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ID PMID Title PublicationDate abstract
31474319 Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphen 2019 Sep 5 Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (B(pos-9)) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and B(pos-9) was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10(-17)). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and B(pos-9) were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.
31837437 Generation of a robust model for inducing autoimmune arthritis in Sprague Dawley rats. 2020 Mar INTRODUCTION: The prerequisite for any experimental model in animals is similarity with the human disease, uniformity in disease severity and incidence. In antigen-induced arthritis models it is generally recognized that the major limitation is inconsistency in terms of incidence and severity. As access to strains like DBA/1 mice or Lewis rats is difficult for resource restrained laboratories, this study aimed to establish a robust and reproducible animal model of rheumatoid arthritis (RA). METHODS: Multiple approaches were undertaken for inducing arthritis in Sprague Dawley (SD) and Wistar rats using complete Freund's adjuvant (CFA), collagen type II (CII) emulsion, or different combinations of CII with low dose CFA along with lipopolysaccharide (LPS). The development of arthritis was evaluated by measuring paw edema, arthritis score, body weight, splenic index, histopathology and radiography of paw tissues. RESULTS: The combination of CII with low dose CFA and one injection of LPS resulted in 100% incidence of arthritis with disease severity ranging from moderate to severe and results were corroborated by histopathology and radiography. DISCUSSION: In a head-to-head comparison between SD and Wistar rats, the disease profile was better sustained and consistent in SD rats, and the use of CII with low dose CFA and LPS induced features akin to human RA. Taken together, a reproducible model of arthritis was established which can be replicated in any laboratory with limited resources.
31464109 Effectiveness of subcutaneously administered methotrexate in patients with rheumatoid arth 2019 Sep BACKGROUND: Subcutaneous methotrexate (sMTX) administration is considered more effective than the oral route due to better bioavailability and a lower rate of adverse drug reactions (ADRs); however, clinical data supporting this hypothesis is scarce. OBJECTIVES: The aim of the study was to evaluate the efficacy and tolerability of sMTX in patients with active rheumatoid arthritis (RA), including a subset classified as an early stage of RA. MATERIAL AND METHODS: A post-marketing, multicenter, open-label, non-randomized, non-interventional study enrolled 771 adult patients with active RA treated with sMTX (Metex®) for 2-6 weeks. The evaluation of therapy effectiveness (DAS28-ESR or DAS28-CRP) and monitoring of ADRs was an element of routine patient management. Therapy effectiveness was scored as the achievement of remission or response (according to European League Against Rheumatism (EULAR)). RESULTS: Among 761 (98.7%) patients that continued sMTX (after 25-31 weeks), clinical response was achieved by 69.5%, remission by 19.2% and low disease activity by 34.2%. Patients aged >60 years were less likely to achieve both remission (odds ratio (OR) = 0.61 (95% confidence interval (95% CI) = 0.39-0.93)) and clinical response (OR = 0.82 (95% CI = 0.71-0.95)), while overweight/obese patients (OR = 1.11 (95% CI = 1.00-1.24)) and those with early RA had greater chance to reach a clinical response (OR = 1.18 (95% CI = 1.03-1.34)). There were 16 ADRs (no serious or severe). In addition, at least 2-fold increase in alanine transaminase (ALT) activity was noted in 10 patients (1.3%). CONCLUSIONS: After 6-month therapy with sMTX, about 70% of patients with RA achieve a clinical response, and remission was observed in 20%. Younger age, overweight/obesity and an early stage of the disease are factors increasing therapy effectiveness; sMTX is well tolerated.
31221137 Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in r 2019 Jun 20 BACKGROUND: Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study. METHODS: To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR. RESULTS: Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively. CONCLUSIONS: VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.
31366827 Novel Compound-Target Interactions Prediction for the Herbal Formula Hua-Yu-Qiang-Shen-Ton 2019 Herbal formulae have a long history in clinical medicine in Asia. While the complexity of the formulae leads to the complex compound-target interactions and the resultant multi-target therapeutic effects, it is difficult to elucidate the molecular/therapeutic mechanism of action for the many formulae. For example, the Hua-Yu-Qiang-Shen-Tong-Bi-Fang (TBF), an herbal formula of Chinese medicine, has been used for treating rheumatoid arthritis. However, the target information of a great number of compounds from the TBF formula is missing. In this study, we predicted the targets of the compounds from the TBF formula via network analysis and in silico computing. Initially, the information of the phytochemicals contained in the plants of the herbal formula was collected, and subsequently computed to their corresponding fingerprints for the sake of structural similarity calculation. Then a compound structural similarity network infused with available target information was constructed. Five local similarity indices were used and compared for their performance on predicting the potential new targets of the compounds. Finally, the Preferential Attachment Index was selected for it having an area under curve (AUC) of 0.886, which outperforms the other four algorithms in predicting the compound-target interactions. This method could provide a promising direction for identifying the compound-target interactions of herbal formulae in silico.
