Diffuse alveolar hemorrhage in patients with systemic lupus erythematosus: data from the Spanish society of rheumathology Lupus Register (RELESSER).

INTRODUCTION:  Diffuse alveolar hemorrhage (DAH) is a rare complication with high mortality in patients with systemic lupus erythematosus (SLE). Early diagnosis and treatment are essential to improve patient prognosis. To determine the characteristics of patients with DAH and their mortality in a Spanish cohort of patients with SLE. METHODS:  Patients from the RELESSER (Spanish Society of Rheumatology Lupus Register) who had had at least one confirmed episode of DAH were included. Epidemiological, clinical, and laboratory characteristics were analyzed. RESULTS:  4024 patients were included in the RELESSER register, 37 (0.9%), had at least one recorded episode of DAH. Only further data for 14 patients could be analyzed. In total, 92.9% were women, and for 4 (28.6%) DAH coincided with the debut of SLE. More than 80% of patients had renal involvement and thrombocytopenia. The most frequent manifestations were dyspnea (85.7%) and hypoxemia (100%), with the classic triad of hemoptysis, anemia and pulmonary infiltrates, appearing in 6 (46.2%) patients. The most frequently used treatments were glucocorticoids (85.7%) and cyclophosphamide (69.2%); plasmapheresis was utilized in 5 patients (35.7%) and 8, (57.1%) received intravenous immunoglobulins; 12 (85.7%) patients required admission to the ICU and 5 (35.7%) died. Tobacco use, history of lupus nephritis (LN), concomitant infection, and treatment with cyclophosphamide were more frequent in patients who died. CONCLUSIONS:  DAH is rare in patients with SLE; in up to one-third of patients, it may appear at the onset of the disease. Some factors, such as smoking, a history of LN, treatment with cyclophosphamide, or concomitant infection, are more prevalent in patients with an unfavorable outcome.

Impact of inflammation on cognitive function in patients with highly inflammatory rheumatoid arthritis.

OBJECTIVE: To evaluate cognitive function in patients with rheumatoid arthritis (RA) and inflammatory activity. PATIENTS AND METHODS: We performed a cross-sectional study of a cohort of patients with RA initiating their first biological treatment due to moderate-to-high inflammation and a healthy control group (no inflammatory diseases) matched for age, sex and educational level. All participants underwent a comprehensive neuropsychological assessment, with cognitive impairment defined as a Montreal Cognitive Assessment (MoCA) score<26. Additional assessments included various cognitive tests (STROOP, forward and backward digit spans), anxiety and depression scales (Hospital Anxiety and Depression Scale), quality of life measures (Quality of Life-Rheumatoid Arthritis) and average inflammatory activity according to the 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) into high activity (DAS28≥3.2) and low activity (DAS28<3.2) groups, also CRP levels and interleukin 6 (IL-6) levels were measured using an ELISA. RESULTS: The study population comprised 140 participants, 70 patients with RA and 70 controls. Patients more frequently experienced cognitive impairment than controls (60% vs 40%; p=0.019) and had lower mean (SD) values in the MoCA (23.6 (3.9) vs 25.1 (3.4); p=0.019. As for subtests of the MoCA, involvement was more marked in patients than in controls for the visuospatial-executive (p=0.030), memory (p=0.026) and abstraction (p=0.039) domains. Additionally, patients scored lower on executive function, as assessed by the backward digit span test (4.0 (1.7) vs 4.7 (1.9); p=0.039). Cognitive impairment is associated with age and a lower educational level in the general population, and among patients with RA with educational level, obesity and average inflammatory activity (DAS28, CRP, and IL-6). CONCLUSIONS: Patients with RA with high inflammatory activity are more susceptible to cognitive impairment, which specifically affects the domains of visuospatial, memory, abstraction and executive function.

Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.

BACKGROUND: In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. RESULTS: In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. CONCLUSIONS: Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Using natural language processing to explore characteristics and management of patients with axial spondyloarthritis and psoriatic arthritis treated under real-world conditions in Spain: SpAINET study.

