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ID PMID Title PublicationDate abstract
34594331 Anti-Carbamylated LL37 Antibodies Promote Pathogenic Bone Resorption in Rheumatoid Arthrit 2021 OBJECTIVE: Antibodies against carbamylated proteins (anti-CarP) are associated with poor prognosis and the development of bone erosions in rheumatoid arthritis (RA). RA neutrophils externalize modified autoantigens through the formation of neutrophil extracellular traps (NETs). Increased levels of the cathelicidin LL37 have been documented in the synovium of RA patients, but the cellular source remains unclear. We sought to determine if post-translational modifications of LL37, specifically carbamylation, occur during NET formation, enhance this protein's autoantigenicity, and contribute to drive bone erosion in the synovial joint. METHODS: ELISA and Western blot analyses were used to identify carbamylated LL37 (carLL37) in biological samples. Anti-carLL37 antibodies were measured in the serum of HLA-DRB1*04:01 transgenic mice and in human RA synovial fluid. RESULTS: Elevated levels of carLL37 were found in plasma and synovial fluid from RA patients, compared to healthy controls. RA NETs release carLL37 and fibroblast-like synoviocytes (FLS) internalized NET-bound carLL37 and loaded it into their MHCII compartment. HLA-DRB1*04:01 transgenic mice immunized with FLS containing NETs developed autoantibodies against carLL37. Anti-carLL37 antibodies were present in RA sera and synovial fluid and they correlated with radiologic bone erosion scores of the hands and feet in RA patients. CarLL37-IgG immune complexes enhanced the ability of monocytes to differentiate into osteoclasts and potentiated osteoclast-mediated extracellular matrix resorption. CONCLUSIONS: NETs are a source of carLL37 leading to induction of anti-carbamylated autoantibody responses. Furthermore, carLL37-IgG immune complexes may be implicated in the bone damage characteristic of RA. These results support that dysregulated NET formation has pathogenic roles in RA.
33243062 Induction of remission in female rheumatoid arthritis patients is associated with stabiliz 2021 Mar Objectives: To study whether female patients with active rheumatoid arthritis (RA) have myocardial abnormalities and whether progression of myocardial involvement can be attenuated by disease-modifying anti-rheumatic drugs (DMARDs).Method: Cardiac magnetic resonance (cMR; 1.5 or 3.0 T), including late gadolinium enhancement (LGE), T1 relaxation time, and ventricular functions, was performed in 30 patients with untreated active early RA starting first DMARDs, and 28 patients with chronic RA with inadequate response to conventional synthetic DMARDs starting biological DMARDs. cMR was repeated in RA patients 1 year later. cMR was conducted once in 22 fibromyalgia (FM) subjects and in 35 healthy volunteers serving as controls. All subjects were non-smoking females without coronary heart disease, heart failure, or diabetes.Results: Compared with controls, 58 RA patients had slightly lower ventricular function, although in the normal range, and longer T1 time at baseline. None of the FM subjects had LGE, but it was frequent in RA (67%). During the 1 year DMARD treatment, Disease Activity Score based on 28-joint count-C-reactive protein declined, ventricular functions tended to improve, but the number of patients with LGE remained unchanged. However, the number of LGE-positive heart segments either decreased or stayed the same in 91% of RA patients. In early RA patients, achieving tight remission was associated with LGE stabilization, after adjustment for age, metabolic syndrome, baseline inflammatory activity, and leisure-time physical activity.Conclusion: Treatment targeted to tight remission in early stages of RA seems to be important to prevent not only joint damage but also myocardial abnormalities.
