Rate of severe and fatal infections in a cohort of patients with interstitial lung disease associated with rheumatoid arthritis: a multicenter prospective study.

Objective: To describe severe infection, foci of infection, microorganisms, associated factors, and impact on mortality in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Patients and methods: The study was based on a multicenter prospective cohort of patients with RA-ILD followed up from 2015 to 2023. The main outcome measures were incident severe infection and fatal infection. We evaluated infectious foci, etiologic agents, vaccination status, variables associated with lung function, and clinical-therapeutic variables in RA. The incidence rate (IR) for infection and mortality was calculated per 100 person-years, and 3 multivariate models were constructed to explore factors associated with infection. Results: We followed up 148 patients with RA-ILD for a median 56.7 months (699.3 person-years). During this period, 142 patients (96%) had at least 1 infection. A total of 368 infectious episodes were recorded, with an IR of 52.6 per 100 person-years. Of the 48 patients who died, 65% did so from infection. Respiratory infections were the most common first infection (74%), infection overall (74%), and fatal infection (80%) and were caused mostly by SARS CoV-2, Streptococcus pneumoniae, Pseudomonas aeruginosa, and influenza A virus. The factors associated with an increased risk of infection and death in patients with RA-ILD were age, inflammatory activity, and therapy with corticosteroids and immunosuppressants. Conclusion: Patients with RA-ILD have a high risk of serious infection, especially respiratory infection. Infection develops early, is recurrent, and is frequently fatal. The presence of associated factors such as advanced age, joint inflammation, and treatment highlight the importance of integrated and preventive medical care.

Exploring the influence of baseline rheumatoid factor levels on TNF inhibitor retention rate in patients with rheumatoid arthritis: a multicentre and retrospective study.

OBJECTIVE: To assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) levels. METHODS: Longitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (

Analysis of comorbidity in rheumatoid arthritis-associated interstitial lung disease: a nested case-cohort study.

OBJECTIVES: To describe comorbid conditions in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to analyze factors associated with multimorbidity. METHODS: Nested case-cohort study of 2 prospective cohorts: one with RA-ILD (cases) and another with RA but not ILD (controls). The cohorts were matched for age, sex, and time since diagnosis. Multimorbidity was defined as the co-occurrence of 2 or more chronic diseases, in addition to RA and ILD. We evaluated the comorbid conditions included in the Charlson Comorbidity Index, cardiovascular risk factors, neuropsychiatric conditions, and other frequent conditions in RA. We also recorded clinical-laboratory variables, inflammatory activity according to the 28-joint Disease Activity Score, C-reactive protein (CRP), physical function, and pulmonary function. We performed 2 multivariate analyses to identify factors associated with multimorbidity in RA and RA-ILD. RESULTS: The final study population comprised 110 cases and 104 controls. Multimorbidity was more frequent among cases than controls (80 [72.7] vs 60 [57.7]; p = 0.021). In both groups, multimorbidity was associated with ILD (OR [95% CI] 1.92 [1.03-3.59]; p = 0.039), age (OR [95% CI] 1.05 [1.01-1.08]; p = 0.004), CRP (OR [95% CI] 1.16 [1.05-1.29]; p = 0.003), and erosions (OR [95% CI] 1.05 [1.01-1.08]; p = 0.004); in the cases, it was associated with CRP (OR [95% CI] 1.17 [1.01-1.35]; p = 0.027), anti-citrullinated peptide antibody (OR [95% CI] 1.23 [1.14-13.02]; p = 0.049), and forced vital capacity (OR [95% CI] 0.79 [0.96-0.99]; p = 0.036). CONCLUSION: In patients with RA, multimorbidity was associated with ILD, systemic inflammation, and advanced age.