Background: Spondyloarthritis (SpA) is a group of related but phenotypically distinct inflammatory disorders that include axial SpA (axSpA) and psoriatic arthritis (PsA). Information on the characteristics and management of these patients in the real world remains scarce. Objectives: To explore the characteristics and management [disease activity assessment and treatment with secukinumab (SEC) or other biologic disease-modifying antirheumatic drugs (bDMARDs)] of axSpA and PsA patients using natural language processing (NLP) in Electronic Health Records (EHRs). Design: National, multicenter, observational, and retrospective study. Methods: We analyzed free-text and structured clinical information from EHR at three hospitals. All adult patients with axSpA, PsA or non-classified SpA from 2018 to 2021 with minimum follow-up of three months were included when starting SEC or other bDMARDs. Clinical variables were extracted using EHRead® technology based on Systemized Nomenclature of Medicine-Clinical Terms (SNOMED CT) terminology. Results: Out of 887,735 patients, 758 were included, of which 328 had axSpA [58.5% male; mean (SD) age of 50.7 (12.7) years], 365 PsA [54.8% female, 53.9 (12.4) years], and 65 non-classified SpA. Mean (SD) time since diagnosis was 36.8 (61.0) and 24.1 (35.2) months for axSpA and PsA, respectively. Only 116 axSpA patients (35.3%) had available Ankylosing Spondylitis Disease Activity Score (ASDAS) or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at bDMARD onset, of which 61 presented active disease. Disease Activity in PSoriatic Arthritis (DAPSA) or Disease Assessment Score - 28 joints (DAS-28) values at bDMARD onset were available for only 61 PsA (16.7%) patients, with 23 of them having active disease. The number of patients with available tender joint count or swollen joint count assessment was 68 (20.7%) and 59 (18%) for axSpA, and 115 (31.5%) and 119 (32.6%) for PsA, respectively. SEC was used in 63 (19.2%) axSpA patients and in 63 (17.3%) PsA patients. Conclusion: Using NLP, the study showed that around one-third of axSpA and one-sixth of PsA patients have disease activity assessments with ASDAS/BASDAI or DAPSA/DAS-28, respectively, highlighting an area of improvement in these patients' management.

Investigating axial spondyloarthritis and psoriatic arthritis patients using natural language processing We conducted a study in Spain to better understand patients with specific rheumatic conditions known as axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). To analyze their characteristics, we used a computer technology called EHRead, which uses Natural Language Processing (NLP) to analyze free text from electronic health records. Out of a large group of patients, we focused on 758 individuals who had axSpA or PsA. Most of the axSpA patients were men, and they were around 51 years old on average. For the PsA patients, most were women, and their average age was about 54 years. We analyzed outcomes and treatments of these patients. Our findings showed that we can describe and assess a cohort of patients from real world using NLP. Besides, only about one-third of axSpA patients and one-sixth of PsA patients had their respective outcomes completely assessed, which indicates that there is potential room for improvement in the management of axSpA and PsA. The most promising feature in our study is the use of NLP, an artificial intelligence technology that helps us understand information in medical records written in free text. This can help us explore the characteristics of patients and their management in the real world, bringing an opportunity to enhance the care of patients with axSpA and PsA.

Inflammatory profile of incident cases of late-onset compared with young-onset rheumatoid arthritis: A nested cohort study.