34465391 Impact of the HLA-DRB1 shared epitope on responses to treatment with tofacitinib or abatac 2021 Aug 31 OBJECTIVES: The aim of this study was to compare the clinical effectiveness of tofacitinib and abatacept and clarify the impact of the HLA-DRB1 shared epitope (SE) on responses to these treatments in patients with rheumatoid arthritis (RA). METHODS: After adjustments by propensity score matching, 70 out of 161 patients receiving tofacitinib and 70 out of 131 receiving abatacept were extracted. The clinical effectiveness of both drugs over 24 weeks and the impact of the copy numbers of SE on effectiveness outcomes were investigated. RESULTS: The percentage of patients in remission in the 28-joint count disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) did not significantly differ between patients receiving tofacitinib and abatacept at week 24 (32% vs 37%, p = 0.359). The mean change at week 4 in DAS28-ESR from baseline was significantly greater in patients receiving tofacitinib than in those receiving abatacept (- 1.516 vs - 0.827, p = 0.0003). The percentage of patients in remission at week 4 was 30% with tofacitinib and 15% with abatacept (p = 0.016). When patients were stratified by the copy numbers of SE alleles, differences in these numbers did not affect DAS28-ESR scores of patients receiving tofacitinib. However, among patients receiving abatacept, DAS28-ESR scores were significantly lower in patients carrying 2 copies of SE alleles than in those carrying 0 copies at each time point throughout the 24-week period. Furthermore, the percentage of patients in remission with DAS28-ESR at week 24 was not affected by the copy numbers of SE alleles in patients receiving tofacitinib (p = 0.947), whereas it significantly increased as the copy numbers became higher in patients receiving abatacept (p = 0.00309). Multivariable logistic regression analyses showed a correlation between the presence of SE and DAS28-ESR remission in patients receiving abatacept (OR = 25.881, 95% CI = 3.140-213.351, p = 0.0025), but not in those receiving tofacitinib (OR = 1.473, 95% CI = 0.291-7.446, p = 0.639). CONCLUSIONS: Although the clinical effectiveness of tofacitinib and abatacept was similar at week 24, tofacitinib was superior to abatacept for changes from baseline in DAS28-ESR and the achievement of remission at week 4. SE positivity was associated with the achievement of DAS28-ESR remission by week 24 in patients receiving abatacept, but not in those receiving tofacitinib.
34075738 Ononin induces cell apoptosis and reduces inflammation in rheumatoid arthritis fibroblast- 2021 Jun 2 As a kind of chronic inflammatory diseases, Rheumatoid arthritis (RA) has a low cure rate and easy recurrence. It has widely reported that abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways are associated with the development of RA inflammation. Blocking the inflammatory signaling pathways of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) can delay the development of RA. Ononin is a natural isoflavone glycoside and plays a key role in modulating inflammation related signaling pathways. However, whether Ononin exerts anti-inflammatory effects on RA inflammation remains unknown. In this study, we evaluated the therapeutic effect of Ononin on RA by establishing a tumor necrosis factor α (TNF-α)-induced RA-FLS cell model. Our data confirmed that Ononin could alleviate TNF-α-induced RA-FLS and MH7A cells viability, increase cell apoptosis, decrease the production of pro-inflammatory cytokines like interleukin-1β (IL-1β) and interleukin 6 (IL-6), and further inhibit the abnormal activation of NF-κB and MAPK pathways. Our results suggested that Ononin could be a potential therapeutic agent for RA.
34321563 The role of IL-18 in addition to Th17 cytokines in rheumatoid arthritis development and tr 2021 Jul 28 We aimed to analyze serum pro-inflammatory profiles of female rheumatoid arthritis (RA) patients and compare them with healthy women to establish the relative importance of pro-inflammatory cytokines in RA and their relation with different treatment regimens. Levels of six cytokines were determined by ELISA assays. A supervised dimensionality reducing approach (PLS-DA Analysis) was applied. All of the cytokines assayed were significantly elevated in the sera of RA female patients than healthy controls with fold change: 21-fold for IL-6; 6.1-fold for IL-17A; 2.5-fold for IL-23; 2.3-fold for IL-18; 1.94-fold for TNF-α; 1.7-fold for IL-12p40. According to the results of the PLS-DA analysis, IL-17A, IL-18, and TNF-α were of higher importance rank compared to IL-23 and IL-12p40. Women in the early stage of RA displayed significantly elevated IL-17A levels than those with longer disease duration: 8.04 pg/ml [8.04-175.3] vs 4.64 pg/ml [2.95-13.31], p = 0.007. IL-6 serum levels were related to higher disease activity. We have demonstrated altered cytokine production within female RA patients on different treatment regimens. Those on Tocilizumab therapy showed elevated IL-6 levels and decreased IL-17A versus the rest of the patients' subgroups. In conclusion, our data support the pivotal role of IL-18 in addition to IL-6, IL-17A, and TNF-α as the hierarchical cytokines in the pathogenesis of RA, particularly valid for women. Therapy with biological agents targeting IL-18 in addition to the Th17 axis may be an adequate approach in RA patients.
