inhibitor p27kip1. In contrast, positive regulators of the cell cycle such as cyclin D2 and D3 as well as CDK2 and CDK4 were found to be downregulated in response to ct-CD45. In summary, we demonstrate that ct-CD45 is present in human plasma and sets the threshold of T-cell activation.
27790752 Increased circulating anti-α6-integrin autoantibodies in psoriasis and psoriatic arthriti 2017 Apr In psoriatic skin, laminin integrity is altered, which could lead to insufficient laminin integrin interactions, leaving the α6-integrin exposed and possibly accessible for autoantibody production. Therefore we investigated the presence of anti-α6-integrin autoantibodies in the serum of patients with psoriasis vulgaris (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in comparison with healthy donors. The level of circulating anti-α6-integrin antibodies was determined by enzyme-linked immunoassay using α6-integrin fragments. Antibodies against at least one recombinant fragment were found in approximately 30% of Ps and PsA patients. In contrast, in RA patients, the frequency of antibodies was similar to healthy controls. Our study shows the presence of anti-α6-integrin antibodies in Ps and PsA but not in RA, which could indicate ongoing abnormal processes in the skin. Anti-α6-integrin autoantibodies may contribute to the formation of micro-wounds in the skin and to the characteristic wound-healing phenotype in psoriasis.
27109064 Major histocompatibility complex harbors widespread genotypic variability of non-additive 2016 Apr 25 Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals.
26359449 Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy 2016 Apr OBJECTIVES: To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. METHODS: In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. RESULTS: Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. CONCLUSIONS: In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. TRIAL REGISTRATION NUMBER: NCT00929864.
26880258 The Use of Avoidance, Adjustment, Interaction and Acceptance Strategies to Handle Particip 2016 Dec OBJECTIVES: Living with a chronic disease means learning to live under new circumstances and involves a continuous adaptation to new ways of living. There is increasing knowledge about how people cope with stressful life events and adapt to new life situations. Approximately a third of patients diagnosed with rheumatoid arthritis (RA) are men; however, few studies have described the needs and experiences of men living with RA. The aim of the present study was to explore men's strategies for handling challenges related to participation in everyday life. METHODS: The present study was associated with the prospective Swedish multicentre early arthritis project (given the Swedish acronym TIRA), which, in 2006-2009, included patients with early RA, contemporarily treated, with a mean disease duration of three years. From this cohort, 25 men, aged 20-63 years, were recruited consecutively. Data were collected in individual interviews, using the critical incident technique. The strategies for dealing with the challenges of RA in everyday life were analysed and categorized using content analysis. RESULTS: Men with RA described four types of strategy for dealing with participation restrictions in everyday life: (i) Adjustment strategies - adjust behaviour, movements, medication, equipment and clothing to find new ways to conduct tasks or activities; (ii) Avoidance strategies - avoid activities, movements, social contacts and sometimes medication; (iii) Interaction strategies - say no, ask for help and work together to handle participation restrictions; and (iv) Acceptance strategies - learn to accept RA, with the pain, the slower work pace and the extended time needed. CONCLUSIONS: According to men's lived experiences, a combination of strategies was used to deal with RA, depending on the situation and the experienced restriction. The results provided an understanding of how men with RA manage their disease, to reduce physical, social and emotional challenges. This knowledge may be used further to develop multi-professional interventions and patient education tailored to men with RA.
