Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
31581593 Detection of Increased Relative Expression Units of Bacteroides and Prevotella, and Decrea 2019 Oct 1 Interactions between gut microbes and disease modifying antirheumatic drugs (DMARDs) have been proposed. The aim of the present study was to evaluate the presence of some specific bacteria in stool samples from Brazilian RA patients receiving DMARDs and correlate these data with diet, clinical parameters, and cytokines. Stool samples were used for gut bacteria evalutation by qPCR. Serum samples were used to quantify IL-4 and IL-10 by flow cytometer. Statistics were performed by Pearson chi-square, Mann-Whitney U test, and Spearman's correlation. The study included 20 RA patients and 30 healthy controls. There were no significant differences (P > 0.05) in dietary habits between RA patients and controls. Concerning gut bacteria, we observed an increase in relative expression units (REU) of Bacteroides and Prevotella species in stool samples from patients, and a decrease in REU of Clostridium leptum when compared with healthy controls. Positive correlation between Prevotella and rheumatoid factor was detected. The IL-4 and IL-10 concentrations were increased in patients when compared with controls. We concluded that gut bacteria are different between RA patients receiving DMARDs and healthy controls. Further studies are necessary to determine the real role of gut microbes and their metabolities in clinical response to different DMARDs in RA patients.
31620540 Ulcerative Colitis and Familial Mediterranean Fever: Can Anakinra Treat Both? 2019 Jul Anakinra is a biological drug used in rheumatoid arthritis and several autoinflammatory diseases. Its main side effects are injection site reactions and increased infection rate. We present a 28-year-old man with familial Mediterranean fever, whose disease went into remission on anakinra, with concomitant flare of his ulcerative colitis.
31308202 Outcome Monitoring and Clinical Decision Support in Polyarticular Juvenile Idiopathic Arth 2020 Feb OBJECTIVE: Inconsistent assessment and treatment may impair juvenile idiopathic arthritis (JIA) outcomes. We aimed to improve polyarticular JIA (rheumatoid factor-positive and -negative) outcomes by standardizing point-of-care disease activity monitoring and implementing clinical decision support (CDS) to reduce treatment variation. METHODS: We performed a quality improvement initiative in an outpatient pediatric rheumatology practice. The interventions, implemented from April to November 2016, included standardized disease activity measurement, disease activity target review, and phased introduction of polyarticular JIA CDS to guide medication selection, dosing, treatment duration, and tapering. Process measures included visit-level target attestation (goal: 50%) and CDS use (goal: 15%). Our goal was to reduce the polyarticular JIA clinical Juvenile Arthritis Disease Activity Score (cJADAS-10) by at least 10%. Included patients had at least 2 visits from April 2016 through July 2017, and were classified as having early (≤ 6 mos) or established disease (> 6 mos). RESULTS: Patients with polyarticular JIA (n = 97; 81% established disease) were observed for 10.3 months (interquartile range: 6.4-12.3). Target attestation and CDS use occurred in a mean of 77% and 45% of polyarticular JIA visits, respectively. The median cJADAS-10 decreased significantly in both early (16.5 to 2.7, p < 0.001) and established polyarticular JIA (2.1 to 1.0, p = 0.01). A high proportion of patients with early disease received biologic therapy (73.7%). In established disease, although prescription of nonbiologic and biologic disease-modifying antirheumatic drugs remained similar overall, adalimumab prescribing increased (12.8% to 23.1%, p = 0.008). CONCLUSION: Implementation of structured disease activity monitoring and CDS in polyarticular JIA was associated with significant reductions in disease activity scores in both early and established disease.