Objectives: To describe the characteristics of patients between late-onset rheumatoid arthritis (LORA) with young-onset (YORA), and analyze their association with cumulative inflammatory burden. Methods: We performed a nested cohort study in a prospective cohort comprising 110 patients with rheumatoid arthritis (RA) and 110 age- and sex-matched controls. The main variable was cumulative inflammatory activity according to the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). High activity was defined as DAS28 ≥ 3.2 and low activity as DAS28 < 3.2. The other variables recorded were inflammatory cytokines, physical function, and comorbid conditions. Two multivariate models were run to identify factors associated with cumulative inflammatory activity. Results: A total of 22/110 patients (20%) met the criteria for LORA (≥ 60 years). Patients with LORA more frequently had comorbid conditions than patients with YORA and controls. Compared with YORA patients, more LORA patients had cumulative high inflammatory activity from onset [13 (59%) vs. 28 (31%); p = 0.018] and high values for CRP (p = 0.039) and IL-6 (p = 0.045). Cumulative high inflammatory activity in patients with RA was associated with LORA [OR (95% CI) 4.69 (1.49-10.71); p = 0.008], smoking [OR (95% CI) 2.07 (1.13-3.78); p = 0.017], anti-citrullinated peptide antibody [OR (95% CI) 3.24 (1.15-9.13); p = 0.025], average Health Assessment Questionnaire (HAQ) score [OR (95% CI) 2.09 (1.03-14.23); p = 0.034], and physical activity [OR (95% CI) 0.99 (0.99-0.99); p = 0.010]. The second model revealed similar associations with inflammatory activity in patients with LORA. Conclusion: Control of inflammation after diagnosis is poorer and comorbidity more frequent in patients with LORA than in YORA patients and healthy controls.

miRNA-Mediated Epigenetic Regulation of Treatment Response in RA Patients-A Systematic Review.

This study aimed to evaluate the role of microRNAs (miRNA) as biomarkers of treatment response in rheumatoid arthritis (RA) patients through a systematic review of the literature. The MEDLINE and Embase databases were searched for studies including RA-diagnosed patients treated with disease-modifying antirheumatic drugs (DMARDs) that identify miRNAs as response predictors. Review inclusion criteria were met by 10 studies. The main outcome of the study was the response to treatment, defined according to EULAR criteria. A total of 839 RA patients and 67 healthy donors were included in the selected studies. RA patients presented seropositivity for the rheumatoid factor of 74.7% and anti-citrullinated C-peptide antibodies of 63.6%. After revision, 15 miRNAs were described as treatment response biomarkers for methotrexate, anti-tumour necrosis factor (TNF), and rituximab. Among treatments, methotrexate presented the highest number of predictor miRNAs: miR-16, miR-22, miR-132, miR-146a and miR-155. The most polyvalent miRNAs were miR-146a, predicting response to methotrexate and anti-TNF, and miR-125b, which predicts response to infliximab and rituximab. Our data support the role of miRNAs as biomarkers of treatment response in RA and point to DMARDs modifying the miRNAs expression. Nevertheless, further studies are needed since a meta-analysis that allows definitive conclusions is not possible due to the lack of studies in this field.

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. FINDINGS: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. INTERPRETATION: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. FUNDING: The Instituto de Salud Carlos III.

Systematic Review and Metaanalysis of Worldwide Incidence and Prevalence of Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis.

Objective: In this study, we aimed to evaluate the worldwide incidence and prevalence of ANCA-associated vasculitis (AAV). Methods: A systematic search of Medline and Embase was conducted until June 2020 for studies that analyzed the incidence and prevalence of patients aged >16 years diagnosed with AAV in different geographical areas. A meta-analysis was undertaken to estimate the pooled incidence per million person-years and prevalence per million persons in AAV overall and for each subtype of AAV: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The 95% confidence interval (CI) and I2 for heterogeneity were calculated. Results: The meta-analysis included 25 studies that met the inclusion criteria and covered a total of 4547 patients with AAV. Frequency increased over time. The global pooled incidence (95% CI) was 17.2 per million person-years (13.3−21.6) and the global pooled prevalence (95% CI) was 198.0 per million persons (187.0−210.0). The pooled incidence per million person-years for each AAV subtype varied from highest to lowest, as follows: GPA, 9.0; MPA, 5.9; and EGPA, 1.7. The individual pooled prevalence per million persons was, as follows: GPA, 96.8; MPA, 39.2; and EGPA, 15.6. AAV was more predominant in the northern hemisphere. By continent, a higher incidence in America and pooled prevalence of AAV was observed in America and Europe. Conclusion: The pooled incidence and prevalence of AAV seem to be increasing over time and are higher in the case of GPA. AAV was generally more frequent (incidence and prevalence) in the northern hemisphere.