31849375 Predictors of denosumab efficacy in treating osteoporosis in patients with rheumatoid arth 2019 Nov We investigated 2-year outcomes of denosumab treatment for osteoporosis in patients with rheumatoid arthritis (RA) and predictors of good outcomes. Study participants were 74 females treated with denosumab for 24 months. After investigating baseline demographics and overall time course for each patient, we divided all cases into two groups according to percent change (%) in bone mineral density (BMD) of lumbar spine (LS-) and total hip (TH-) at 24 months (-24m); two thirds of the patients were allocated to the good outcome group (LS-GO and TH-GO), and the other third to the non-good outcome group (LS-NG and TH-NG). We performed multivariate analysis to confirm predictors of greater increases in LS- and TH-BMD. LS-BMD-24m and TH-BMD-24m increased significantly from baseline. We observed greater %LS-BMD-24m in LS-GO group than in LS-NG group, while %TH-BMD-24m showed no significant group-dependent difference. N-terminal propeptide of type 1 collagen (P1NP) and tartrate-resistant acid phosphatase (TRACP)-5b decreased more in LS-GO group than in LS-NG group at each time point. We observed greater %TH-BMD-24m in TH-GO group than in TH-NG group, while %LS-BMD-24m showed no significant group-dependent difference. Only P1NP-6m showed a larger decrease in TH-GO group relative to TH-NG group. Multivariate analysis confirmed that the larger decrease in P1NP-6m was associated with the greater increase in LS-BMD-24m, while the combined use of biologics was associated with the greater increase in TH-BMD-24m. In conclusions, denosumab increased BMD in RA patients with osteoporosis. The combined use of biologics and denosumab may provide useful treatment options.
30284004 Arthroscopic synovectomy of the knee joint for rheumatoid arthritis. 2019 Aug OBJECTIVE: To investigate the effect of knee arthroscopic synovectomy (AS) on the disease activity, quality-of-life (QoL), and the functional status of patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: A retrospective analysis was conducted on the outcomes of AS performed on 138 RA patients; pre-surgery assessments were done using Disease Activity score (DAS 28) and Routine Assessment of Patient Index Data З (RAPID-3) on а multidimensional health-assessment questionnaire for disease activity, EuroQol-5D (EQ-5D) and the Short-Form Medical Outcomes Study (SF-36) for quality of life, and the Health Assessment Questionnaire (HAQ) for functional status. The pain response to SA was measured by а visual analogue score (VAS) and the Knee Society Score (KSS). RESULTS: All parameters assessed in the study showed significant positive changes: the activity of the disease decreased, and patients' functional status and QoL improved. CONCLUSION: AS is effective treatment for recurrent synovitis of the knee in RA patients. This technique improves the functional status of patients and their quality of life and reduces the activity of the disease.
30784067 Intra-articular mucilages: behavioural and histological evaluations for a new model of art 2019 Jun OBJECTIVES: The creation of a new valid preclinical model of articular pain by the intra-articular (i.a.) injection of mucilages for the screening of new treatments against arthritis. METHODS: A single intra-articular injection (20 μl) of mucilages (from Althaea officinalis roots and Linum usitatissimun seeds) or vegetal components (Amorphophallus konjac gum powder and β-glucan, used as reference standard) were assessed in the rat. The pathology progression was monitored by behavioural measurements (paw pressure test, von Frey test, incapacitance test and beam balance test) and compared to that induced by the i.a. injections of monoiodioacetate (MIA) and Complete Freund's Adjuvant (CFA), well-recognized models of osteoarthritis and rheumatoid arthritis, respectively. KEY FINDINGS: Among all, the mucilage of L. usitatissimun showed the best pro-algic profile inducing a painful long-lasting condition. Hypersensitivity was characterized as a mixed form of inflammatory and neuropathic pain by the responsiveness to ibuprofen (100 mg/kg, p.o.) and pregabalin (30 mg/kg, p.o.). The histological evaluation of joint showed a damage that represents both MIA and CFA features. CONCLUSIONS: In conclusion, a single i.a. injection of L. usitatissimun mucilage can represent a valid model to assess articular pain in the rat for the screening of new treatments against arthritis.