Safety and Effectiveness of Abatacept in a Prospective Cohort of Patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: To prospectively evaluate the safety and efficacy profile of abatacept in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: We performed a prospective observational multicenter study of a cohort of patients with RA-ILD treated with abatacept between 2015 and 2021. Patients were evaluated using high-resolution computed tomography and pulmonary function tests at initiation, 12 months, and the end of follow-up. The effectiveness of abatacept was evaluated based on whether ILD improved, stabilized, progressed, or was fatal. We also evaluated factors such as infection, hospitalization, and inflammatory activity using the 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR). Cox regression analysis was performed to identify factors associated with progression of lung disease. RESULTS: The study population comprised 57 patients with RA-ILD treated with abatacept for a median (IQR) of 27.3 (12.2-42.8) months. Lung disease had progressed before starting abatacept in 45.6% of patients. At the end of follow-up, lung disease had improved or stabilized in 41 patients (71.9%) and worsened in 13 (22.8%); 3 patients (5.3%) died. No significant decreases were observed in forced vital capacity (FVC) or in the diffusing capacity of the lung for carbon monoxide (DLCO).The factors associated with progression of RA-ILD were baseline DAS28-ESR (OR [95% CI], 2.52 [1.03-3.12]; p = 0.041), FVC (OR [95% CI], 0.82 [0.70-0.96]; p = 0.019), and DLCO (OR [95% CI], 0.83 [0.72-0.96]; p = 0.018). Only 10.5% of patients experienced severe adverse effects. CONCLUSION: Pulmonary function and joint inflammation stabilized in 71% of patients with RA-ILD treated with abatacept. Abatacept had a favorable safety profile.

Importance of Vaccination against SARS-CoV-2 in Patients with Interstitial Lung Disease Associated with Systemic Autoimmune Disease.

Objectives: To describe the frequency of COVID-19 and the effect of vaccination in patients with interstitial lung disease and systemic autoimmune disease (ILD-SAD) and to identify factors associated with infection and severity of COVID-19. Methods: We performed a cross-sectional multicenter study of patients with ILD-SAD followed between June and October 2021. The main variable was COVID-19 infection confirmed by a positive polymerase chain reaction (PCR) result for SARS-CoV-2. The secondary variables included severity of COVID-19, if the patient had to be admitted to hospital or died of the disease, and vaccination status. Other variables included clinical and treatment characteristics, pulmonary function and high-resolution computed tomography. Two logistic regression was performed to explore factors associated with "COVID-19" and "severe COVID-19". Results: We included 176 patients with ILD-SAD: 105 (59.7%) had rheumatoid arthritis, 49 (27.8%) systemic sclerosis, and 22 (12.54%) inflammatory myopathies. We recorded 22/179 (12.5%) SARS-CoV-2 infections, 7/22 (31.8%) of them were severe and 3/22 (13.22%) died. As to the vaccination, 163/176 (92.6%) patients received the complete doses. The factors associated with SARS-CoV-2 infection were FVC (OR (95% CI), 0.971 (0.946−0.989); p = 0.040), vaccination (OR (95% CI), 0.169 (0.030−0.570); p = 0.004), and rituximab (OR (95% CI), 3.490 (1.129−6.100); p = 0.029). The factors associated with severe COVID-19 were the protective effect of the vaccine (OR (95% CI), 0.024 (0.004−0.170); p < 0.001) and diabetes mellitus (OR (95% CI), 4.923 (1.508−19.097); p = 0.018). Conclusions: Around 13% of patients with ILD-SAD had SARS-CoV-2 infection, which was severe in approximately one-third. Most patients with severe infection were not fully vaccinated.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

OBJECTIVES: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. METHODS: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. RESULTS: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. CONCLUSIONS: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules.

Efficacy and Safety of Rituximab in Autoimmune Disease-Associated Interstitial Lung Disease: A Prospective Cohort Study.

