Association of rheumatoid arthritis and its severity with human leukocytic antigen-DRB1 alleles in Kurdish region in North of Iraq

Background Rheumatoid arthritis is a complex multifactorial chronic disease, the importance of human leukocytic antigen (HLA) as a major genetic risk factor for rheumatoid arthritis was studied worldwide. The objective of this study is to identify the association of HLA-DRB1 subtypes with rheumatoid arthritis and its severity in Kurdish region. Methods A case–control study recruited 65 rheumatoid arthritis patients and 100 healthy individuals as control group all over the Kurdistan region/Iraq. Both patient and control groups are genotyped using polymerase chain reaction with sequence specific primer. Anti-CCP antibodies were measured by ELISA test. Rheumatoid factor, C-reactive protein, and disease activity score 28 which measured by DAS-28 values were calculated. The DAS-28 was used to assess the clinical severity of the patients. Results HLA-DRB1-0404 and HLA-DRB1-0405 frequencies showed a strong association with disease susceptibility (P < 0.001). The frequency of HLA-DRB1-0411 and HLA-DRB1-0413 were significantly higher in control group (P < 0.001). The frequency of rheumatoid factor and Anti-CCP were significantly higher among shared epitope-positive patients compared to shared epitope-negative patients (P < 0.001). Regarding the disease activity by DAS-28, rheumatoid arthritis patients didn’t show significant difference between the shared epitope-positive and shared epitope-negative patients. Conclusions HLA-DR0404 and HLA-DR0405 alleles are related to RA, while HLA-DR1-0411 and HLA-DRB1-0413 protect against RA in the Kurdistan region in the North of Iraq.

Estrogen Receptors, ERK 1/2 Phosphorylation and Reactive Oxidizing Species in Red Blood Cells From Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a significantly increased risk of cardiovascular mortality, mainly attributed to accelerated atherosclerosis. Methods: Thirty-two women (aged more than 18 years) with RA, and 25 age-matched healthy women were included in this study. Biomarkers of inflammation, red blood cells (RBCs) redox balance, estrogen receptor alpha (ER-&alpha;) expression as well as ERK 1/2 phosphorylation content were evaluated in RA patients at baseline and six months after treatment with disease modifying anti‐rheumatic drugs (DMARDs). Results: For the first times we demonstrated that in RA patients: i) disease activity score (DAS-28) positively correlated with RBC ER-&alpha; expression, and negatively with total antioxidant capacity of plasma; ii) RBC ER-&alpha; expression positively correlated with systemic inflammatory biomarkers and oxidative stress parameters as well as ERK 1/2 phosphorylation; and iii) DMARDs treatments improved the clinical condition measured by DAS-28 score decrease, although the RBCs appeared to be more prone to pro-oxidant status associated to the expression of survival molecules. Conclusion: Our data strongly suggest that RBCs could also participate in vascular homeostasis through fine modulation of an intracellular signal linked to the ER-&alpha;.

Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy

Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10−16), fatty acids (p = 8.0 × 10−12), and ceramides (p = 9.8 × 10−13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.

C-Reactive Protein-to-Albumin Ratio: A Novel Inflammatory Marker and Disease Activity Sign in Early Rheumatoid Arthritis

Objective A novel inflammation-based score, C-reactive protein (CRP)-to-albumin ratio (CAR), has been shown to have an association with the inflammatory status in several diseases. We aimed to analyse the association between CAR and disease activity in patients with early rheumatoid arthritis (RA) and to determine the cut-off value of CAR in early and established RA. Methods A total of 177 patients with RA and 111 age and gender-matched healthy controls were included in this study. Cases with a disease duration of less than 1 year were classified as early RA. Serum albumin, CRP, erythrocyte sedimentation rate (ESR), Disease Activity Score-28 (DAS-28-ESR), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores were recorded. Results CAR was 2.44 (0.21–30.83) in the RA group and 0.45 (0.21–10.47) in the control group (p<0.001). Eighty-seven (49.15%) of the RA cases were classified as early RA. The analyses indicated that the ESR, CRP and CAR values were higher in patients with early RA than in those with established RA and controls. CAR was correlated with albumin, CRP, ESH, DAS-28 and HAQ scores in both early RA and established RA groups. The receiver operating characteristic curves revealed a CAR cut-off value of 2.67 (80% sensitivity and 85% specificity) and 1.63 (77% sensitivity and 72% specificity) for the prediction of early and established RA, respectively. Conclusion CAR, a formulated ratio, has been described as a predictor for disease activity in patients with early RA as well as in those with established RA. However, CAR has higher sensitivity and specificity for early RA than for established RA.

