ResearchPad - rheumatoid-arthritis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure]]> https://www.researchpad.co/article/elastic_article_7008 To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA).MethodsSynovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi‐IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis (RNA‐Seq) in the early RA (n = 91) and TNFi‐IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2).ResultsSemiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi‐IR cohort (P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts.ConclusionWe describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA. ]]> <![CDATA[Early non-response to certolizumab pegol in rheumatoid arthritis predicts failure to achieve low disease activity at 1 year: data from a prospective observational study]]> https://www.researchpad.co/article/Nd38eff5b-c3c8-49e2-929f-bc42c19cc9d1

Objective

To evaluate the performance of clinical criteria for predicting late treatment failure in patients with early non-response to certolizumab pegol (CZP).

Methods

A protocol-specified analysis of interim data from ECLAIR, a 3-year longitudinal, prospective, observational, multicentre study of patients with active rheumatoid arthritis (RA) initiating CZP treatment in France, was conducted. Clinical measures assessed were Clinical Disease Activity Index (CDAI), Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28(ESR)) and Health Assessment Questionnaire Disability Index (HAQ-DI). Early non-response was measured at 3 months (M3) and failure to achieve low disease activity (LDA) at 12 months (M12).

Results

574/792 enrolled patients were treated at M3. The numbers available for predictability analyses were 532 (CDAI), 434 (DAS28(ESR)) and 496 (HAQ-DI). Of the three indices evaluated, the highest predictor of non-response value was observed for the CDAI (88.8% (95% CI 81.0 to 94.1)), indicating that up to 88% of patients identified as non-responders at M3 failed to achieve LDA at M12, regardless of baseline disease severity or treatment history. The specificity for this measure was also very high (96.0%), indicating that less than 5% of patients who achieved CDAI response at M12 had not responded at M3. Similar predictability was observed for DAS28(ESR), but only in patients with high disease activity at baseline and/or those previously treated by a biological disease-modifying antirheumatic drug.

Conclusion

CDAI non-response at M3 is a predictor of failure to achieve the therapeutic target of LDA at M12 in patients with RA initiating treatment with CZP.

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<![CDATA[Pathogenesis of ischaemic and non-ischaemic heart diseases in rheumatoid arthritis]]> https://www.researchpad.co/article/N2e6a96da-6035-4029-882b-82308000dc92

Rheumatoid arthritis (RA) is characterised by a chronic inflammatory condition of the joints, but the comorbidities of RA predominantly contribute to the reduced lifespan associated with this disease. Clinical data indicate that cardiovascular disease is the major comorbidity associated with mortality in RA. In this review, we aimed to describe the pathogenesis of heart failure in RA. First, we emphasised the fundamental differences between ischaemic and non-ischaemic heart diseases and referred to their relevance in excessive cardiovascular-dependent mortality in RA. Second, we highlighted aspects of asymptomatic changes in cardiac tissue and in coronary blood vessels that are commonly found in patients with diagnosed RA. Third, we focused on high-grade systemic inflammation as a key trigger of ischaemic and non-ischaemic heart diseases in RA, and described the implication of conventional and biologic antirheumatic medications on the development and progression of heart disease. In particular, we discussed the roles of tumour necrosis factor-alpha (TNF-α) and anti-TNF-α therapies on the development and progression of ischaemic and non-ischaemic heart diseases in RA.

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<![CDATA[NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology]]> https://www.researchpad.co/article/5c9bc275d5eed0c484ee3f0b

Objectives

NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans.

Methods

Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model.

Results

The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine.

Conclusions

NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production.

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<![CDATA[A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families]]> https://www.researchpad.co/article/5c8acceed5eed0c48499036b

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N = 30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 77 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 43 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 3.78*10−3 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N = 110). Only one SNV in SUPT20H: c.73A>T (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.