34779378 Restless Leg Syndrome and Sleep Disorders in Patients with Rheumatoid Arthritis and Its Re 2021 OBJECTIVES: We aimed to investigate the prevalence of restless legs syndrome (RLS) and sleep disorders in patients with rheumatoid arthritis (RA), and the association of iron deficiency with them. MATERIALS AND METHODS: The study included 72 patients with RA (59 females, 13 males), and 50 healthy control subjects (57 females, 15 males). Assessments were made using the International RLS Rating Scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Fatigue Severity Scale (FSS), Beck anxiety and depression index and the SF-36 quality of life scores. RESULTS: We found that the frequency of RLS in RA patients was 29.1% and 13.8% in healthy control (p = 0.021). RA patients had 44.4% iron deficiency and 5.5% anemia of chronic disease. We found that 52.3% of patients with iron deficiency had RLS. There was an independent relationship between present of RLS and FSS (Beta [β] = 0.317, p = 0.005) and total iron binding capacity (TIBC) (β = 0.244, p = 0.031). There was an independent relationship between RLS severity score and PSQI (β = 0.264, p = 0.025) and social functionality (β = 0.302, p = 0.009). CONCLUSION: The prevalence of iron deficiency is high in RA in the developing countries. Analysis obtained in patients with RA is suggestive of an association between iron deficiency and increased frequency of RLS. The presence of RLS in patients with RA negatively affects sleep quality, psychiatric status, and quality of life of patients with RA. TIBC value may be a predictive marker for early detection of RLS in patients with RA.
34453959 Molecular toxicity of methotrexate in rheumatoid arthritis treatment: A novel perspective 2021 Sep Rheumatoid arthritis (RA) is an autoimmune inflammatory systematic complication which is a chronic disorder that severely affects bones and joints and results in the quality of life impairment. Methotrexate (MTX), an FDA-approved drug has maintained the standard of care for treating patients affected with RA. The mechanism of MTX includes the inhibition of purine and pyrimidine synthesis, suppression of polyamine accumulation, promotion of adenosine release, adhesion of the inflammatory molecules, and controlling of cytokine cascade in RA. The recommended dose for RA patients is 5-25 mg of MTX per week, depending on the severity of the disease but MTX has proven to be cytotoxic with side effects affecting various tissues when treating RA patients even with low doses over a prolonged period of time. The mechanism of such toxicity is not entirely understood. This review strives to understand it by correlating the different pathways, including MTX in folate metabolism, Sirt1/Nrf2/γ-gcs, and γ-gcs/CaSR-TNF-α/NF-kB signaling. In addition to this, the importance of targeted therapy combination with MTX on RA treatment and combinations approved from the clinical trials are also briefly discussed. Overall, this review elucidates the various MTX molecular mechanisms and toxicity at the molecular level, the limitations, and the scope for future directions.