miRNA-485-5p, an Inflammation-Related microRNA, May be a Diagnostic Biomarker of Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) is a chronic systematic autoimmune disorder that is characterized by symmetrical and inflammatory destruction of distal joints. Dysregulation of microRNAs(miRNAs) are frequently involved in inflammation, and can contribute to pathogenesis and progression of RA. This study aimed to investigate the expression of multiple inflammation-related miRNAs of RA patients and the latent mechanism, and identify novel diagnostic biomarkers. Methods Samples of 100 patients with RA and 72 healthy controls were included. The expression of predicted inflammation-related miRNAs, including miR-16, miR-17, miR-132, miR-140, miR-150, miR-181, miR-200-c, miR-203, miR-223 and miR-485-5p and RA associated genes, including IL-17, IL-18, DAS-28, MMP3, TLR-4, IRAK-4 in plasma and peripheral blood mononuclear cells (PBMCs) of RA patients compared with healthy controls (HC), were detected by qRT-PCR and ELISA. The interaction between miR-485-5p and TLR-4 or IRAK-4 was verified through dual luciferase report assays, western-blot and correlation analysis. The potential of miR-485-5p to be a biomarker for RA diagnostics was valued by ROC curves. Results Among the differentially expressed miRNAs, the expression of miR-485-5p exhibited significantly lower in plasma and PBMCs of the RA patients and was well relevant in the various body fluid samples. The expression of miR-485-5p was negatively correlated with the expression of DAS-28, IL-17, IL-18 and MMP-3, which are significant features of RA. Moreover, the ROC curve of plasma and PBMC miR-485-5p for RA revealed a high diagnostic accuracy. Furthermore, miR-485-5p could inhibit the expression of inflammatory cytokines in macrophages by targeting TLR4 and IRAK4, and the expression of miR-485-5p negatively correlated with the level of TLR4 and IRAK4 in the plasma of RA. Conclusion Collectively, our results indicated that down-expression of miR-485-5p was remarkably related to the deterioration of RA progression via the impact on inflammatory cytokines in macrophages, and may serve as a potential diagnostic biomarker and therapeutic target for RA.

Changes of DCE‐MRI Parameters in Patients with Rheumatoid Arthritis before and after Therapy and Their Value for the Efficacy Evaluation of Patients

Objective. To explore the changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters in patients with rheumatoid arthritis (RA) before and after therapy and their value for the efficacy evaluation of patients. Methods. Totally, 90 patients with RA confirmed in our hospital between January 2018 and January 2020 were enrolled. All of them were examined with a Siemens Magnetom Avanto 1.5T imaging system, and data about the rate of enhancement in early stage (REE) and steep slope maximum (SSmax) were obtained. Then, the disease activity score in 28 joints (DAS-28), REE, and SSmax were analyzed, and the associations of SSmax and REE with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and DAS-28 were investigated. Additionally, the patients were assigned to the acute-stage group and the chronic-stage group according to their time-signal intensity curves after therapy, and the two groups were compared in SSmax, REE, ESR, CRP, and DAS-28. Corresponding receiver operating characteristic (ROC) curves were drawn for the analysis of potential markers for efficacy improvement in patients. Results. After therapy, REE, SSmax, ESR, DAS-28, and CRP in the synovium of all patients declined greatly (all P < 0.05 ), with higher levels observed in the acute-stage group than those in the chronic-stage group (all P < 0.05 ). SSmax and REE of patients were positively bound up with their ESR, CRP, and DAS-28 (all P < 0.05 ). Additionally, according to ROC curve-based analysis, both SSmax and REE can be adopted as biological indexes for distinguishing between patients at the acute phase from those at the chronic stage, and joint detection of them can boost the sensitivity of DAS-28. Conclusion. The SSmax and REE levels in RA patients after treatment were significantly decreased, and the levels in patients in the chronic phase were lower than those in patients in the acute phase. SSmax and REE are highly expressed in RA patients, and the combined detection can enhance the value of DAS-28 in the assessment of RA, and it is worthy of clinical promotion.