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<![CDATA[Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study]]> https://www.researchpad.co/article/5c6f14fad5eed0c48467abf4

In recent years, low dose naltrexone (LDN) has been used as an off-label therapy for several chronic diseases. Results from small laboratory and clinical studies indicate some beneficial effects of LDN in autoimmune diseases, but clinical research on LDN in rheumatic disease is limited. Using a pharmacoepidemiological approach, we wanted to test the hypothesis that starting LDN leads to reduced dispensing of medicines used in the treatment of rheumatic disease. We performed a controlled before-after study based on the Norwegian Prescription Database (NorPD) to compare prescriptions to patients one year before and one year after starting LDN in 2013. The identified patients (n = 360) were stratified into three groups based on LDN exposure. Outcomes were differences in dispensing of medicines used in rheumatic disease. In persistent LDN users, there was a 13% relative reduction in cumulative defined daily doses (DDD) of all medicines examined corresponding to -73.3 DDD per patient (95% CI -120,2 to -26.4, p = 0.003), and 23% reduction of analgesics (-21.6 DDD (95% CI -35.5 to -7.6, p<0.009)). There was no significant DDD change in patients with lower LDN exposure. Persistent LDN users had significantly reduced DDDs of NSAID and opioids, and a lower proportion of users of DMARDs (-6.7 percentage points, 95% CI -12.3 to-1.0, p = 0.028), TNF-α antagonists and opioids. There was a decrease in the number of NSAID users among patients with the least LDN exposure. Important limitations are that prescription data are proxies for clinical effects and that a control group unexposed to LDN is lacking. The results support the hypothesis that persistent use of LDN reduces the need for medication used in the treatment of rheumatic and seropositive arthritis. Randomised clinical trials on LDN in rheumatic disease are warranted.

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<![CDATA[Associations between antenatal prednisone exposure and long-term cortisol and cortisone concentrations in children born to women with rheumatoid arthritis: results from a nationwide prospective cohort study]]> https://www.researchpad.co/article/5c8ad95dd5eed0c4849a0e6d

Objectives

To identify whether children with antenatal prednisone exposure have chronically elevated cortisol and cortisone concentrations, an altered body composition or higher blood pressure. In addition, to identify whether maternal rheumatoid arthritis disease (RA) activity is associated with these alterations.

Methods

In this prospective study, 56 children (mean age=10.0 years) with and 61 children (mean age=9.6 years) without antenatal prednisone exposure, born to women with RA, were included. Hair cortisol and cortisone were analysed using liquid chromatography–tandem mass spectrometry. Linear regression models were built to analyse differences between the two groups, corrected for relevant covariates. Hair cortisol concentrations were also compared between the study population and an age-matched healthy reference group(n=150 children, mean age=9.8 years).

Results

Hair cortisol and cortisone concentrations were similar in children with and without antenatal prednisone exposure (median cortisol 1.14 pg/mg (IQR 0.67–1.75) and 1.15 pg/mg (IQR 0.65–2.21) and median cortisone 6.76 pg/mg (IQR 5.42–8.86) and 7.40 pg/mg (IQR 5.39–10.73), respectively). Antenatal prednisone exposure and maternal RA disease activity were also not associated with body composition or blood pressure. Hair cortisol concentrations were not different in children born to mothers with RA compared with children from the reference group.

Conclusion

This, in its kind, large and unique long-term prospective study demonstrates that low-dose antenatal prednisone exposure and maternal RA disease activity are not associated with negative consequences in prepubertal childhood. The findings of this study are reassuring and support the assumption that low-dose maternal prednisone use during pregnancy is safe for the offspring, at least until the age of approximately 10 years.

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<![CDATA[TIM family gene polymorphism and susceptibility to rheumatoid arthritis: Systematic review and meta-analysis]]> https://www.researchpad.co/article/5c65dcedd5eed0c484dec596

Background

TIM-family proteins are expressed on different immune cells such as dendritic cells, macrophages, type 1 and 2 T helper (Th) cells. Therefore, they have the ability to contribute to the various intracellular signals and immune responses, importantly the regulation of Th1 and Th17 cell differentiation, which plays a remarked role in fight against inflammatory and autoimmune diseases. Association of TIM family gene polymorphisms with rheumatoid arthritis (RA) has been frequently investigated. The findings however are not entirely consistent. Therefore, we carried out the present meta-analysis to examine the association between RA and the following TIM family gene polymorphisms: rs41297579, rs1036199, rs10515746, and rs7700944.