31728208 Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 indepen 2019 Rheumatoid arthritis (RA) is a multifactorial disease which is complicated by apoptosis resistance. Autophagy is one of the key mechanisms which are involved in the development of resistance to apoptosis as well as to the standard therapies against RA. Aberration in autophagy and apoptosis homeostasis results in the development of oxidative stress thus complicates the pathogenesis of RA. In the given study, tomorou, an indigenous herb of Hunza-Nagar Valley, has been evaluated for its pro-apoptotic, anti-inflammatory, and anti-rheumatic activity. Several major classes of bioactive phytochemicals including steroids, terpenoids, phenols, flavonoids, and essential oils have been detected in the aqueous and ethyl acetate extracts of tomorou through phytochemical analysis. Plant extracts depicted enhanced free radical scavenging activity through di-phenyl-2-picryl hydrazyl hydrate (DPPH) assay and ameliorated the symptoms of arthritis in collagen induced arthritic (CIA) mice model. Moreover, the 6 week extract treatment resulted in the reduction of IL-6 serum levels thus making it an effective anti-inflammatory agent. Upregulation of microtubule-associated proteins light chain 3b (LC3b) and downregulation of UNC51-like kinase 1 (ULK-1) in arthritic mice proposed a ULK-1 independent non-canonical autophagy pathway. Treatment with extracts upregulated the expression of caspase 3 which in turn inhibited the activity of LC3b thus altering the autophagy pathway. However, ULK-1 expression was restored to normal in aqueous extract treated group whereas it was upregulated in ethyl acetate extract treated group. On the other hand, a novel LC3b-independent autophagy pathway was observed in mice treated with ethyl acetate extract due to ULK-1 upregulation. Despite of significantly high IL-6 levels, the arthritic symptoms waned off which suggested the participation of IL-6 in LC3b-independent autophagy pathway in the extract prepared in ethyl acetate. Conclusively, the study established pro-apoptotic, antioxidant, anti-inflammatory and anti-rheumatic activity of tomorou and suggested an intricate autophagy pathway shift.
31492040 Effect of Baricitinib and Adalimumab in Reducing Pain and Improving Function in Patients w 2019 Sep 5 Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks' treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation.
30621359 Efficacy of Integrating a Novel 16-Gene Biomarker Panel and Intelligence Classifiers for D 2019 Jan 6 Introducing novel biomarkers for accurately detecting and differentiating rheumatoid arthritis (RA) and osteoarthritis (OA) using clinical samples is essential. In the current study, we searched for a novel data-driven gene signature of synovial tissues to differentiate RA from OA patients. Fifty-three RA, 41 OA, and 25 normal microarray-based transcriptome samples were utilized. The area under the curve random forests (RF) variable importance measurement was applied to seek the most influential differential genes between RA and OA. Five algorithms including RF, k-nearest neighbors (kNN), support vector machines (SVM), naïve-Bayes, and a tree-based method were employed for the classification. We found a 16-gene signature that could effectively differentiate RA from OA, including TMOD1, POP7, SGCA, KLRD1, ALOX5, RAB22A, ANK3, PTPN3, GZMK, CLU, GZMB, FBXL7, TNFRSF4, IL32, MXRA7, and CD8A. The externally validated accuracy of the RF model was 0.96 (sensitivity = 1.00, specificity = 0.90). Likewise, the accuracy of kNN, SVM, naïve-Bayes, and decision tree was 0.96, 0.96, 0.96, and 0.91, respectively. Functional meta-analysis exhibited the differential pathological processes of RA and OA; suggested promising targets for further mechanistic and therapeutic studies. In conclusion, the proposed genetic signature combined with sophisticated classification methods may improve the diagnosis and management of RA patients.
30243782 Recommendations for the assessment and optimization of adherence to disease-modifying drug 2019 Jan BACKGROUND: Adherence to treatment is a key issue in chronic inflammatory rheumatic diseases (CIRDs). OBJECTIVE: To develop recommendations to facilitate in daily practice, the management of non-adherence to disease-modifying drugs in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, connective tissue diseases or other CIRDs. METHODS: The process comprised (a) systematic literature reviews of methods (including questionnaires) to measure non-adherence, risk factors for non-adherence and efficacy of targeted interventions; (b) development of recommendations through consensus of 104 rheumatologist and nurse experts; (c) assessment of agreement and ease of applicability (1-5 where 5 is highest) by the 104 experts. RESULTS: (a) Overall, 274 publications were analysed. (b) The consensus process led to 5 overarching principles and 10 recommendations regarding adherence. Key points include that adherence should be assessed at each outpatient visit, at least using an open question; questionnaires and hydroxychloroquine blood level assessments may also be useful. Risk factors associated to non-adherence were listed. Patient information and education, and patient/physician shared decision, are key to optimize adherence. Other techniques such as formalized education sessions, motivational interviewing and cognitive behavioral therapy may be useful. All health professionals can get involved and e-health may be a support. (c) The agreement with the recommendations was high (range of means, 3.9-4.5) but ease of applicability was lower (2.7-4.4). CONCLUSIONS: Using an evidence-based approach followed by expert consensus, this initiative should improve the assessment and optimization of adherence in chronic inflammatory rheumatic disorders.
31469249 Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability t 2020 Jan OBJECTIVE: To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. METHODS: Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively. RESULTS: The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). CONCLUSION: Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.