33791811 Sorafenib suppresses proliferation rate of fibroblast-like synoviocytes through the arrest 2021 Mar 1 OBJECTIVES: Rheumatoid arthritis, a recurrent incendiary autoimmune joint syndrome, features by prominent synovial hyperplasia. Fibroblast-like synoviocytes are the executive components in the pathogenesis of rheumatoid arthritis. It is generally accepted that excessive proliferation and reduced apoptosis of fibroblast-like synoviocytes lead to synovial hyperplasia. Our previously studies found that sorafenib could inhibit adjuvant arthritis in rats and induced adjuvant arthritis fibroblast-like synoviocytes apoptosis. Presently, we aim to investigate the inhibitory effect with mechanisms of action of sorafenib on adjuvant arthritis fibroblast-like synoviocytes proliferation. METHODS: Cell counting kit-8 and flow cytometry detection were conducted to monitor FLSs proliferation and cell cycle. Western blotting and qPCR assays were performed to detect P21, P53, CDK4, CyclinD1 and proliferating cell nuclear antigen content levels. KEY FINDINGS: Sorafenib significantly inhibited adjuvant arthritis fibroblast-like synoviocytes proliferation with an IC50 value of 4 µmol/L by a concentration-dependent pattern, which accompanies by G1 cell cycle arrest. Also, sorafenib significantly decreased the levels of P21, CyclinD1, CDK4 and proliferating cell nuclear antigen, as well as up-regulated P53 expression in adjuvant arthritis fibroblast-like synoviocytes. CONCLUSIONS: Sorafenib could inhibit adjuvant arthritis fibroblast-like synoviocytes proliferation via arresting G1/S cell cycle progression, which was partially through CDK4/CyclinD1-mediated pathway, as well as up-regulating P53 and down-regulating proliferating cell nuclear antigen expressions. These results suggest that sorafenib may provide a new paradigm for rheumatoid arthritis treatment.
33605404 Do people with rheumatoid arthritis maintain their physical activity level at treatment on 2021 Oct 2 OBJECTIVES: To describe how many people with RA reduce their baseline physical activity level over the first year of MTX treatment, and which factors predict this. METHODS: Data came from the Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of people with early RA starting MTX. Participants reported demographics and completed questionnaires at baseline, and 6 and 12 months, including reporting the number of days per week they performed ≥20 min of physical activity, coded as none, low (1-3 days) or high (4-7 days). The physical activity levels of participants over 12 months are described. Predictors of stopping physical activity were assessed using multivariable logistic regression. RESULTS: In total, 1468 participants were included [median (interquartile range) age 60 (50, 69) years; 957 (65.2%) women]. At baseline, the physical activity levels of the people with RA were: none = 408 (27.8%), low = 518 (35.3%) and high = 542 (36.9%). Eighty percent of participants maintained some physical activity or began physical activity between assessments (baseline to 6 months = 79.3%, 6 months to 12 months = 80.7%). In total, 24.1% of participants reduced physical activity and 11.3% of participants stopped performing physical activity between baseline and 6 months (6 months to 12 months: 22.6% and 10.2%, respectively). Baseline smoking, higher disability and greater socioeconomic deprivation were associated with stopping physical activity. CONCLUSION: Many people with early RA were not performing physical activity when starting MTX, or stopped performing physical activity over the first year of treatment. These people may require interventions to stay active. These interventions need to be mindful of socioeconomic barriers to physical activity participation.
35069583 The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and P 2021 OBJECTIVE: The purpose of this study was to evaluate the efficacy of denosumab treatment in patients with rheumatoid arthritis (RA). METHODS: The Medline, Embase and Cochrane Library databases were searched for relevant clinical studies. Studies that assessed the efficacy of denosumab in patients with RA were identified. The primary endpoints were the percent changes in bone mineral density (BMD), and the changes in modified total Sharp score (mTSS), modified Sharp erosion score and joint space narrowing (JSN) score. Pooled analyses were calculated using random-effect models. RESULTS: After searching the literature and performing further detailed assessments, 10 studies with a total of 1758 patients were included in the quantitative analysis. Pooled analyses showed that denosumab treatment significantly increased the percent changes in lumbar spine BMD [mean difference (MD): 5.12, confidence intervals (CI): 4.15 to 6.09], total hip BMD (MD: 2.72, 95% CI: 1.80 to 3.64) and femoral neck BMD (MD: 2.20, 95% CI: 0.94 to 3.46) compared with controls. Moreover, denosumab treatment significantly decreased the changes in mTSS (MD: -0.63, 95% CI: -0.86 to -0.41) and modified Sharp erosion score (MD: -0.62, 95% CI: -0.88 to -0.35). Subgroup analysis indicated that denosumab was superior to bisphosphonates for the improvement of BMD and the mitigation of joint destruction. CONCLUSION: Denosumab treatment was associated with increased BMD and alleviated progression of joint destruction in RA patients, even when compared with bisphosphonates.