Methods

A systematic search of Scopus, PubMed, and Web of Science databases was conducted through December 2018. Combined odds ratios (OR) with their corresponding 95% confidence intervals (CI) were calculated under different possible genetic models.

Results

A total of eight case-control studies were included in the present meta-analysis. The results demonstrated significant association of RA with TIM-3 rs1036199 polymorphism under dominant (OR, 1.93, 95% CI, 1.43–2.61) and allelic models (OR, 1.74, 95% CI, 1.31–2.30). None of the other examined polymorphisms indicated significant association with RA.

Conclusions

The present meta-analysis revealed that the TIM-3 rs1036199 polymorphism might confer susceptibility to RA. Further studies are required to reassert our findings.

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<![CDATA[Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study]]> https://www.researchpad.co/article/5c82b29bd5eed0c484e5a12c

Objectives

We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.

Methods

Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.

Results

Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0–54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.

Conclusions

A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

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<![CDATA[Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study]]> https://www.researchpad.co/article/5c82b2c8d5eed0c484e5a4fe

Objectives

This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day.

Methods

Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks.

Results

Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups.

Conclusions

In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

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<![CDATA[Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis]]> https://www.researchpad.co/article/5c52181dd5eed0c4847973f1

Objective

Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA).

Methods

The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, <25, 25–30, >30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes.

Results

We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed ≥7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI >30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI ≤25.

Conclusion

DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups.

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<![CDATA[Increased risk of rheumatoid arthritis among patients with Mycoplasma pneumonia: A nationwide population-based cohort study in Taiwan]]> https://www.researchpad.co/article/5c466572d5eed0c4845193ac

Objective

An association between Mycoplasma pneumonia (MP) and rheumatoid arthritis (RA) had been reported in animal studies for decades. However, clinical evidence for this association is lacking. Therefore, this study aimed to provide epidemiologic evidence to clarify the relationship between MP and development of RA.

Methods

This 13-year nationwide, population-based, retrospective cohort study analyzed the risk of RA in a cohort of MP patients. We cross linked and compared the database of those with catastrophic illnesses to make sure the diagnoses of RA are correctly labeled. We selected 116,053 hospitalized patients diagnosed with MP between 2000 and 2012 from the Taiwan National Health Insurance Research Database and 464,212 matched controls at a 1:4 ratio by age, gender, and index year, in relation to the risk of developing RA. The follow-up period referred to the initial diagnosis of MP until the date of RA diagnosis, censoring of RA, or 31st December 2013. The Cox proportional hazard model was used to analyze the association between MP and incidence of RA among patients with different potential risks.

Results

The adjusted hazard ratio (HR) for incidental RA in the MP group was 1.37 (95% confidence interval CI = 0.87–2.16), compared to non-MP controls. Stratified analysis revealed that the adjusted HR was 3.05 (95% CI = 1.16–7.99, p = 0.02) in a subgroup of patients over the age of 65.The adjusted HR of RA for the MP group among aged ≦19 years and ≥ 65 years was 3.19 (95% CI = 1.04.9.76) and 4.14 (95% CI = 1.27,13.4) within the first 2 years of follow-up.

Conclusion

This cohort study demonstrated that patients with MP had a higher risk of developing RA, especially in the first 2 years, in those aged younger than 19 and over 65.

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<![CDATA[Developing key performance indicators for prescription medication systems]]> https://www.researchpad.co/article/5c478c87d5eed0c484bd2e34

Objective

To develop key performance indicators that evaluate the effectiveness of a prescription medication system.

Methods

A modified RAND/UCLA appropriateness method was used to develop key performance indicators (KPIs) for a prescription medication system. A broad list of potential KPIs was compiled. A multidisciplinary group composed of 21 experts rated the potential KPIs. A face-to-face meeting was held following the first rating exercise to discuss each potential KPI individually. The expert panel undertook a final rating of KPIs. The final set of KPIs were those indicators where at least 80 percent of experts rated the indicator highly i.e. rating of ≥ 7 on a scale from 1 to 9.