31060286 Dietary Habits Bursting into the Complex Pathogenesis of Autoimmune Diseases: The Emerging 2019 May 5 The incidence and prevalence of autoimmune diseases have increased in Western countries over the last years. The pathogenesis of these disorders is multifactorial, with a combination of genetic and environmental factors involved. Since the epidemiological changes cannot be related to genetic background, which did not change significantly in that time, the role of environmental factors has been reconsidered. Among these, dietary habits, and especially an excessive salt, typical of processed foods, has been implicated in the development of autoimmune diseases. In this review, we summarize current evidence, deriving both from experimental models and clinical studies, on the capability of excessive salt intake to exacerbate proinflammatory responses affecting the pathogenesis of immune-mediated diseases. Data on several diseases are presented, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and Crohn's disease, with many of them supporting a proinflammatory effect of salt. Likewise, a hypertonic microenvironment showed similar effects in experimental models both in vivo and in vitro. However, murine models of spontaneous autoimmune polyneuropathy exposed to high salt diet suggest opposite outcomes. These results dictate the need to further analyse the role of cooking salt in the treatment and prevention of autoimmune diseases, trying to shape a fine tuning between the possible advantages of a restricted salt intake and the changes in circulating metabolites, mediators, and hormones which come along salt consumption and could in turn influence autoimmunity.
30964554 Dipeptidyl peptidase-4 inhibitors lower the risk of autoimmune disease in patients with ty 2019 Aug AIMS: To evaluate the real-world effect of dipeptidyl peptidase-4 inhibitor (DPP4i) on the incidence of autoimmune diseases (AD), including rheumatoid arthritis (RA), inflammatory bowel diseases, multiple sclerosis and systemic lupus erythematosus. METHODS: We identified new users of DPP4i (n = 497 619) or non-DPP4i (n = 643 165) oral combination therapy between 1 January 2011 and 30 June 2015 among patients with type 2 diabetes mellitus in the Korean national health insurance claims database. Patients were followed from the date of initiation of combination therapy until AD outcome, censoring for treatment discontinuation or switching, death or end of study (31 August 2016). Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for RA, inflammatory bowel diseases, other AD (multiple sclerosis and systemic lupus erythematosus), and the composite of all outcomes were estimated using propensity score (PS)-adjusted Cox model. RESULTS: In the PS-weighted and PS-matched analysis, the risk of incident RA was decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.67 [95% CI 0.49-0.92] and aHR 0.72 [95% CI 0.51-1.01], respectively). In both analyses, the risk of incident composite AD was also decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.82 [95% CI 0.68-0.99] and aHR 0.76 [95% CI 0.62-0.93], respectively). CONCLUSIONS: In this large population-based cohort study, upfront DPP4i combination therapy was associated with a lower risk of composite AD compared with initial non-DPP4i combination therapy.
31616406 Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Disea 2019 Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role. Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated. Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function. Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response. Similar BCR hyporesponsiveness was also noted specifically in SLE CD27(-) B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells. Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo. Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs). The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40-CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs. The hyporesponsiveness of AID B cells is similar to a form of functional anergy.
31053401 BOB.1 controls memory B-cell fate in the germinal center reaction. 2019 Jul During T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical autoimmune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination.
30547379 Use of Auto-Injector for Methotrexate Subcutaneous Self-Injections: High Satisfaction Leve 2019 Mar INTRODUCTION: The objective of the study was to compare compliance and acceptability of a new auto-injector (AI) versus syringe for administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: We conducted a randomized, open-label, parallel group study comparing AI to pre-filled syringe (PFS). Adult patients with RA (ACR/EULAR 2010) receiving MTX (orally or by injection) for at least 3 months were allocated to AI or PFS for 6 months and then were allocated to AI for 6 further months. Two co-primary endpoints were defined at M6: percentage of patients with compliance at least 80%; change in functional capacity assessed by Health Assessment Questionnaire (HAQ). Secondary endpoints included quality of life (RaQoL), RA activity (DAS28), and acceptability. Local safety at injection site was assessed at each visit. RESULTS: Two-hundred and sixty-five patients were randomized. The main analysis was conducted on per protocol set (99 AI and 98 PFS). Compliance was 96.2% in AI and 98.9% in PFS. Good complier rates were 89.9% and 94.9%, thus a difference of - 5.0% (- 18.9%; 8.9%). HAQ remained stable in both groups. No difference was found on RaQoL, change in RA activity, and safety profile. Autonomy, acceptability, and patient satisfaction were better with AI, and patients having had the experience of both AI and PFS preferred AI (p < 0.001). CONCLUSIONS: Although this study did not demonstrate non-inferiority of AI versus PFS, compliance was excellent in the two groups, and AI, which was preferred by patients, is a valuable alternative to PFS for administration of MTX. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02553018. FUNDING: Nordic Pharma SAS.