ПЕРЕБІГ COVID-19 ІНФЕКЦІЇ У ПАЦІЄНТІВ З ЗАПАЛЬНИМИ ЗАХВОРЮВАННЯМИ СУГЛОБІВ

Метою цієї роботи є оцінка клінічної симптоматики COVID-19 інфекції у пацієнтів з запальними захворюваннями суглобів (ЗЗС) на тлі різних видів базисної терапії. Дана робота є фрагментом моноцентрового ретроспективного дослідження. Для оцінки впливу ЗЗС на симптоматику COVID-19 інфекції використані елементи дизайну «випадок-контроль». Показано, що у пацієнтів з ЗЗС (n = 32) з низькою активністю процесу або в стадії ремісії на тлі прийому будь-яких хворобомодифікуючих антиревматичних препаратів (ХМАРП) (синтетичних, біологічних, таргетних) перебіг захворювання було порівняно з таким у групі контролю (n = 96). Рідше зазначалося підвищення температури вище 380С, відношення шансів (ВШ) 2,84, 95% довірливий інтервал (ДВ) 1,24 - 6,51. Легкий перебіг інфекції зазначався у 18 (56,3%) пацієнтів з ЗЗС, помірний - у 14 (43,7%), важкого перебігу у наших пацієнтів не було відзначено. Гострий COVID-19 зустрівся у 23 (71.9%) пацієнтів, постійна симптоматика COVID-19 - у 9 (29,1%) пацієнтів з ЗЗС, post-COVID-19 і long-COVID-19 не зустрілися. Було оцінено перебіг основного захворювання до (в межах 3 місяців) COVID-19 інфекції і після (через 3 місяці) початку COVID-19 інфекції. Активність ревматоїдного артриту (РА) при первинному обстеженні з використанням Disease Activity Score (DAS) 28 (С-РБ) та повторному склала 2.3±0,7 vs 2.5±0,7, р=0.57. ASDAS (С-РБ) був використаний для оцінки активности АС та склав: 1.5±0,4 до і 1.7±0,4 після, р=0.31. Сумарна оцінка BASDAI (Bath AS Disease Activity Index) у пацієнтів з АС та Нр-АСпА: 2.8±0,7 vs 3.1±0,9 р=0.34. Для пацієнтів з ПсА розраховували PASDAS (Psoriatic Arthritis Disease Activity Score): 1.8±0,5 vs 2.1±0,6 р=0.27. Іншими словами, COVID-19 інфекція не привела до загострення ВЗС. Ці дані свідчать про важливість диференційованого підходу до модифікації лікування ЗЗС на період хвороби COVID-19 інфекції. На 4-й - 6-му тижні від дебюту COVID-19 у всіх пацієнтів з ЗЗС і 31 в контрольній групі визначалися антитіла IgG до SARS-CoV-2. В результаті в групі пацієнтів ЗЗС (n = 32) індекс позитивності склав (М ± SD) 3,9 ± 1,2 (ранги 1,4 - 6,9), а в контрольній групі (n = 31) 5,1 ± 1,7 (ранги 2,3 - 7,8), р = 0.001. У жодного з пацієнтів не було відзначено відсутність вироблення антитіл, хоча, безумовно, їх титр був нижче, ніж в групі контролю. В результаті можна сказати, що низька активність ЗЗС або ремісія можуть служити хорошим прогнозом перебігу та наслідків COVID-19. Для досягнення цієї мети можуть використовуватися, як синтетичні ХМАРП препарати, так і біологічні, і таргетні.