OBJECTIVES: To analyze the efficacy and safety of rituximab (RTX) in connective tissue disease associated with interstitial lung disease (CTD-ILD). METHODS: We performed a multicenter, prospective, observational study of patients with CTD-ILD receiving rituximab between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline, at 12 months, and at the end of follow-up. 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 (DLCO) > 15% and radiological progression or death. We recorded clinical characteristics, time to initiation of RTX, concomitant treatment, infections, and hospitalization. A Cox regression analysis was performed to identify factors associated with worsening ILD. RESULTS: We included 37 patients with CTD-ILD treated with RTX for a median (IQR) of 38.2 (17.7-69.0) months. At the end of the follow-up, disease had improved or stabilized in 23 patients (62.1%) and worsened in seven (18.9%); seven patients (18.9%) died. No significant decline was observed in median FVC (72.2 vs. 70.8; p = 0.530) or DLCO (55.9 vs. 52.2; p = 0.100). The multivariate analysis showed the independent predictors for worsening of CTD-ILD to be baseline DLCO (OR (95% CI), 0.904 (0.8-0.9); p = 0.015), time to initiation of RTX (1.01 (1.001-1.02); p = 0.029), and mycophenolate (0.202 (0.04-0.8); p = 0.034). Only 28 of the 37 patients (75.6%) were still undergoing treatment with RTX: two patients (5.4%) stopped treatment due to adverse events and seven patients (18.9%) died owing to progression of ILD and superinfection. CONCLUSION: Lung function improved or stabilized in more than half of patients with CTD-ILD treated with RTX. Early treatment and combination with mycophenolate could reduce the risk of progression of ILD.

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.

Multidisciplinary Unit Improves Pregnancy Outcomes in Women with Rheumatic Diseases and Hereditary Thrombophilias: An Observational Study.

Rheumatic diseases (RD) and hereditary thrombophilias (HT) can be associated with high-risk pregnancies. This study describes obstetric outcomes after receiving medical care at a multidisciplinary consultation (MC) and compares adverse neonatal outcomes (ANOs) before and after medical care at an MC. This study is a retrospective observational study among pregnant women with RD and HT treated at an MC of a university hospital (southern Spain) from 2012 to 2018. Absolute risk reduction (ARR) and number needed to treat (NNT) were calculated. A total of 198 pregnancies were registered in 143 women (112 with RD, 31 with HT), with 191 (96.5%) pregnancies without ANOs and seven (3.5%) pregnancies with some ANOs (five miscarriages and two foetal deaths). Results previous to the MC showed 60.8% of women had more than one miscarriage, with 4.2% experiencing foetal death. MC reduced the ANO rate by AAR = 60.1% (95%CI: 51.6-68.7%). The NNT to avoid one miscarriage was 1.74 (95%CI: 1.5-2.1) and to avoid one foetal death NNT = 35.75 (95CI%: 15.2-90.9). A total of 84.8% of newborns and 93.2% of women did not experience any complication. As a conclusion, the follow-up of RD or HT pregnant women in the MC drastically reduced the risk of ANOs in this population with a previous high risk.

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.

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.

Two-year efficacy of tocilizumab in patients with active rheumatoid arthritis in clinical practice. / Eficacia a 2 años de tocilizumab en pacientes con artritis reumatoide activa en la práctica clínica habitual.

OBJECTIVES: To evaluate the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in clinical practice, retention rates of the drug and predictors of response. METHODS: We performed a descriptive, prospective, longitudinal, open-label study in patients receiving TCZ (8mg/kg/4 weeks) in a clinical practice setting. The clinical responses were evaluated using the European League Against Rheumatism (EULAR) response criteria, and the low activity and remission rates according to the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index (CDAI). RESULTS: The EULAR response rate was 86.63% and the DAS28 remission rate was 53.7% after 6 months of treatment; rates of low disease activity were 52.9% on CDAI and 47.1% on DAS28 at month 24. There were no statistically significant differences in EULAR response, rates of low activity and remission on DAS28 between patients receiving TCZ alone and those receiving TCZ in combination therapy, or between patients positive or negative for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies. The naïve biological therapy patients showed better remission and low activity rates after 6 months of treatment. The retention rate was 61% at month 24. Adverse events were among the most frequent causes of discontinuation. CONCLUSIONS: Tocilizumab is effective in RA, has a similar efficacy when used alone or in combination with synthetic disease-modifying antirheumatic drugs (DMARDs) and shows high retention rates.