31872185 Extraction of Rheumatoid Arthritis Disease Activity Measures From Electronic Health Record 2019 Dec OBJECTIVE: The accurate and efficient collection and documentation of disease activity measures (DAMs) is critical to improve clinical care and outcomes research in rheumatoid arthritis (RA). This study evaluated the performance of an automated process to extract DAMs from medical notes in the electronic health record (EHR). METHODS: An automated text processing system was developed to extract the Disease Activity Score for 28 joints (DAS28) and its clinical and laboratory elements from the Veterans Affairs EHR for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry. After automated text processing derivation, data accuracy was assessed by comparing the automated text processing system and manual extraction with gold standard chart review in a separate validation phase. RESULTS: In the validation phase, 1569 notes from 596 patients at 3 sites were evaluated, with 75 (6%) notes detected only by automated text processing, 85 (5%) detected only by manual extraction, and 1408 (90%) detected by both methods. The accuracy of automated text processing ranged from 90.7% to 96.7% and the accuracy of manual extraction ranged from 91.3% to 95.0% for the different clinical and laboratory elements. The accuracy of the two methods to calculate the DAS28 was 78.1% for automated text processing and 78.3% for manual extraction. CONCLUSION: The automated text processing approach is highly efficient and performed as well as the manual extraction approach. This advance has the potential for significant improvements in the collection, documentation, and extraction of these data to support clinical practice and outcomes research relevant to RA as well as the potential for broader application to other health conditions.
31763619 Tumour necrosis factor inhibitor exposure and radiographic outcomes in Veterans with rheum 2019 OBJECTIVES: The aim was to estimate the impact of TNF inhibitor (TNFi) exposure on radiographic disease progression in US Veterans with RA during the first year after initiating therapy. METHODS: This historical longitudinal cohort design used clinical and claims data to evaluate radiographic progression after initiation of TNFi. US Veterans with RA initiating TNFi treatment (index date), ≥ 6 months pre-index and ≥ 12 months post-index VA enrolment/activity, and initial (6 months pre-index to 30 days post-index) and follow-up (10-18 months post-index) bilateral hand radiographs were eligible. The cumulative TNFi exposure and change in modified Sharp score (MSS) between initial and follow-up radiographs were calculated. The percentage of patients with clinically meaningful change in MSS (≥ 5) for each month of exposure was assessed using a longitudinal marginal structural model with inverse probability of treatment weights. Mean values and CIs were generated using 1000 bootstrapped samples. RESULTS: For 246 eligible patients, the mean (s.d.) age was 58 (11) years; 81% were male. The mean (s.d.) initial MSS was 19.6 (33.4) (range 0-214). The mean change (s.d.) in MSS was 0.3 (3.6) (median 0, range -19 to 22). Patients with the greatest exposure had the least radiographic progression for both crude and adjusted model analyses. Adjusted rates of MSS change ≥ 5 points (95% CI) were 10.6% (9.8%, 11.4%) for patients with 3 months of exposure compared with 5.4% (5.1%, 5.7%) for patients with 12 months of exposure. CONCLUSION: One-year changes in radiographic progression were small. Patients with the greatest cumulative TNFi exposure experienced the least progression.