Clinical characteristics and risk factors associated with lymphoma in patients with systemic lupus erythematosus: a nationwide cohort study.

OBJECTIVES: To assess the characteristics and risk of lymphoma in a large cohort of patients with SLE. METHODS: A case-cohort analysis was performed within a dynamic cohort of SLE patients from the Spanish Society of Rheumatology Lupus Registry (RELESSER). Clinical and analytical features were compared between the lymphoma SLE group and the control SLE group using an independent-sample Student's t-test or Mann-Whitney test for continuous variables and the χ2 test for categorical variables with Fisher's exact test if necessary. The multivariate analysis was based on a generalized linear model. RESULTS: Twenty-one patients with SLE and lymphoma and 3965 non-lymphoma controls with SLE were studied. Most lymphomas were of B cell origin (n = 15/21), with diffuse large B cell lymphoma being the most frequent histological type (8/21, 38.1%). As in the general population, the risk of lymphoma in SLE was higher in male than in female patients and increased with age. In the lymphoma SLE group, bivariate analysis showed a significantly higher percentage of pericarditis, organic brain syndrome, seizures, vasculitis, haemolytic anaemia, splenomegaly, venous thrombosis and mean modified (excluding lymphoma) SLICC/ACR damage index. In contrast, renal involvement, positive anti-dsDNA, and antimalarials ever were less frequent. CONCLUSIONS: In this large multicentre Spanish cohort, we identified characteristics of SLE that are associated with a higher risk of lymphoma. Antimalarials were significantly negatively associated with risk of lymphoma in SLE patients. Nevertheless, further prospective studies are needed to clarify these findings.

Relationship between polyautoimmunity and sarcopenic obesity in rheumatoid arthritis patients.

OBJECTIVE: Sarcopenia is a major cause of morbidity in rheumatoid arthritis patients. Our purpose was to determine whether polyautoimmunity is associated with sarcopenia and alterations in whole body composition in patients with rheumatoid arthritis (RA). METHODS: We performed a cross-sectional observational study of a series of cases of RA. All patients were recruited consecutively from a rheumatology clinic. Body composition by dual-energy x-ray absorptiometry (DEXA) was assessed. The variables of interest were polyautoimmunity (RA associated with other autoimmune diseases), sarcopenia, fat mass, and body mass index (BMI). Other variables included were clinical-analytical and inflammatory cytokines and adipokines. The relationship between sarcopenic obesity and the presence of polyautoimmunity was studied using multivariate analysis. RESULTS: Of the 94 patients with RA included in the study, 15 (16%) had polyautoimmunity. A total of 23 patients with RA (24.5%) had sarcopenia, which was more prevalent in patients with polyautoimmunity than in patients without polyautoimmunity (46.7% vs 20.3%; p = .029). Sarcopenia was not associated with body fat content (p = .870) or with BMI (p = .998). The multivariate analysis showed the factors associated with polyautoimmunity in RA to be sarcopenia (odds ratio [95% CI], 4.80 [1.49-13.95]), BMI (1.18 [1.04-1.35]), and resistin (1.249 [1.01-1.53]). CONCLUSION: Sarcopenia and obesity were more prevalent in patients with RA and polyautoimmunity. Resistin values were also higher in this group than in patients with RA without polyautoimmunity.

Effectiveness, safety and economic analysis of Benepali in clinical practice.