34057740 Porphyromonas gingivalis induces periodontitis, causes immune imbalance, and promotes rheu 2021 Sep Periodontitis induced by bacteria especially Porphyromonas gingivalis (P. gingivalis) is the most prevalent microbial disease worldwide and is a significant risk factor for systemic diseases such as rheumatoid arthritis (RA). RA and periodontitis share similar clinical and pathologic features. Moreover, the prevalence of RA is much higher in patients with periodontitis than in those without periodontitis. To explore the immunologic mechanism of periodontitis involved in RA, we established a mouse model of periodontitis and then induced RA. According to the results of paw thickness, arthritis clinical score, arthritis incidence, microscopic lesion using H&E staining, and micro-CT analysis, periodontitis induced by P. gingivalis promoted the occurrence and development of collagen-induced arthritis (CIA) in mice. Furthermore, periodontitis enhanced the frequency of CD19(+) B cells, Th17, Treg, gMDSCs, and mMDSCs, whereas down-regulated IL-10 producing regulatory B cells (B10) in CIA mice preinduced for periodontitis with P. gingivalis. In vitro stimulation with splenic cells revealed that P. gingivalis directly enhanced differentiation of Th17, Treg, and mMDSCs but inhibited the process of B cell differentiation into B10 cells. Considering that adoptive transfer of B10 cells prevent RA development, our study, although preliminary, suggests that down-regulation of B10 cells may be the key mechanism that periodontitis promotes RA as the other main immune suppressive cells such as Treg and MDSCs are up-regulated other than down-regulated in group of P. gingivalis plus CIA.
34635095 Factors associated with mortality in rheumatoid arthritis-associated interstitial lung dis 2021 Oct 11 BACKGROUND: Interstitial lung disease (ILD) is a common and potentially life-threatening complication for rheumatoid arthritis (RA) patients. However, there is a lack of clear prognostic factors in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. The purpose of this study was to complete a systematic review and meta-analysis of the factors associated with mortality in RA-ILD patients. METHODS: Medline, EMBASE and the Cochrane Library were searched up to September 1, 2020. The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, pooled hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) and pooled risk ratios (RRs) with 95% CIs were calculated to assess the factors associated with mortality in RA-ILD. RESULTS: Twenty-three of 3463 articles were eligible, and ten factors associated with mortality for RA-ILD were evaluated in the meta-analysis. Older age (HRs = 1.04, 95% CI 1.03-1.05), male sex (HRs = 1.44, 95% CI 1.21-1.73), having a smoking history (HRs = 1.42, 95% CI 1.03-1.96), lower diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (HRs = 0.98, 95% CI 0.97-1.00), forced vital capacity (FVC)% predicted (HRs = 0.99, 95% CI 0.98-1.00), composite physiological index (CPI) (HRs = 1.04, 95% CI 1.02-1.06), usual interstitial pneumonia (UIP) pattern on HRCT (HRs = 1.88, 95% CI 1.14-3.10 and RRs = 1.90, 95% CI 1.50-2.39), emphysema presence (HRs = 2.31, 95% CI 1.58-3.39), and acute exacerbation of ILD (HRs = 2.70, 95% CI 1.67-4.36) were associated with increased mortality in RA-ILD, whereas rheumatoid factor (RF) positive status was not associated. CONCLUSIONS: Through this systematic review and meta-analysis, we found that older age, male sex, smoking history, higher CPI, lower DLCO% predicted, lower FVC% predicted, UIP pattern on HRCT, emphysema presence and acute exacerbation of ILD were associated with an increased risk of mortality in RA-ILD.
34521259 Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients s 2021 Oct Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10(-8)). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.