Results

292 KPIs were identified from the published literature. After removing duplicates and combining similar indicators 71 KPIs were included. The final ranking resulted in six indicators being ranked 7 or higher by 80% of the respondents and an additional seven indicators being ranked 7 or higher by ≥70 but ≤80% of respondents. The six selected indicators include four specific disease areas, measure structural and process aspects of health service delivery, and assessed three of the domains of healthcare quality: efficiency, effectiveness, and safety.

Conclusions

These indicators are recommended as a starting point to assess the current performance of prescription medication systems. Consideration should be given to developing indicators in additional disease areas as well as indicators that measure the domains of timeliness and patient–centeredness. Future work should focus on the feasibility of measuring these indicators.

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<![CDATA[Mortality, disability, and healthcare expenditure of patients with seropositive rheumatoid arthritis in Korea: A nationwide population-based study]]> https://www.researchpad.co/article/5c3e4f99d5eed0c484d772af

Background

We investigated the mortality and disability rate, as well as the healthcare expenditure, for patients with newly diagnosed seropositive rheumatoid arthritis (RA) who were followed-up for up to 10 years, compared to the general population in Korea.

Methods

We conducted a nationwide population-based study using a National Health Insurance Service-National Sample Cohort of the Korean population, consisting of 1 million individuals who submitted medical care claims between 2002 and 2013. RA was identified using as the International Classification of Diseases code M05 (seropositive RA), with prescription of any disease-modifying anti-rheumatic drug (DMARD). Our analysis was based on the data of 1655 patients with incident seropositive RA and 8275 non-RA controls. The controls were matched to the RA cohort by sex, age at the time of diagnosis, duration of follow-up, geographic region, type of social security, and household income.

Results

The most commonly used conventional synthetic DMARDs were hydroxychloroquine (71.30%) and methotrexate (69.5%), with adalimumab being the most commonly used biologic DMARD (2.54%). The mortality rate was significantly higher in the RA than the control group (incidence rate ratio [IRR] 1.29, 95% confidence interval [CI] 1.02–1.64) in the first 10 years after diagnosis. Specifically, mortality due to infectious diseases (IRR 4.41, 95% CI 1.60–12.17) and pneumonia (IRR 3.92, 95% CI 1.46–10.53) was significantly higher in the RA than control group. The disability rate was higher in the RA than control group over the first 10 years of the disease (IRR 2.27, 95% CI 1.77–2.92), which was attributed to a higher incidence of physical disability (IRR 3.81, 95% CI 2.81–5.15). Annual health expenditure was greater for the RA than the control group.

Conclusions

Therefore, the rate of mortality and disability, as well as healthcare expenditure, are higher for patients with RA over the first 10 years of the disease onset, than the general population of Korea. The use of claim data has limited the quality of information and there is a limit to the observation period, and we expect the prospective national-wide multicenter cohort for longer period to overcome these limitations.

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<![CDATA[Epidemiology and treatment patterns of rheumatoid arthritis in a large cohort of Arab patients]]> https://www.researchpad.co/article/5c23f27ed5eed0c484046fb1

Objectives

There is limited information on the epidemiology and treatment patterns of rheumatoid arthritis (RA) across the Arab region. We aim in this study to describe the demographic characteristics, clinical profile, and treatment patterns of patients of Arab ancestry with RA.

Methods

This is a cross sectional study of 895 patients with established rheumatoid arthritis enrolled from five sites (Jordan, Lebanon, Qatar, Kingdom of Saudi Arabia (KSA), and United Arab Emirates). Demographic characteristics, clinical profile, and treatment patterns are compared between the five countries.