OBJECTIVE: To assess the effectiveness, safety and cost of Etanercept biosimilar in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA) and psoriatic arthritis (PsA) compared to the standard drug in real clinical practice. PATIENTS AND METHODS: Retrospective observational study. Case series of 138 patients with RA, SpA or PsA treated with at least one dose of Benepali® (n = 79) or Enbrel® (n = 59). Drug retention time was the primary efficacy endpoint compared to the biosimilar and the original. The proportion of patients achieving low disease activity or remission after 52 weeks was used as the secondary outcome. Safety was assessed by means of the adverse effects incidence rate. A cost minimization analysis was performed. RESULTS: No differences were observed regarding treatment retention time between drugs (median [95% confidence interval, 95% CI] at 12.0 months [10.2-12.0] for the biosimilar and 12.0 months [12.0-12.0] for the original). Similar improvements, in terms of inflammatory activity and physical function, were obtained after 52 weeks except for patients with SpA and PsA who, in general, experienced improvements of BASDAI and ASDAS with the original compared with the biosimilar. No significant differences were observed in the total number of adverse effects (.43 events/patient-years versus the biosimilar and .53 versus the original). Using the biosimilar in place of the original drug resulted in a net savings of 118,383.55 € (1,747.20 €/patient-years) for the hospital. CONCLUSION: The biosimilar Benepali is as effective and safe as the original and much more cost-effective.

Characteristics and Predictors of Progression Interstitial Lung Disease in Rheumatoid Arthritis Compared with Other Autoimmune Disease: A Retrospective Cohort Study.

OBJECTIVES: To describe the characteristics and progression of interstitial lung disease in patients with associated systemic autoimmune disease (ILD-SAI) and to identify factors associated with progression and mortality. PATIENTS AND METHODS: We performed a multicenter, retrospective, observational study of patients with ILD-SAI followed between 2015 and 2020. We collected clinical data and performed pulmonary function testing and high-resolution computed tomography at diagnosis and at the final visit. The main outcome measure at the end of follow-up was forced vital capacity (FVC) >10% or diffusing capacity of the lungs for carbon monoxide >15% and radiological progression or death. Cox regression analysis was performed to identify factors associated with worsening of ILD. RESULTS: We included 204 patients with ILD-SAI: 123 (60.3%) had rheumatoid arthritis (RA), 58 had (28.4%) systemic sclerosis, and 23 (11.3%) had inflammatory myopathy. After a median (IQR) period of 56 (29.8-93.3) months, lung disease had stabilized in 98 patients (48%), improved in 33 (16.1%), and worsened in 44 (21.5%). A total of 29 patients (14.2%) died. Progression and hospitalization were more frequent in patients with RA (p = 0.010). The multivariate analysis showed the independent predictors for worsening of ILD-SAI to be RA (HR, 1.9 [95% CI, 1.3-2.7]), usual interstitial pneumonia pattern (HR, 1.7 [95% CI, 1.0-2.9]), FVC (%) (HR, 2.3 [95% CI, 1.4-3.9]), and smoking (HR, 2.7 [95%CI, 1.6-4.7]). CONCLUSION: Disease stabilizes or improves after a median of 5 years in more than half of patients with ILD-SAI, although more than one-third die. Data on subgroups and risk factors could help us to predict poorer outcomes.

Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis.

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients. Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions. Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort. Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.

Interactions between rheumatoid arthritis antibodies are associated with the response to anti-tumor necrosis factor therapy.

BACKGROUND: Blocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 50-60% of rheumatoid arthritis (RA) patients. However, there are yet no biomarkers to stratify patients for anti-TNF therapy. Rheumatoid factor (RF) and anti-cyclic-citrullinated antibodies (anti-CCP) have been evaluated as biomarkers of response but the results have shown limited consistency. Anti-carbamylated protein (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4) antibodies have been much less studied. Despite being linked to common immune processes, the interaction between these markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy. METHODS: For this objective, a prospective cohort of n = 80 RA patients starting anti-TNF therapy was recruited. Serum determinations at baseline were performed for RF, anti-CCP, anti-CarP and anti-PAD4 antibodies using enzyme-linked immunosorbent assays (ELISA). The clinical response to anti-TNF therapy was determined at week 12 using the change in DAS28 score. Association was performed using multivariate linear regression adjusting for baseline DAS28, sex and age. RESULTS: The interaction between pairs of antibodies was tested by the addition of an interaction term. We found two highly significant antibody interactions associated with treatment response: anti-CarP with anti-PAD4 (p = 0.0062), and anti-CCP with RF (p = 0.00068). The latter antibody interaction was replicated in an independent retrospective cohort of RA patients (n = 199, p = 0.04). CONCLUSIONS: The results of this study suggest that antibody interaction effects are important factors in the response to anti-TNF therapy in RA.