33113036 Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage 2021 Apr Fibroblast-like synoviocytes (FLSs) are important non-immune cells located mostly in the inner layer of the synovium. Indeed, these cells are specialized mesenchymal cells, implicated in collagen homeostasis of the articular joint and provide extracellular matrix (ECM) materials for cartilage and contribute to joint destruction via multiple mechanisms. RA FLS interactions with immune and non-immune cells lead to the development and organization of tertiary structures such as ectopic lymphoid-like structures (ELSs), tertiary lymphoid organs (TLOs), and secretion of proinflammatory cytokines. The interaction of RA FLS cells with immune and non-immune cells leads to stimulation and activation of effector immune cells. Pathological role of RA FLS cells has been reported for many years, while molecular and cellular mechanisms are not completely understood yet. In this review, we tried to summarize the latest findings about the role of FLS cells in ELS formation, joint destruction, interactions with immune and non-immune cells, as well as potential therapeutic options in rheumatoid arthritis (RA) treatment. Our study revealed data about interactions between RA FLS and immune/non-immune cells as well as the role of RA FLS cells in joint damage, ELS formation, and neoangiogenesis, which provide useful information for developing new approaches for RA treatment.
33514426 The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian pop 2021 Jan 30 BACKGROUND: Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. METHODS: We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. RESULTS: We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30-5.49, P(GWAS) = 7.22 × 10(-29)) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37-0.62, P(GWAS) = 2.58 × 10(-08)). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09-0.30, P(GWAS) = 1.60 × 10(-09)). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. CONCLUSIONS: Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.
34718291 Anti-TNF Therapy and the Risk of Malignancies and Infections in Inflammatory Rheumatic Dis 2021 Spring BACKGROUND: Early diagnosis is the key to successful treatment of inflammatory rheumatic diseases and the use of conventional disease-modifying antirheumatic drugs (csDMARD) and biologic disease-modifying antirheumatic drugs (bDMARD) or biologics have substantially contributed to better disease control. Biological drugs have been approved for the treatment of rheumatoid arthritis (RA), juvenile arthritis (JIA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). SUBJECTS AND METHODS: The study involved 79 adult patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), psoriatic arthritis (PsA) or undifferentiated spondyloarthropathy (USpA) - the last three clinical entities belong to a common group called spondyloarthropathies (SpA); receiving anti-TNF therapy at the department of Rheumatology and Rehabilitation, Clinical Hospital Center Zagreb. The duration of therapy was a minimum of 1 month, with the mean duration of 32.0±24.0 months. The infections recorded were infections that appeared during treatment or soon after the treatment was stopped. RESULTS: During the course of therapy 17 patients (21.5%) experienced an infection, with the total number of 21 infections. This resulted in an overall incidence rate (IR) of 9.9/100 patient-years. Of the patients with RA 76.5% developed an infection, which was significantly higher than for patients with SpA (p<0.001). The IR/100 patient-years for all infections in RA patients was 23.7 compared to 2.8 in patients with SpA. Female gender was associated with a significantly higher infection rate (70.6%, p=0.005). There were 8 infections that were considered serious, yielding an IR of 3.8/100 patient-years. There was only one malignancy case in our study. CONCLUSION: Every fifth patient developed an infection during the course of anti-TNF therapy, and more than one third of all infections were serious. RA and female gender was associated with a significantly increased number of infections.