Results

The majority of our patients are women, have an average disease duration of 10 years, are married and non-smokers, with completed secondary education. We report a high (>80%) ever-use of methotrexate (MTX) and steroids among our RA population, while the ever-use of disease modifying anti-rheumatic drugs (DMARDs) and TNF-inhibitors average around 67% and 33%, respectively. There are variations in RA treatment use between the five country sites. Highest utilization of steroids is identified in Jordan and KSA (p-value < 0.001), while the highest ever-use of TNF-inhibitors is reported in KSA (p-value < 0.001).

Conclusion

Disparities in usage of RA treatments among Arab patients are noted across the five countries. National gross domestic product (GDP), as well as some other unique features in each country likely affect these. Developing treatment guidelines specific to this region could contribute in delivering standardized therapies to RA patients.

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<![CDATA[Menopausal hormone therapy and the incidence of carpal tunnel syndrome in postmenopausal women: Findings from the Women’s Health Initiative]]> https://www.researchpad.co/article/5c102901d5eed0c484248c7e

Importance

Carpal tunnel syndrome (CTS) is a common and debilitating condition that commonly affects postmenopausal women.

Objective

To determine the effect of menopausal hormone therapy (HT) in healthy postmenopausal women on CTS risk.

Design

We conducted a secondary analysis of the Women’s Health Initiative’s (WHI) HT trials linked to Medicare claims data. Separate intention-to-treat analyses were performed for the two trials; the conjugated equine estrogens alone (CEE alone) and the trial of CEE plus medroxyprogesterone acetate (MPA) trial. (ClinicalTrials.gov, NCT number): NCT00000611.

Setting

Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers.

Participants

The sample size included in the analysis was 16,053 community-dwelling women aged ≥65 years at study entry or those who later aged into Medicare eligibility, and who were enrolled in Medicare (including Part A and/or Part B coverage).

Intervention

Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E+P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14203).

Main outcome(s)

The primary outcome was incident CTS and the secondary outcome was therapeutic CTS procedure occurring during the intervention phases of the trials.

Results

A total of 16,053 women were randomized in both trials. During mean follow up of 4.5 ± 2.8 years in the CEE trial (n = 6,833), there were 203 incident CTS cases in the intervention and 262 incident CTS cases in the placebo group (HR, 0.78; 95% CI, 0.65–0.94; P = 0.009). The CEE+MPA trial (n = 9,220) followed participants for a mean of 3.7 ± 2.3 years. There were 173 incident CTS cases in the intervention compared to 203 cases in the placebo group (HR, 0.80, 95% CI, 0.65–0.97; P = 0.027).

Conclusions

These findings suggest a protective effect of menopausal HT on the incidence of CTS among postmenopausal women. A potential therapeutic role for other forms of estrogen therapy in the management of CTS warrants future research.

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<![CDATA[Biomarkers of erosive arthritis in systemic lupus erythematosus: Application of machine learning models]]> https://www.researchpad.co/article/5c1028cdd5eed0c4842481eb

Objective

Limited evidences are available on biomarkers to recognize Systemic Lupus erythematosus (SLE) patients at risk to develop erosive arthritis. Anti-citrullinated peptide antibodies (ACPA) have been widely investigated and identified in up to 50% of X-ray detected erosive arthritis; conversely, few studies evaluated anti-carbamylated proteins antibodies (anti-CarP). Here, we considered the application of machine learning models to identify relevant factors in the development of ultrasonography (US)-detected erosive damage in a large cohort of SLE patients with joint involvement.

Methods

We enrolled consecutive SLE patients with arthritis/arthralgia. All patients underwent joint (DAS28, STR) and laboratory assessment (detection of ACPA, anti-CarP, Rheumatoid Factor, SLE-related antibodies). The bone surfaces of metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered with a dichotomous value (0/1), obtaining a total score (0–20). Concerning machine learning techniques, we applied and compared Logistic Regression and Decision Trees in conjunction with the feature selection Forward Wrapper method.