30482092 Screening for cognitive dysfunction in systemic lupus erythematosus: the Montreal Cognitiv 2019 Jan BACKGROUND: Cognitive dysfunction (CD) is among the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Traditional neuropsychological testing and the Automated Neuropsychologic Assessment Metrics (ANAM) have been used to assess CD but neither is an ideal screening test. The Montreal Cognitive Assessment Questionnaire (MoCA) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) are brief and inexpensive tests. This study evaluated the MoCA and IQCODE as screening tools. METHODS: SLE patients fulfilling American College of Rheumatology (ACR) classification criteria were evaluated using the ANAM as the reference standard. The performance characteristics of the MoCA and IQCODE were assessed in comparison with normal controls (NCs) and rheumatoid arthritis (RA) patients. Four different definitions of CD were utilized. RESULTS: In total, 78 patients were evaluated. MoCA and ANAM scores were significantly correlated ( r = 0.51, p < 0.001). At the optimal cutoff, the sensitivity of the MoCA was ≥ 90% (depending on definition of CD) vs RA patients and ≥83% vs NCs. ANAM and IQCODE scores did not correlate ( p = 0.8152). IQCODE sensitivities were low for both RA patients and NCs regardless of definition and cutoff used. CONCLUSION: The MoCA appears to be a promising and practical screening tool for identification of patients with SLE at risk for CD.
30535001 Association of author's financial conflict of interest with characteristics and outcome of 2019 May 1 OBJECTIVE: To examine the prevalence, types and temporal trends of reported financial conflicts of interest (FCOIs) among authors of drug therapy randomized controlled trials (RCTs) for RA and their association with study outcomes. METHODS: We identified original, non-phase 1, parallel-group, drug therapy RA RCTs published in the years 2002-03, 2006-07, and 2010-11. Two investigators independently obtained trial characteristics data. Authors' FCOIs were classified as honoraria/consultation fees receipt, employee status, research grant, and stock ownership. Multivariable logistic regression was performed to identify whether FCOIs were independently associated with study outcome. RESULTS: A total of 146 eligible RCTs were identified. Of these, 83 (58.4%) RCTs had at least one author with an FCOI [employee status: 63 (43.2%), honoraria/consultation fees receipt: 49 (33.6%), research grant: 30 (20.5%), and stock ownership: 28 (19.2%)]. A remarkable temporal increase in reporting of honoraria/consultation fees receipt, research grant, and stock ownership was seen. The reporting of any FCOI itself was not associated with positive outcome [50/73 (68.5%) with author FCOI vs 36/52 (69.2%) without author FCOI, P = 0.93]. However, honoraria/consulting fees receipt was independently associated with increased likelihood of a positive outcome [adjusted odds ratio (95% CI) of 3.24 (1.06-9.88)]. In general, trials with FCOIs were significantly more likely to be multicentre, have larger enrolment, use biologic or a small molecule as the experimental intervention, and have better reporting of some methodological quality measures. CONCLUSION: FCOI reporting in RA drug RCT authors is common and temporally increasing. Receipt of honoraria/consulting fees was independently associated with a positive study outcome.
31774828 ITGAM is a risk factor to systemic lupus erythematosus and possibly a protection factor to 2019 INTRODUCTION: ITGAM has consistently been associated with susceptibility to systemic lupus erythematosus (SLE) in many ethnically diverse populations. However, in populations with higher Amerindian ancestry (like Yucatan) or highly admixed population (like Mexican), ITGAM has seldom been evaluated (except few studies where patients with childhood-onset SLE were included). In addition, ITGAM has seldom been evaluated in patients with rheumatoid arthritis (RA). Here, we evaluated whether four single nucleotide polymorphisms (SNPs), located within ITGAM, were associated with SLE and RA susceptibility in patients from Mexico. METHODS: Our study consisted of 1,462 individuals, which included 363 patients with SLE (292 from Central Mexico and 71 from Yucatan), and 621 healthy controls (504 from Central Mexico and 117 from Yucatan). Our study also included 478 patients with RA from Central Mexico. TaqMan assays were used to obtain the genotypes of the four SNPs: rs34572943 (G/A), rs1143679 (G/A), rs9888739 (C/T), and rs1143683 (C/T). We also verified the genotypes by Sanger sequencing. Fisher's exact test and permutation test were employed to evaluate the distribution of genotype, allele, and haplotype between patients and controls. RESULTS: Our data show that all four ITGAM SNPs are significantly associated with susceptibility to SLE using both genotypic and allelic association tests (corrected for multiple testing, but not for population stratification). A second study carried out in patients from Yucatan, a southeastern part of Mexico (with a high Amerindian ancestry), also replicated SLE association with all four SNPs, including the functional SNP, rs1143679 (OR = 24.6 and p = 9.3X10-6). On the other hand, none of the four SNPs are significant in RA after multiple testing. Interestingly, the GACC haplotype, which carries the ITGAM rs1143679 (A) minor allele, showed an association with protection against RA (OR = 0.14 and p = 3.0x10-4). CONCLUSION: Our data displayed that ITGAM is a risk factor to SLE in individuals of Mexican population. Concurrently, a risk haplotype in ITGAM confers protection against RA.