33554691 Muscle wasting, a neglected complication associated with physical dysfunction in elderly p 2021 Jul Objective: Little is known about muscle wasting in elderly patients with rheumatoid arthritis (RA). We examined muscle characteristics and their clinical significance in this group.Method: Consecutive RA patients were recruited and clinical data were collected. Muscle mass and distribution were assessed using bioelectric impedance analysis. Myopenia was defined as an appendicular skeletal muscle mass index (ASMI) ≤ 7.0 kg/m(2) (men) and ≤ 5.7 kg/m(2) (women).Results: Among the 643 RA patients recruited, 165 (25.7%) were elderly patients (age ≥ 60 years) with a mean age of 65.1 ± 4.5 years. Compared with young patients (age < 60 years), elderly RA patients had significantly higher Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) (median 3.4 vs 3.2), Health Assessment Questionnaire Disability Index (HAQ-DI) (0.38 vs 0.13), and modified total Sharp score (mTSS) (16 vs 9), and a higher proportion of myopenia (54.5% vs 41.4%; all p < 0.01). Elderly RA patients with myopenia (n = 90, 14.0%) had significantly higher DAS28-CRP (3.6 vs 3.0), HAQ-DI (0.50 vs 0.12), and mTSS (21 vs 7) than young RA patients without myopenia (n = 280, 43.5%; all p < 0.0083). Multivariate logistic and linear regression analyses showed that myopenia, high HAQ-DI, active smoking, hypertension, diabetes, and coronary atherosclerotic heart disease were the main relevant characteristics of elderly RA patients. Age positively correlated with HAQ-DI, and ASMI negatively correlated with HAQ-DI (both p < 0.01). Further mediation analysis showed that ASMI partially mediated the association between age and HAQ-DI.Conclusion: Our data reveal that half of elderly RA patients manifest myopenia which aggravates physical dysfunction as a mediator of age. Myopenia, a neglected complication in elderly RA patients, should be recognized and further investigated.
33257900 The immunology of rheumatoid arthritis. 2021 Jan The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.
34226211 Early-life famine exposure and rheumatoid arthritis in Chinese adult populations: a retros 2021 Jul 5 OBJECTIVE: This study aimed to explore the association between famine exposure in early life and the odds of rheumatoid arthritis (RA) in adulthood. DESIGN: A population-based retrospective cohort study. SETTING: China. PARTICIPANTS: A total of 111 706 participants (1775 with RA) born from 1956 to 1964 were selected from the baseline survey of a large cohort in China. PRIMARY AND SECONDARY OUTCOME MEASURES: Four famine exposure groups were generated based on dates of birth, namely prenatal-exposed, infant-exposed, preschool-exposed and non-exposed groups. Logistic regressions were used to explore the association between famine exposure and self-reported RA in adulthood, adjusting for sex, region, monthly income, highest education, alcohol consumption, tobacco use, body mass index (BMI) and metabolic equivalent tasks. Analyses were also performed with stratification for sex (female or male), residing region (urban or rural), famine severity (severe or non-severe) and BMI (≥24 or <24). RESULTS: The study included 1775 (1.59%) RA cases and 109 931 (98.41%) non-RA controls. Among them, 22 413 (20.06%) were prenatal-exposed, 14 899 (13.34%) were infant-exposed and 34 356 (30.76%) were preschool-exposed. Prenatal exposure to famine was not associated with onset of RA in adulthood. Infant-exposed group and preschool-exposed group had significantly elevated odds of getting RA compared with non-exposed group (infant-exposed: OR=1.44, 95% CI 1.24 to 1.67; preschool-exposed: OR=1.38, 95% CI 1.22 to 1.57, p<0.001), and the relationship was stronger among women, urban residents and participants with BMI ≥24. Similar results were additionally observed when an age-balanced control group was used. CONCLUSIONS: Exposure to the Great Chinese Famine in early life after birth especially in infancy may be associated with a higher risk of RA in adulthood. Strengthening early-life nutrition could be an implication to prevent future RA.
33001009 The Functional Impact of Alternative Splicing and Single Nucleotide Polymorphisms in Rheum 2021 Advances in genomics and proteomics aid the identification of genes associated with various diseases. Genome-Wide Association Studies (GWAS) have identified multiple loci as risk alleles for susceptibility to Rheumatoid Arthritis (RA). A bisection of RA risk can be attributed to genetic factors. Over 100 associated genetic loci that encompass immune regulatory factors have been found to be linked with RA. Aberrant Single Nucleotide Polymorphisms (SNPs) and alternative splicing mechanisms in such loci induce RA. These aberrations are viewed as potential therapeutic targets due to their association with a multitude of diseases. This review presents a few imperious genes whose alterations can cause severe bone deformities culminating in RA.