Results

We enrolled 120 SLE patients [M/F 8/112, median age 47.0 years (IQR 15.0); median disease duration 120.0 months (IQR 156.0)], 73.3% of them referring at least one episode of arthritis. Erosive damage was identified in 25.8% of patients (mean±SD 0.7±1.6), all of them with clinically evident arthritis. We applied Logistic Regression in conjunction with the Forward Wrapper method, obtaining an AUC value of 0.806±0.02. As a result of the learning procedure, we evaluated the relevance of the different factors: this value was higher than 35% for ACPA and anti-CarP.

Conclusion

The application of Machine Learning Models allowed to identify factors associated with US-detected erosive bone damage in a large SLE cohort and their relevance in determining this phenotype. Although the scope of this study is limited by the small sample size and its cross-sectional nature, the results suggest the relevance of ACPA and anti-CarP antibodies in the development of erosive damage as also pointed out in other studies.

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<![CDATA[Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial]]> https://www.researchpad.co/article/5c22c480d5eed0c484a9311a

Objectives

Recent studies suggest that implementation of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) leads to higher inflammatory activity in seronegative compared with seropositive patients at time of diagnosis. Our aim was to compare the disease course in seronegative and seropositive patients classified according to the 2010 criteria.

Methods

DMARD-naïve patients with RA fulfilling the 2010 criteria were included in the treat-to-target ARCTIC trial and followed for 24 months. We stratified patients as seropositive (rheumatoid factor (RF)+, anticitrullinated protein antibodies (ACPA)+ or both) or seronegative (RF– and ACPA–) and compared disease activity, radiographic progression, treatment response and remission rates across groups.

Results

230 patients were included with mean (SD) age 51.4 (13.7) years, and 61% were female. 34 patients (15%) were seronegative. At 24  months, disease activity measures, radiographic progression and remission rates were similar between groups, despite more inflammatory activity in seronegative patients at baseline. Treatment response was slower in seronegative compared with seropositive patients. The groups received similar treatment.

Conclusion

Our findings suggest that among patients with RA classified according to the 2010 ACR/EULAR criteria, seronegative patients respond well to modern treatment strategies. However, treatment response was somewhat slower in seronegative patients and radiographic progression was similar in seronegative and seropositive patients. Our results indicate that seronegative RA is not a mild form of the disease and requires intensive treat-to-target therapy similar to treatment of seropositive RA.

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<![CDATA[Investigating sirukumab for rheumatoid arthritis: 2-year results from the phase III SIRROUND-D study]]> https://www.researchpad.co/article/5c22c48fd5eed0c484a93782

Objectives

The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs).

Methods

Patients were randomised 1:1:1 to sirukumab 100  mg every 2 weeks (q2w), 50  mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104.

Results

Of 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment.

Conclusions

Sirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

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<![CDATA[A set of conformationally well-defined L/D-peptide epitopes provides a serological bar code for autoantibody subtypes]]> https://www.researchpad.co/article/5b6dda0f463d7e7491b405e9

Which conformational parameters lead to an antibody-affine peptide antigen? And in how many different conformations can we actually present the respective conformational epitope? To provide answers from a chemical point of view, we direct the bending and tethering of peptide backbones by the utilisation of a hydrophobic cluster, disulfides, and d-amino acids. Each mutation is employed pairwise on directly opposite sides of a β-hairpin. In combination, these synthetic modules guide the formation of complementary β-sheet-like structures, whereby the oppositely configured (l/d-)bi-disulfide pairs form with high regioselectivity. The conformational properties of the peptides are assessed by NMR spectroscopy and correlated with their antibody affinity in ELISA. From a pool of thus designed peptide antigens with distinctive complementary affinities against known rheumatoid arthritis (RA) autoantibodies, we select a set of epitopes for an immunoassay with sera of RA patients. We want to put emphasis on the idea, that the different conformational properties of the chosen antigens, containing the same epitope sequence, are mirrored in the distribution of autoantibody subtypes (or of the antibody polyclonality, respectively). Such directly comparable information can only be delivered by a set of peptides, rather than a single one. The hairpin-restriction technology of l/d-configured bi-disulfide amino acid pairs is not limited to RA but applicable to other shape-persistent hairpin motifs which are supposed to identify subgroups of protein receptors.

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