The role of urinary Retinol binding protein (RBP) as a novel biomarker in early detection of kidney affection in patients with psoriatic arthritis

Background PsA is a chronic multisystem inflammatory disorder with various systemic diseases. Renal involvement in patients with PsA is sparsely studied and its association is still unclear. This entity is called “Psoriatic Nephropathy”. RBP has been proposed as the most sensitive marker for detection of renal tubule function loss. Aim We aim at early detection of renal tubular damage by measuring the level of urinary RBP as a novel biomarker in patients with psoriatic arthritis in relation to activity and severity. Methods We conducted a Cross-sectional study of 30 PsA patients from Physical Medicine, Rheumatology and Rehabilitation and Dermatology outpatients’ clinics at Ain Shams University Hospitals. They were subjected to full medical history taking and thorough clinical examination with calculation of DAS 28, PASI and HAQ scores. Full Laboratory evaluation included CBC, ESR, CRP, serum creatinine, BUN, SGOT, SGPT, urine analysis, estimated GFR (eGFR) and urinary RBP were measured for all the participants. The urinary RBP and eGFR were compared with 30 age and sex matched healthy controls. Results The urinary RBP mean±SD (ng/ml) was found to be 351.667±119.397 in patients and was statistically significantly higher in them than in controls 93.16±30.836 (t = 11.482, p &lt; 0.001) and it was statistically significantly correlated with disease duration, disease activity according to DAS 28 and the severity of skin affection according to PASI score. While eGFR (ml/min) was found to be 131.729±28.943 in patients and it was statistically significantly lower in them than in controls 146.708±16.607 (t=-2.459, p = 0.017), however there was no statistically significant correlations with either DAS 28 or PASI scores. Conclusion Urinary RBP has been described as a novel biomarker in early detection of kidney affection and renal tubular damage in psoriatic arthritis patients.

The Effect of Follow ups with Weekly Phone Calls on the Outcome and Quality of Life Among the Patients with Rheumatoid Arthritis

Background: The present study aimed at evaluating the effect of weekly phone calls on treatment outcomes and quality of life among a group of Iranian patients with rheumatoid arthritis (RA). Materials and Methods: In this randomized clinical trial study, 60 patients aged 15-85 with RA were randomly assigned to intervention and control groups. The intervention group, in addition to a monthly assessment on a weekly basis, received a full 3-month follow-up telephone conversation in order to follow the correct and regular use of the drug and respond to the patients’ questions. The control group was only evaluated routinely. Finally, the severity of the disease activity (based on DAS-28) and the quality of life (based on the SF-12 questionnaire) were evaluated after three months. Results: After three months from the onset of intervention, a significant reduction was observed in the number of tender joints, mean erythrocyte sedimentation rate (ESR), and total score of DAS-28 in the intervention group compared to the control group. In addition, after three months of treatment, the quality of life for the intervention group improved significantly more than that of the control group. Conclusion: A weekly phone call with the patients suffering from RA with the purpose to guide the therapeutic process and respond to the patients’ questions could positively improve the severity of the disease along with the quality of life among the patients.

Efficacy and Safety of Metformin Use in Rheumatoid Arthritis: A Randomized Controlled Study

Objective: To evaluate the efficacy and safety of metformin use in rheumatoid arthritis (RA) patients receiving conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs).Methods: A prospective, randomized, controlled, single blinded, study was carried on 66 RA patients with moderate and high disease activity state, receiving csDMARDs. Patients were simply randomized to receive either metformin 850 mg twice daily (Metformin group, n = 33), or placebo twice daily (Control group, n = 33) in addition to their stable anti-rheumatic regimen and followed up for 6 months. Serum C-reactive protein (CRP), disease activity of 28 joints based on CRP (DAS-28-CRP), and quality of life (QOL) were evaluated at baseline and then every 3 months. Moreover, serum adiponectin was assessed at baseline and after 6 months.Results: Sixty patients completed the study. Drop out was due to intolerance to metformin side effects (n = 3) and non-compliance (n = 3). Metformin significantly decreased CRP levels and DAS-28-CRP after 6 months compared to the control group (p-value &lt;0.001). A significant improvement in QOL of metformin group was observed as early as after 3 months (p-value = 0.006) with a continued improvement observed at 6 months (p-value &lt;0.001) compared to the control group. Despite the significantly higher serum adiponectin in the metformin group at baseline, it was significantly reduced after 6 months in the metformin group with median percent change of −63.49% compared to the significant increase in the control group with median percent change of 92.40%.Conclusion: Metformin significantly improved inflammation, disease severity, and QOL in RA patients with high safety profile.Clinical Trial Registration: Clinical-Trials.gov, identifier [NCT08363405].