28711461 Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring in 2019 Mar OBJECTIVES: To describe the prevalence of comorbidities in patients with RA in Spain and discuss their management and implications using data from the Spanish cohort of the multinational study on COMOrbidities in Rheumatoid Arthritis (COMORA). METHODS: This is a national sub-analysis of the COMORA study. We studied the demographics and disease characteristics of 200 adults patients diagnosed with RA (1987 ACR), and routine practices for screening and preventing the following selected comorbidities: cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and depression. RESULTS: Patients had a mean age of 58 years and a mean RA duration of 10 years. Mean DAS28 score was 3.3 and approximately 25% of patients were in remission (DAS28 <2.6). Forty-four (22%) patients had ≥1 comorbidity, the most frequent being depression (27%) and obesity (26%). A history of myocardial infarction or stroke was observed in 5% and 1% of patients, respectively, and any solid tumor in 6%. Having a Framingham Risk Score >20% (51%), hypercholesterolemia (46%) or hypertension (41%) and smoking (25%) were the most common CV risk factors. For prostate, colon and skin cancers, only 9%, 10% and 18% of patients, respectively, were optimally monitored. Infections were also inadequately managed, with 7% and 17% of patients vaccinated against influenza and pneumococcal, respectively, as was osteoporosis, with 47% of patients supplemented with vitamin D and 56% with a bone densitometry performed. CONCLUSIONS: In Spain, the prevalence of comorbidities and CV risk factors in RA patients with established and advanced disease is relatively high, and their management in clinical daily practice remains suboptimal.
28789978 A composite indicator to assess the quality of care in the management of patients with rhe 2019 May OBJECTIVE: The current guidelines in the treatment of rheumatoid arthritis (RA) include the early diagnosis and early use of disease modifying drugs to achieve remission or low disease activity level, known as "Treat to Target" (T2T). The objective of this study is to develop a composite indicator (CI) to evaluate the quality of care in the management of patients with RA, according to the T2T strategy and other general recommendations concerning the management of these patients. MATERIAL AND METHOD: The phases of the construction of the CI were: 1) selection of quality criteria through expert judgment; 2) prioritization of the criteria, according to relevance and feasibility, applying the Delphi methodology (two rounds) involving 20 experts; 3) design of quality indicators; and 4) calculation of the weighted CI, using the mean value in relevance and feasibility granted by the experts. The source of information for the calculation of the CI are the medical records of patients with RA. RESULTS: Twelve criteria out of 37 required a second Delphi round. Thirty-one criteria were prioritized. These criteria presented a median in relevance and feasibility greater than or equal to 7.5, with an interquartile range of less than 3.5, and a level of agreement (score greater than or equal to 8) greater than or equal to 80%. CONCLUSIONS: The constructed CI allows us to evaluate the quality of care of patients with RA following the T2T strategy in the rheumatology units of Spanish hospitals, offering a valid and easily interpretable summary measure.
31544222 A case of denosumab-associated membranous nephropathy in a patient with rheumatoid arthrit 2020 Feb We herein report a case of anti-RANKL monoclonal antibody-associated membranous nephropathy (MN). A 67-year-old woman with a history of rheumatoid arthritis treated with prednisolone and methotrexate for more than 30 years and osteoporosis treated with eldecalcitol and teriparatide for 4 years had achieved a stable disease condition. Her kidney function was normal and her urinalysis was negative for hematuria and proteinuria. An anti-RANKL monoclonal antibody (denosumab) was administered for the treatment of osteoporosis. Four months later, proteinuria appeared (2.3 g/g creatinine) and remained positive for about 6 months, therefore, she was admitted to our hospital. An immunofluorescence study revealed fine granular deposits of immunoglobulin G (IgG) and C3 along the capillary walls. Staining for IgG subclasses showed positive staining for IgG1 (3+), IgG2 (1+), IgG3 (1+), and IgG4 (1+); phospholipase A2 receptor was negative. Electron microscopy showed partial subepithelial and intramembranous deposits and focal thickening of the glomerular basement membrane. No evidence of malignancy or infectious disease was seen. After cessation of denosumab, the proteinuria gradually improved. Based on the renal biopsy results and clinical course (development of marked proteinuria in the presence of denosumab with subsequent amelioration in the absence of the drug), we diagnosed the patient with secondary MN due to denosumab. This is the first reported case of denosumab-associated MN.