26027508 Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone 2015 Oct Osteoclastogenesis requires immunoreceptor tyrosine-based activation motif signaling. Multiple immunoreceptors associated with immunoreceptor tyrosine-based activation motif adaptor proteins, including DNAX-activating protein 12 kDa (DAP12) and Fc receptor common γ (FcRγ), have been identified in osteoclast lineage cells, and some are involved in arthritis-induced bone destruction. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with DAP12. Whether Siglec-15 is involved in arthritis-induced bone lesions, however, remains unknown. Here we used a murine antigen-induced arthritis model to examine the role of Siglec-15 in the development of bone lesions induced by joint inflammation. Arthritis was unilaterally induced in the knee joints of 8-week-old female wild-type (WT) and Siglec-15(-/-) mice, and the contralateral knees were used as a control. The degree of joint inflammation, and cartilage and subchondral bone destruction in Siglec-15(-/-) mice was comparable to that in WT mice, indicating that Siglec-15 is not involved in the development of arthritis and concomitant cartilage and subchondral bone destruction. On the other hand, the degree of periarticular bone loss in the proximal tibia of the arthritic knee was significantly lower in Siglec-15(-/-) mice compared to WT mice. Although osteoclast formation in the metaphysis was enhanced in both WT and Siglec-15(-/-) mice after arthritis induction, mature multinucleated osteoclast formation was impaired in Siglec-15(-/-) mice, indicating impaired osteoclast bone resorptive function in the periarticular regions of the arthritic joint in Siglec-15(-/-) mice. Confirming this result, Siglec-15(-/-) primary unfractionated bone marrow cells harvested from arthritic femurs and tibiae failed to develop into mature multinuclear osteoclasts. Our findings suggest that Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction, in inflammatory arthritis, such as rheumatoid arthritis.
27069015 Synovial fluid mononuclear cells provide an environment for long-term survival of antibody 2016 Dec OBJECTIVES: In rheumatoid arthritis (RA), observations point to a crucial role for (autoreactive) B cells in disease pathogenesis. Here, we studied whether cells from the synovial environment impact on the longevity of autoreactive B cell responses against citrullinated antigens. METHODS: Synovial fluid mononuclear cells and peripheral blood mononuclear cells (SFMC/PBMC) were obtained from patients with established RA and assessed for the presence of B cell subpopulations. Cells spontaneously secreting anti-citrullinated protein antibodies (ACPA-IgG) directly ex vivo were detected by antigen-specific Enzyme-Linked ImmunoSpot (ELISpot) assay. SFMC and PBMC were cultured to assess the degree of spontaneous ACPA-IgG secretion. Cells surviving for several weeks were characterised by carboxyfluorescein succinimidyl ester (CFSE) labelling and Ki-67 staining. RESULTS: Cells spontaneously secreting ACPA-IgG were readily detectable in peripheral blood and synovial fluid (SF) of patients with ACPA-positive RA. SFMC showed an up to 200-fold increase in ex vivo ACPA-IgG secretion compared with PBMC despite lower numbers of B cells in SFMC. ELISpot confirmed the presence of spontaneously ACPA-IgG-secreting cells, accounting for up to 50% (median 12%) of all IgG-secreting cells in SF. ACPA-IgG secretion was remarkably stable in SFMC cultures, maintained upon depletion of the CD20(+) B cell compartment and detectable for several months. CFSE labelling and Ki-67 staining confirmed the long-term survival of non-dividing plasma cells (PCs). CONCLUSIONS: This study demonstrates a high frequency of differentiated, spontaneously ACPA-IgG-secreting cells in SF. These cells are supported by SFMC for prolonged survival and autoantibody secretion, demonstrating that the synovial compartment is equipped to function as inflammatory niche for PC survival.
26895524 Glu106 targeted inhibitors of ORAI1 as potential Ca(2+) release-activated Ca(2+) (CRAC) ch 2016 Dec Calcium release-activated calcium modulator 1(ORAI1) is an integral component of the calcium release-activated calcium channel (CRAC) channel complex and plays a central role in regulating Ca(2 + )concentrations in T-lymphocytes. It is critical for many physiological processes, including cell-proliferation, cytokine production and activation of the immune system. Loss of ORAI1 function is linked with rheumatoid arthritis (RA) and hence pharmacological blockers of ORAI1 could be potential therapeutic agents for the treatment of RA. In this study, we have used a high-throughput screening approach to inhibit the binding of Ca(2+ )toward ORAI1 and the interactions are verified through induced fit docking. The results hint that these compounds act by possibly binding with, and thereby blocking Ca(2+)-binding with ORAI1 (E106). The molecular dynamics (MD) simulations shows strong support toward the hit compounds by showing the ligand potency throughout the simulation timescale of 30 ns. We have thus identified a novel class of highly stable, potential lead compounds that directly bind with the selectivity filter region E106 and block Ca(2+) binding on ORAI1. This resulting alteration in the pore geometry of ORAI1 due to the strong blocking mechanism of lead compounds will greatly diminish its function and the downstream activities that result from the same including decreased production of cytokines in autoimmune disorders. This study may lay the foundation for finding novel lead compounds for clinical trials that could positively modulate the course of autoimmune disorders with ORAI1 as its specific target.