31610524 Methotrexate-associated lymphoproliferative disorder with hypopituitarism and central diab 2019 Oct 12 SUMMARY: Patients treated with immunosuppressive drugs, especially methotrexate (MTX), rarely develop lymphoproliferative disorders (LPDs), known as MTX-related LPD (MTX-LPD). The primary site of MTX-LPD is often extranodal. This is the first reported case of MTX-LPD in the pituitary. A 65-year-old woman was admitted to our hospital with symptoms of oculomotor nerve palsy and multiple subcutaneous nodules. She had been treated with MTX for 11 years for rheumatoid arthritis. Computed tomography showed multiple masses in the orbit, sinuses, lung fields, anterior mediastinum, kidney, and subcutaneous tissue. Brain magnetic resonance imaging revealed a sellar mass. She was diagnosed with hypopituitarism and central diabetes insipidus based on endocrine examination. Although pituitary biopsy could not be performed, we concluded that the pituitary lesion was from MTX-LPD, similar to the lesions in the sinuses, anterior mediastinum, and subcutaneous tissue, which showed polymorphic LPD on biopsy. MTX was discontinued, and methylprednisolone was administered to improve the neurologic symptoms. After several weeks, there was marked improvement of all lesions, including the pituitary lesion, but the pituitary function did not improve. When pituitary lesions are caused by MTX-LPD, the possibility of anterior hypopituitarism and central diabetes insipidus needs to be considered. Further studies are needed to investigate the effectiveness of early diagnosis and treatment of MTX-LPD in restoring pituitary dysfunction. LEARNING POINTS: Pituitary lesions from MTX-LPD may cause hypopituitarism and central diabetes insipidus. Pituitary metastasis of malignant lymphoma and primary pituitary lymphoma, which have the same tissue types with MTX-LPD, have poor prognosis, but the lesions of MTX-LPD can regress only after MTX discontinuation. In cases of pituitary lesions alone, a diagnosis of MTX-LPD may be difficult, unless pituitary biopsy is performed. This possibility should be considered in patients treated with immunosuppressive drugs. Pituitary hypofunction and diabetes insipidus may persist, even after regression of the lesions on imaging due to MTX discontinuation.
30981150 Tibialis posterior muscle pain effects on hip, knee and ankle gait mechanics. 2019 Aug BACKGROUND: Tibialis posterior (TP) dysfunction is a common painful complication in patients with rheumatoid arthritis (RA), which can lead to the collapse of the medial longitudinal arch. Different theories have been developed to explain the causality of tibialis posterior dysfunction. In all these theories, pain is a central factor, and yet, it is uncertain to what extent pain causes the observed biomechanical alterations in the patients. The aim of this study was to investigate the effect of experimental tibialis posterior muscle pain on gait mechanics in healthy subjects. METHODS: Twelve healthy subjects were recruited for this randomized crossover study. Experimental pain was induced by ultrasound-guided injection of 1 mL hypertonic saline into the upper part of the right tibialis posterior muscle with the use of isotonic saline as non-pain-inducing control. Subsequently, kinematic data during three self-paced over ground walking for each condition were collected. Ground reaction forces and external moments were measured from force plates installed in the floor. Painful areas were evaluated using body charts and pain intensity scoring via a verbal numerical rating scale. FINDINGS: Decreased hip internal rotation was observed during the pain condition at the end of the stance phase. There were no changes in gait velocity and duration of stand phase between the pain and no pain conditions. Reduced external joint moment was found for external knee rotation and for external hip rotation. INTERPRETATION: The study has demonstrated that induced pain in the TP muscle evokes kinematic alteration in the hip and the knee joints, but not in the ankle, which suggest an underlying early stage joint compensatory mechanism. These findings suggest the need to include those joints in current physical evaluations of tibialis posterior dysfunction.
31777832 The Relation Between Disease Activity, Patient-Reported Outcomes, and Grip Force Over Time 2019 Oct OBJECTIVE: The objective of this study is to identify early predictors of future reduced grip force in patients with rheumatoid arthritis (RA) and to identify early predictors of grip force over time. METHODS: In a structured follow-up of an inception cohort of patients with early RA, average grip force values of the dominant hand were evaluated and compared with the expected based on age- and sex-specific reference values. Potential predictors of reduced grip force (less than 50% of expected) at 5 years were examined using logistic regression. Differences in percentage of expected grip force values over the study period and differences in change over time, by baseline disease parameters, were estimated using mixed linear-effects models. RESULTS: Among 200 patients with early RA, 44% had reduced grip force 5 years after diagnosis. Baseline characteristics that predicted reduced grip force at 5 years included high scores for the Health Assessment Questionnaire Disability Index (odds ratio 1.54 per SD; 95% confidence interval 1.13-2.11), high scores for pain and patient global assessment, and low grip force. C-reactive protein levels, the erythrocyte sedimentation rate, the 28-joint Disease Activity Score (DAS28), rheumatoid factor, anti-cyclic citrullinated peptide antibodies, joint counts, and synovitis of individual joints in the dominant upper extremity did not predict reduced grip force. Patients with baseline synovitis of the wrist or metacarpophalangeal joints or patients with a high DAS28 had lower estimated grip force at inclusion but also greater improvement of grip force over time. CONCLUSION: Patient-reported outcomes predicted reduced grip strength 5 years after diagnosis. This underlines the prognostic importance of disability in early RA. Joint counts and synovitis in individual joints may change rapidly in early RA and appear to be less predictive of long-term hand function.