31189913 Detection of Fine Radiographic Progression in Finger Joint Space Narrowing Beyond Human Ey 2019 Jun 12 The visual assessment of joint space narrowing (JSN) on radiographs of rheumatoid arthritis (RA) patients such as the Genant-modified Sharp score (GSS) is widely accepted but limited by its subjectivity and insufficient sensitivity. We developed a software application which can assess JSN quantitatively using a temporal subtraction technique for radiographs, in which the chronological change in JSN between two radiographs was defined as the joint space difference index (JSDI). The aim of this study is to prove the superiority of the software in terms of detecting fine radiographic progression in finger JSN over human observers. A micrometer measurement apparatus that can adjust arbitrary joint space width (JSW) in a phantom joint was developed to define true JSW. We compared the smallest detectable changes in JSW between the JSDI and visual assessment using phantom images. In a clinical study, 222 finger joints without interval score change on GSS in 15 RA patients were examined. We compared the JSDI between joints with and without synovial vascularity (SV) on power Doppler ultrasonography during the follow-up period. True JSW difference was correlated with JSDI for JSW differences ranging from 0.10 to 1.00 mm at increments of 0.10 mm (R(2) = 0.986 and P < 0.001). Rheumatologists were difficult to detect JSW difference of 0.30 mm or less. The JSDI of finger joints with SV was significantly higher than those without SV (P = 0.030). The software can detect fine differences in JSW that are visually unrecognizable.
31372853 LncRNA GAS5 overexpression downregulates IL-18 and induces the apoptosis of fibroblast-lik 2019 Nov BACKGROUND: Long non-coding RNA (lncRNA) growth arrest specific transcript 5 (GAS5) negatively regulates interleukin-18 (IL-18) in ovarian cancer, while IL-18 contributes to the development of rheumatoid arthritis (RA). Therefore, GAS5 may also participate in RA. METHODS: GAS5 and IL-18 in plasma of RA patients (n = 60) and healthy controls (n = 60) were measured by RT-qPCR and ELISA, respectively. Linear regression was performed to analyze the correlations between plasma levels of IL-18 and GAS5 in both RA patients and healthy controls. RESULTS: In the present study, we found that plasma GAS5 was downregulated, while IL-18 was upregulated in RA patients than in healthy controls. A significant and inverse correlation between GAS5 and IL-18 was found in RA patients but not in healthy controls. IL-18 treatment did not significantly alter the expression of GAS5 in fibroblast-like synoviocytes, while GAS5 overexpression led to the inhibited expression of IL-18. GAS5 overexpression also resulted in the promoted apoptosis of fibroblast-like synoviocytes. CONCLUSIONS: Therefore, GAS5 overexpression may improve RA by downregulating IL-18 and inducing the apoptosis of fibroblast-like synoviocytes. Key points • The present study mainly showed that overexpression of GAS5 may assist the treatment of RA. • The mechanism of GAS5 for the treatment of RA involves the downregulating inflammatory IL-18 and mediating the apoptosis of fibroblast-like synoviocytes. • GAS5 and IL-8 were correlated in RA patients but not in healthy controls.