27429986 MicroRNA-21 Promotes Proliferation of Fibroblast-Like Synoviocytes through Mediation of NF 2016 MicroRNA-21 (miR-21) is overexpressed in patients with rheumatoid arthritis (RA). This study was designed to investigate the effect and mechanism of miR-21 on cell proliferation in fibroblast-like synoviocytes (FLS) of RA. FLS were primary-cultured from a rat RA model. RA-FLS and normal FLS were infected with lentivirus (anti-miR-21 or pro-miR-21) for overexpression or downregulation of miR-21, respectively. The effects of miR-21 overexpression or inhibition on nucleoprotein NF-κB levels and FLS cell proliferation were evaluated by western blotting and MTT assays. The effects of an inhibitor of NF-κB nuclear translocation (BAY 11-7082) were also evaluated. The results showed that the levels of miR-21 and nucleoprotein NF-κB were increased in FLS of RA model rats compared to the control group. Downregulation of miR-21 in RA FLS led to a significant decrease in nucleoprotein NF-κB levels and cell proliferation rates compared to the antinegative control (NC) group. However, miR-21 overexpression in normal FLS resulted in a significant increase of nucleoprotein NF-κB levels and cell proliferation rates compared to the pro-NC group. The effects of miR-21 overexpression were reversed by BAY 11-7082. We concluded that upregulated miR-21 in FLS in RA model rats may promote cell proliferation by facilitating NF-κB nuclear translocation, thus affecting the NF-κB pathway.
26939566 Genetic variants associated with rheumatoid arthritis patients and serotypes in European p 2016 Mar OBJECTIVES: To replicate the association of rheumatoid arthritis (RA) susceptibility loci in an independent European sample and to assess their specificity with anti-citrullinated protein antibodies (ACPA) status. METHODS: A selection of 64 SNP previously associated with RA have been typed in a cohort of 267 RA patients (169 ACPA-positive and 98 ACPA-negative) and 152 controls from the Rheumatology Units of the University Hospital of Pisa (Italy) and the University of Pécs Medical Center (Hungary). Regression analyses were performed first considering overall RA patients and secondly, taking both serotype subgroups as different disease entities. The results have been adjusted for age, gender and origin of individuals. RESULTS: The well-known CD2, REL, TNFAIP3, IRF5, PTPRC, and CCR6 have been confirmed as RA disease associated loci together with recently discovered BACH2, RASGRP1, and IKZF3 loci, taking all RA patients as a unique phenotype. Results from both serological subgroups separately reflect the specificity of these susceptibility loci and show additional ACPA-positive specific associations for variants at IL6R, IL2RA, BLK, DDX6, IL6, and TLE3 genes. CONCLUSIONS: The results from GAPAID project are consistent with previously established RA disease associations for CD2, PTPRC, REL, CCR6, TNFAIP3, IRF5, BLK, IL2RA, and DDX6 loci. In addition, IL6R, BACH2, RASGRP1, TLE3, and IKZF3 are replicated for the first time in an independent European population and IL6 appears to be a suggestive new RA associated locus. The stratified analysis based on ACPA status provides further support for distinct genetic aetiologies of RA subsets, which might have therapeutic implications.
25239880 Red cell distribution width is associated with cardiovascular risk and disease parameters 2015 Apr OBJECTIVE: Since red cell distribution width (RDW) has been associated with cardiovascular (CV) disease and inflammation in several conditions, the main aim of this study was to evaluate its prognostic value in RA patients and its potential associations with clinical features. METHODS: The history of CV events was retrospectively reviewed in 160 RA patients and RDW was recorded at disease onset and 6 and 12 months after diagnosis to calculate the accumulated value [area under the curve (AUC) RDW] and change during the first year (ΔRDW). In addition, RDW was analysed in 110 patients with established disease in relation to clinical features. RESULTS: Increased RDW at diagnosis and AUC RDW were able to predict the occurrence of CV events in RA patients [hazard ratio (HR) 1.247 (95% CI 1.079, 1.441), P = 0.003 and HR 1.038 (95% CI 1.018, 1.059), P = 0.0001, respectively] after adjusting by potential confounding factors. Receiver operating characteristic curve analyses revealed a better power of discrimination for the AUC RDW (P = 3.394 × 10(-5)). In addition, an increase in RDW during the first year was associated with poor CV outcome (P = 0.010). On the other hand, RDW in patients with established RA was significantly associated with disease activity, acute phase reactants and severity. CONCLUSION: RDW at disease onset may be used as an early marker of CV risk in RA, whereas in patients with established disease it was related to the activity of the disease. These findings suggest that RDW can be considered as a surrogate marker of inflammation and, consequently, CV risk in RA patients.