31175453 Cochlear involvement in patients with systemic autoimmune rheumatic diseases: a clinical a 2019 Sep PURPOSE: Inner ear involvement has been reported in systemic rheumatic disease while detection of cochlin-specific antibodies has been reported in patients with idiopatic sensorineural hearing loss, suggesting cochlin's strong link to autoimmune hearing loss. The aim of this cross-sectional study was to calculate the prevalence of sensorineural hearing loss (SNHL) in patients with systemic rheumatic diseases, and to investigate any potential correlation with human antibodies to cochlin. METHODS: Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and systemic sclerosis (SSc) according to the criteria of American College of Rheumatology were included in the study. All patients underwent a complete ear-nose-throat physical examination and audiological evaluation with pure tone audiometry and impedance audiometry. Pure tone average was calculated, taking as a starting point the hearing loss in dB according to the recommendation 02/1 of "Bureau International d' Audiophonologie" (BIAP) so as an average hearing threshold value. Sera of all patients were tested for the presence of IgG antibodies to human cochline (COCH-IgG). Sex and age-matched healthy subjects were included as controls to each group. RESULTS: A total of 133 patients were studied; 60 with RA, 41 with SLE, 24 with SS and 8 with SSc. 61.4% of patients reported vertigo, 41% hyperacousis, 39% hearing loss, 38% tinnitus, 37.9% headache and 2.1% sensation of ear pressure with unremarkable otoscopy. The prevalence of SNHL calculated for patients affected by RA, SLE, SS and SSc was 66.6%, 31.71%, 54.17%, and 75% respectively. The calculated average hearing thresholds value in RA was increased in comparison to SLE (p < 0.05). In addition it was also higher in patients with RA and secondary SS, in comparison to RA patients (p > 0.05). There was statistically significant correlation of average hearing threshold with disease activity score 28 (DAS28) in RA, but no correlation observed with disease activity index (SLEDAI) in SLE. COCH-IgG antibodies were detected in only two samples. The results were compared with those of their respective sex and age-matched healthy subjects. CONCLUSION: Our study revealed increased prevalence of SNHL in patients with systemic autoimmune rheumatic disease but no correlation of hearing loss with COCHIgG antibodies. The mechanism of inner ear damage remains unknown; thus, additional prospective studies will be needed to elucidate its pathogenesis.
31024565 FcγR-TLR Cross-Talk Enhances TNF Production by Human Monocyte-Derived DCs via IRF5-Depend 2019 Antigen-presenting cells (APCs) such as dendritic cells (DCs) are crucial for initiation of adequate inflammatory responses, which critically depends on the cooperated engagement of different receptors. In addition to pattern recognition receptors (PRRs), Fc gamma receptors (FcγRs) have recently been identified to be important in induction of inflammation by DCs. FcγRs that recognize IgG immune complexes, which are formed upon opsonization of pathogens, induce pro-inflammatory cytokine production through cross-talk with PRRs such as Toll-like receptors (TLRs). While the physiological function of FcγR-TLR cross-talk is to provide protective immunity against invading pathogens, undesired activation of FcγR-TLR cross-talk, e.g., by autoantibodies, also plays a major role in the development of chronic inflammatory disorders such as rheumatoid arthritis (RA). Yet, the molecular mechanisms of FcγR-TLR cross-talk are still largely unknown. Here, we identified that FcγR-TLR cross-talk-induced cytokine production critically depends on activation of the transcription factor interferon regulatory factor 5 (IRF5), which results from induction of two different pathways that converge on IRF5 activation. First, TLR stimulation induced phosphorylation of TBK1/IKKε, which is required for IRF5 phosphorylation and subsequent activation. Second, FcγR stimulation induced nuclear translocation of IRF5, which is essential for gene transcription by IRF5. We identified that IRF5 activation by FcγR-TLR cross-talk amplifies pro-inflammatory cytokine production by increasing cytokine gene transcription, but also by synergistically inducing glycolytic reprogramming, which is another essential process for induction of inflammatory responses by DCs. Combined, here we identified IRF5 as a pivotal component of FcγR-TLR cross-talk in human APCs. These data may provide new potential targets to suppress chronic inflammation in autoantibody-associated diseases that are characterized by undesired or excessive FcγR-TLR cross-talk, such as RA, systemic sclerosis, and systemic lupus erythematous.