Food groups associated with immune-mediated inflammatory diseases: a Mendelian randomization and disease severity study.

BACKGROUND/OBJECTIVES: Immune-mediated inflammatory diseases (IMIDs) are prevalent diseases. There is, however, a lack of understanding of the link between diet and IMIDs, how much dietary patterns vary between them and if there are food groups associated with a worsening of the disease. SUBJECTS/METHODS: To answer these questions we analyzed a nation-wide cohort of n = 11,308 patients from six prevalent IMIDs and 2050 healthy controls. We compared their weekly intake of the major food categories, and used a Mendelian randomization approach to determine which dietary changes are caused by disease. Within each IMID, we analyzed the association between food frequency and disease severity. RESULTS: After quality control, n = 11,230 recruited individuals were used in this study. We found that diet is profoundly altered in all IMIDs: at least three food categories are significantly altered in each disease (P < 0.05). Inflammatory bowel diseases showed the largest differences compared to controls (n ≥ 8 categories, P < 0.05). Mendelian randomization analysis supported that some of these dietary changes, like vegetable reduction in Crohn's Disease (P = 2.5 × 10-10, OR(95% CI) = 0.73(0.65, 0.80)), are caused by the disease. Except for Psoriatic Arthritis and Systemic Lupus Erythematosus, we have found ≥2 food groups significantly associated with disease severity in the other IMIDs (P < 0.05). CONCLUSIONS: This cross-disease study demonstrates that prevalent IMIDs are associated to a significant change in the normal dietary patterns. This variation is highly disease-specific and, in some cases, it is caused by the disease itself. Severity in IMIDs is also associated with specific food groups. The results of this study underscore the importance of studying diet in IMIDs.

Predictors of Progression and Mortality in Patients with Prevalent Rheumatoid Arthritis and Interstitial Lung Disease: A Prospective Cohort Study.

OBJECTIVES: To describe a prospective cohort of patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD) and identify risk factors associated with disease progression and mortality in this cohort. PATIENTS AND METHODS: We performed a multicenter, prospective, observational study of patients with RA-ILD receiving disease-modifying antirheumatic drugs (DMARDs) between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 60 months. The main endpoint was "Progression to ILD at the end of follow-up" in terms of the following outcomes: (1) improvement (i.e., improvement in forced vital capacity (FVC) ≥10% or diffusing capacity of the lungs for carbon monoxide (DLCO) ≥15% and absence of radiological progression); (2) nonprogression (stabilization or improvement in FVC ≤10% or diffusing capacity of the lungs for carbon monoxide (DLCO) <15% and absence of radiological progression); (3) progression (worsening of FVC >10% or DLCO >15% and radiological progression); or (4) death. We recorded demographic and clinical characteristics, lung function, and the incidence of adverse events. A Cox regression analysis was performed to identify factors associated with the worsening of ILD. RESULTS: After 60 months, lung disease had stabilized in 66 patients (56.9%), improved in 9 (7.8%), and worsened in 23 (19.8%). Eighteen patients (15.5%) died, with a mean survival of 71.8 (1.9) months after diagnosis of ILD. The Cox multivariate analysis revealed the independent predictors of worsening of RA-ILD to be usual interstitial pneumonia (hazard ratio (HR), 2.6 (95%CI, 1.0-6.7)), FVC <80% (HR, 3.8 (95%CI, 1.5-6.7)), anticitrullinated protein antibody titers (HR, 2.8 (95%CI, 1.1-6.8)), smoking (HR, 2.5 (95%CI, 1.1-6.2)), and treatment with abatacept, tocilizumab, or rituximab (HR, 0.4 (95%CI, 0.2-0.8)). During follow-up, 79 patients (68%) experienced an adverse event, mostly infection (61%). Infection was fatal in 10/18 patients (55.5%) during follow-up. CONCLUSIONS: Lung function is stable in most patients with RA-ILD receiving treatment with disease-modifying anti-rheumatic drugs (DMARDs), although one-third worsened or died. Identifying factors associated with worsening in RA-ILD is important for clinical management.