24431396 Chronicity of rheumatoid arthritis affects the responsiveness of physical function, but no 2015 Mar BACKGROUND: In previous studies it has been indicated that functional measures are less responsive in patients with established or late rheumatoid arthritis (RA) as compared with early RA, potentially because chronic irreversible functional damage is present. Therefore, they may not be useful as disease activity measures. We aimed to investigate whether this is specific to functional measures, or if it similarly also relates to other typical RA disease activity measures. METHODS: We performed a pooled analysis of patient level clinical trial data of patients with RA. We investigated the effects of duration of RA on the responsiveness of all RA core set measures by using logistic regression analysis. We performed a number of sensitivity analyses to support our findings. RESULTS: The probability of response in functional scores decreased from ~60% in early disease to ~30% in established/late disease (p=0.0023). No other core set variable or composite index behaved in this way. The effect of chronicity solely on functional responses was confirmed in all sensitivity analyses, particularly also when joint damage was used as a surrogate of chronicity, responsiveness decreased from >60% in patients with little structural damage to <20% in patients with severe joint damage (p<0.001). CONCLUSIONS: Physical function is among the most important outcomes of RA, but in contrast with other core set measures it is not a reliable measure for disease activity.
27186644 Effect of tumor necrosis factor-α inhibitors on ambulatory 24-h blood pressure. 2017 Feb Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used in inflammatory rheumatic diseases (IRD). The risk of cardiovascular disease is elevated in patients with IRD and TNF-α inhibitors reduce this risk. We assessed whether the beneficial effect of TNF-α inhibitors on cardiovascular risk is mediated by blood pressure reduction. We measured blood pressure levels with 24-h ambulatory blood pressure measurements device in patients with IRD before and 3 months after treatment with TNF-α inhibitors. The study population consisted of 15 subjects (6 men; mean age 45.9 ± 14.1 years). Most patients had either rheumatoid arthritis or psoriatic arthritis and adalimumab was the most common TNF-α inhibitor used. Mean 24-h systolic and diastolic blood pressure levels remained the same after treatment (121 ± 12/66 ± 7 before and 123 ± 11/67 ± 10 mm Hg after; p = 0.88 and 0.66, respectively). The study demonstrates that TNF-α inhibitors have no effect on blood pressure levels.
29071924 [Influence of Heat-reinforcing Needling on Expression of Plasma Atp 5 O mRNA and Atp 6 V 1 2016 Aug 25 OBJECTIVE: To observe influences of heat-reinforcing needling (HRN) on scores of traditional Chinese medicine (TCM) symptoms and expression of plasma ATP synthase subunit O (Atp 5 O) mRNA and lysosomal V 1 subunit B 2 (Atp 6 V 1 B 2) mRNA in patients with wind-cold-damp retention type rheumatoid arthritis (RA), so as to investigate its biological mechanisms in "heat production". METHODS: Sixty wind-cold-damp retention type RA patients were randomly allocated to HRN group (n=30) and control group (n=30). Guanyuan (CV 4), Qihai (CV 6), bilateral Zusanli (ST 36), and local acupoints near the knee-joint were selected for needling stimulation. Patients of the HRN group were treated by manipulating the acupuncture needle with HRN, and those of the control group treated by manipulating the needle with uniform reinforcing-reducing method. The treatments were performed once daily, 5 days a week, and two weeks altogether. The other 30 healthy volunteers were recruited as the normal control group. The TCM symptom scoring system (0-31 points, 11 items as the severities of pain, swelling and tenderness of the knee-joint) was used to evaluate the status of RA, and quantitative real-time PCR (RT-PCR) was used to detect the expression of plasma Atp 5 O mRNA and Atp 6 V 1 B 2 mRNA following removal of red blood cells. RESULTS: After the treatment, the TCM scores of both the HRN and control groups were significantly decreased (P<0.05), and that of the HRN group was significantly lower than that of the control group (P<0.05). Before the treatment, the expression levels of plasma Atp 5 O mRNA and Atp 6 V 1 B 2 mRNA in RA patients were significantly lower than those of the normal group (P<0.05), and after the treatment, the expression levels of plasma Atp 5 O mRNA and Atp 6 V 1 B 2 mRNA were significantly increased in both HRN and control groups compared to pre-treatment in the same one group (P<0.05), and the up-regulated Atp 5 O mRNA and Atp 6 V 1 B 2 mRNA levels were remarkably higher in the control group than in the HRN group (P<0.05). CONCLUSIONS: Both heat-producing needling and uniform reinforcing-reducing needling can improve RA patients' clinical symptoms, which may be associated with their actions in up-regulating expressions of plasma Atp 5 O mRNA and Atp 6 V 1 B 2 mRNA.