29939099 Combination effect of anti-rheumatic medications for coronary artery diseases risk in rheu 2019 Feb OBJECTIVES: To determine whether a combination of anti-rheumatic drugs is associated with the risk of coronary artery diseases (CAD) in incident rheumatoid arthritis (RA) patients. METHODS: This population-based cohort study used administrative data to identify 6260 newly-diagnosed patients with RA (age ≥20 years) as the study group. The study end-point was occurrence of CAD according to the ICD-9-CM codes. Exposure to different combinations of drugs and the risk of CAD was assessed. These included different combinatiosn of celecoxib (Cx), hydroxychloroquine (HCQ), methotrexate (MTX), and sulfasalazine (SSZ). Patients who never used Cx, HCQ, MTX, or SSZ were used as a reference group. A Cox proportional hazards model was used to estimate the hazard ratio (HR) of disease after controlling for demographic and other co-morbidities. When the proportionality assumption was violated, the spline curve of the Scaled Schoenfeld residuals was fitted to demonstrate the estimated effect on CAD over time for drug usage. RESULTS: Among RA patients, the adjusted HR (95% confidence interval) of CAD for "Cx only", "Cx and HCQ ever", and "Cx, HCQ, MTX, and SSZ ever", were 0.29 (0.19-0.44), 0.46 (0.24-0.88), and 0.42 (0.24- 0.75), respectively, during the first period of 0-3, 4, or 7 years. However, they became 1.04 (0.78-1.38), 1.16 (0.62-2.19), and 0.59 (0.32-1.08), respectively, during the second time period of 3, 4, or 7-10 years. The adjusted HR (95% CI) of CAD for "Cx, MTX, and SSZ ever" remains constant at 0.12 (0.02-0.89). CONCLUSIONS: Celecoxib-DMARDs drug combinations were associated with reduced CAD risk on incident RA patients, and some of them exhibited the time-varying drug effect.
31673410 Imputing missing data of function and disease activity in rheumatoid arthritis registers: 2019 OBJECTIVE: To compare several methods of missing data imputation for function (Health Assessment Questionnaire) and for disease activity (Disease Activity Score-28 and Clinical Disease Activity Index) in rheumatoid arthritis (RA) patients. METHODS: One thousand RA patients from observational cohort studies with complete data for function and disease activity at baseline, 6, 12 and 24 months were selected to conduct a simulation study. Values were deleted at random or following a predicted attrition bias. Three types of imputation were performed: (1) methods imputing forward in time (last observation carried forward; linear forward extrapolation); (2) methods considering data both forward and backward in time (nearest available observation-NAO; linear extrapolation; polynomial extrapolation); and (3) methods using multi-individual models (linear mixed effects cubic regression-LME3; multiple imputation by chained equation-MICE). The performance of each estimation method was assessed using the difference between the mean outcome value, the remission and low disease activity rates after imputation of the missing values and the true value. RESULTS: When imputing missing baseline values, all methods underestimated equally the true value, but LME3 and MICE correctly estimated remission and low disease activity rates. When imputing missing follow-up values at 6, 12, or 24 months, NAO provided the least biassed estimate of the mean disease activity and corresponding remission rate. These results were not affected by the presence of attrition bias. CONCLUSION: When imputing function and disease activity in large registers of active RA patients, researchers can consider the use of a simple method such as NAO for missing follow-up data, and the use of mixed-effects regression or multiple imputation for baseline data.
31444373 Association of MTMR3 rs12537 at miR-181a binding site with rheumatoid arthritis and system 2019 Aug 23 Single nucleotide polymorphisms (SNPs) in microRNA-target sites influence an individual's risk and prognosis for autoimmune diseases. Myotubularin-related protein 3 (MTMR3), an autophagy-related gene, is a direct target of miR-181a. We investigated whether MTMR3 SNP rs12537 in the miR-181a-binding site is associated with the susceptibility and progression of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overall, 94 patients with RA, 80 patients with SLE, and 104 healthy volunteers were recruited. Genotyping and expression analysis of circulating MTMR3 and miR-181a were performed by qPCR. The autophagic marker MAP1LC3B was measured by ELISA. The rs12537 minor homozygote (TT) genotype was a candidate risk factor of both RA and SLE. rs12537TT was associated with lower serum MTMR3 expression and higher LC3B levels than other genotypes in patients with both diseases. Serum miR-181a expression was higher in rs12537TT carriers than in other genotypes among SLE patients. Serum miR-181a and MTMR3 levels were inversely correlated in SLE but not in RA patients. rs12537TT and serum miR-181a were positively associated with disease severity in both diseases. Our results identify a novel role of rs12537 in the susceptibility and progression of RA and SLE, possibly through impacting the interaction between miR-181a and MTMR3 leading to increased autophagy.
31276602 Optimising low-dose methotrexate for rheumatoid arthritis-A review. 2019 Oct Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with contribution of variability in concentrations of active polyglutamate metabolites, associated with clinical efficacy and toxicity. Prescribing remains heterogeneous across population groups, disease states and regimens. This review examines current knowledge of dose-response of oral methotrexate in the setting of rheumatoid arthritis, and how this could help inform dosage regimens.