Psychological factors associated with sleep disorders in patients with axial spondyloarthritis or psoriatic arthritis: A multicenter cross-sectional observational study.

BACKGROUND: Studies in axial spondyloarthritis (AxSp) have shown that intensity of pain, anxiety, depression and inflammatory activity are associated with poor sleep quality. AIM: To describe mood and sleep disorders and positive psychological factors in patients with AxSp and psoriatic arthritis (PsA) and to evaluate the psychological factors that are potentially involved in sleep disorders. DESIGN: Multicenter cross-sectional observational study based on a series of patients with AxSp and PsA. PARTICIPANTS: Participants were selected consecutively from patients aged ≥18 years with AxSp or PsA followed at the rheumatology department of 4 Spanish hospitals. INCLUSION CRITERIA: age ≥18 years, AxSp (ASAS criteria) or PsA (CASPAR criteria), ability to understand the study and prepared to complete the questionnaires. METHODS: Main outcomes: Oviedo Sleep Quality questionnaire result. SECONDARY OUTCOMES: psychological status evaluated using the Hospital Anxiety and Depression Scale (HADS) questionnaire, health-related quality of life evaluated using SF-36, perception of pain evaluated using the short questionnaire for assessment of pain (BDU) and fatigue evaluated using the Fatigue Scale (FACIT) questionnaire. We performed a descriptive multivariate linear regression analysis to study factors that were independently associated with sleep disorders. The STROBE guidelines were adopted. RESULTS: We included 301 patients (152 [50.5%] with AxSp and 149 [49.5%] with PsA). The multivariate linear regression analysis for the whole sample showed that insomnia was inversely associated with emotional recovery and biologic disease-modifying antirheumatic drugs and directly associated with depression in both groups. The analysis by disease (AxSp and PsA) showed that insomnia was independently associated with depression and emotional recovery. CONCLUSIONS: Insomnia may be associated with other mood disorders, quality of life and inflammatory activity in the patients studied here. RELEVANCE TO CLINICAL PRACTICE: A nurse intervention can be carried out to prevent sleep disorders knowing the consequences and triggers of the problem.

Incidence and case fatality rate of COVID-19 in patients with inflammatory articular diseases.

OBJECTIVE: To describe the incidence and fatality of coronavirus disease 2019 (COVID-19) and identify risk factors to fatality in patients with inflammatory articular diseases (IAD). METHODS: This is a cross-sectional observational study of IAD patients and COVID-19 with controls matched for age, sex, and RT-PCR. A control group was used to compare the cumulative incidence (CI) and case fatality rate (CFR). The main outcomes of the study were CI and CFR. Other variables included comorbidities, treatments, and characteristics of the COVID-19. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with IAD. RESULTS: Of the 1537 patients who fulfilled the inclusion criteria, 23/1537 (1.49%) had IAD 13 (0.8%) had rheumatoid arthritis (RA), 5 psoriatic arthritis (PsA) (0.3%) and 5 axial spondyloarthritis (0.3%). There were no significant differences in CI of COVID-19 and CFR in patients with IAD compared with COVID-19 patients without IAD. In RT-PCR positive patients, the CI of COVID-19 in PsA and AS was higher. Of the 23 IAD patients, 2 RA patients (8.6%) died. The patients did no show characteristics of the COVID-19 disease different from the population. In multivariate analysis, the factor associated with fatality in patients with IAD was older age (OR [95% CI], 1.1 [1.0-1.2]). CONCLUSION: COVID-19 CI, fatality rate and other features do not seem to be increased in IAD patients. Older age was associated with fatality in patients with IAD.

Non-anti-TNF biologic agents are associated with slower worsening of interstitial lung disease secondary to rheumatoid arthritis.

OBJECTIVES: To analyze the effect of disease-modifying antirheumatic drugs (DMARDs) on the outcome of interstitial lung disease secondary to rheumatoid arthritis (RA-ILD). PATIENTS AND METHODS: We performed a multicenter, prospective, observational study of patients with RA-ILD receiving DMARDs between 2015 and 2017. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 24 months. The radiological assessment was centralized. The main outcome measure at 24 months was changed in lung function (improvement, stabilization, worsening, or death). We recorded the 28-joint Disease Activity Score 28 (DAS28) and adverse events. A logistic regression analysis was performed to identify factors associated with worsening of ILD. RESULTS: After 24 months, lung disease was stabilized in 40 patients (57.1%), improved in 8 (11.4%), and worse in 21 (30.0%). One patient (1.4%) died. The factors associated with worsening of ILD in the multivariate analysis were treatment with abatacept, tocilizumab, or rituximab (OR, 0.102 [95%CI, 0.015-0.686]), DAS28 (OR, 1.969 [95%CI, 1.005-3.857]), and smoking (OR, 6.937 [95%CI, 1.378-4.900]). During follow-up, 30 patients (42.9%) experienced an adverse event, which was severe in 12 cases (17.1%). CONCLUSIONS: Lung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. Non-anti-TNF DMARDs reduce the risk of worsening of lung disease in 90% of patients. The inflammatory activity of RA and smoking, on the other hand, are associated with worsening. Key Points • We have performed prospectively evaluated lung and joint function in patients with RA-ILD receiving treatment with various DMARDs. • In our study, the lung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. • Neither csDMARDs nor anti-TNF agents were associated with a significant risk of worsening of lung disease, whereas non-anti-TNF bDMARDs could reduce the risk of worsening of lung disease. • Smoking and poor control of joint involvement were the main factors associated with worsening of lung disease.

Analysis of Clinical-Analytical Characteristics in Patients with Rheumatoid Arthritis and Interstitial Lung Disease: Case-Control Study. / Análisis de las características clínico-analíticas de pacientes con artritis reumatoide y enfermedad pulmonar intersticial: casos y controles.

OBJECTIVES: To study the differences between rheumatoid arthritis (RA)-interstitial lung disease (ILD) patients and RA patients without ILD in severity markers and disease activity and to identify factors associated with the presence of ILD in RA patients. PATIENTS AND METHODS: Patients: RA-ILD patients selected from a multicentre cohort in Andalusia, Spain. CONTROLS: RA-patients without ILD paired by sex, age and disease duration. PROTOCOL: RA patients are reviewed every 3-6months in rheumatology consultation. All patients are reviewed according to a predetermined protocol with systematic data collection. OUTCOMES: description of ILD type, differences in severity markers and disease activity in both groups. Other variables: ILD type by imaging technique (HRCT): nonspecific interstitial pneumonia (NSIP)/usual interstitial pneumonia (UIP). Lung function by PTF. Activity and severity markers of arthritis by DAS28-ESR, HAQ, RF, ACPA and erosions. Treatment with DMARD. STATISTICAL ANALYSIS: descriptive and paired T-test or Chi-square test followed by binary logistic regression (DV: ILD in patients with RA). RESULTS: Eighty-two patients were included, 41 RA-ILD and 41 RA controls. RF and ACPA positivity, serositis and osteoporosis were more frequent in RA-ILD patients. No significant differences in DAS28 were observed (P=.145) between RA-ILD and RA control patients. RA-ILD patients presented worse HAQ scores (P=.006). All patients were treated with disease modifying antirheumatic drugs (DMARDs). The risk of developing ILD in RA patients is tripled by a history of smoking or the presence of erosive arthritis (R2=.36). CONCLUSIONS: The results of our study support the higher frequency of UIP and NSIP in RA patients. DLCO is the most sensitive parameter to detect ILD in RA patients. Our study showed that ILD in RA patients was associated with RA severity (presence of erosions and ACPA) and with a history of smoking.