26235697 Early medication use in new-onset rheumatoid arthritis may delay joint replacement: result 2015 Aug 3 INTRODUCTION: Use of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) may prevent joint damage and potentially reduce joint replacement surgeries. We assessed the association between RA drug use and joint replacement in Quebec, Canada. METHODS: A cohort of new-onset RA patients was identified from Quebec's physician billing and hospitalization databases from 2002-2011. The outcome was defined using procedure codes submitted by orthopedic surgeons. Medication use was obtained from pharmacy databases. We used alternative Cox regression models with time-dependent variables measuring the cumulative effects of past use during different time windows (one model focussing on the first year after cohort entry) for methotrexate (MTX), and other DMARDs. Models were adjusted for baseline sociodemographics, co-morbidity and prior health service use, time-dependent cumulative use of other drugs (anti-tumor necrosis factor [anti-TNF] agents, other biologics, cyclooxygenase-2 inhibitors [COXIBs], nonselective nonsteroidal antiinflammatory drugs [NSAIDs], and systemic steroids), and markers of disease severity. RESULTS: During follow-up, 608 joint replacements occurred among 11,333 patients (median follow-up: 4.6 years). The best-fitting model relied on the cumulative early use (within the first year after cohort entry) of MTX and of other DMARDs, with an interaction between MTX and other DMARDs. In this model, greater exposure within the first year, to either MTX (adjusted hazard ratio, HR = 0.95 per 1 month, 95% confidence interval, 95% CI 0.93-0.97) or other DMARDs (HR = 0.97, 95% CI 0.95-0.99) was associated with longer time to joint replacement. CONCLUSIONS: Our results suggest that longer exposure to either methotrexate (MTX) or other DMARDs within the first year after RA diagnosis is associated with longer time to joint replacement surgery.
26055762 Pericardial mass in a patient with rheumatoid arthritis. 2015 Jun 8 A 65-year-old man presented with long-standing rheumatoid arthritis (RA), severe fatigue and mild arthritis of metacarpophalaneal joints. Physical examination revealed S3, II/IV decrescendo diastolic murmur and 2+ LL oedema. Anticyclic citrullinated peptide antibodies were >250 units. Echocardiogram showed an 8 cm pericardial mass with no atrial or ventricular collapse and mild to moderate aortic regurgitation. Cardiac MRI defined the mass as a heterogeneous entity attached to the right, anterior and inferior heart borders, with compression on right cardiac structures and the left ventricle. CT-guided biopsy demonstrated fibrinous material without granulomas or infection. Fatigue did not improve on immunosuppression with low-dose prednisone and leflunamide. Cardiac tamponade was confirmed by heart catheterisation and the mass was surgically excised with partial pericardiectomy. The patient had a dramatic improvement and, 4 years later, he remains asymptomatic cardiac wise. This case highlights the clinical significance of pericardial disease in RA and its response to therapy.
27405509 Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with 2017 Mar OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.
25687553 Determinants of reaching drug-free remission in patients with early rheumatoid or undiffer 2015 Aug OBJECTIVE: The aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy. METHODS: We included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year. RESULTS: After 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013). CONCLUSION: After 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained.