Interstitial lung disease (ILD) contributes significantly to morbidity and mortality in connective tissue disease (CTD). Early detection and accurate diagnosis are essential for informing treatment decisions and prognosis in this setting. Clear guidance on CTD-ILD screening, however, is lacking.

To establish recommendations for CTD-ILD screening based on the current evidence.

Following an extensive literature research and evaluation of articles selected for their recency and relevance to the characterization, screening, and management of CTD-ILD, an expert panel formed by six pulmonologists from the Portuguese Society of Pulmonology, six rheumatologists from the Portuguese Society of Rheumatology, and six radiologists from the Portuguese Society of Radiology and Nuclear Medicine participated in a multidisciplinary discussion to produce a joint statement on screening recommendations for ILD in CTD.

The expert panel achieved consensus on when and how to screen for ILD in patients with systemic sclerosis, rheumatoid arthritis, mixed connective tissue disease, Sjögren syndrome, idiopathic inflammatory myopathies and systemic lupus erythematous.

Despite the lack of data on screening for CTD-ILD, an expert panel of pulmonologists, rheumatologists and radiologists agreed on a series of screening recommendations to support decision-making and enable early diagnosis of ILD to ultimately improve outcomes and prognosis in patients with CTD.

Late-Onset Rheumatoid Arthritis (LORA) is receiving increased clinical attention due to global aging trends. LORA presents distinct diagnostic, clinical, and therapeutic challenges. It often presents with a balanced gender distribution, acute onset, preferential involvement of larger joints, and decreased seropositivity. The diagnostic process is complex due to atypical presentations, comorbidities, and limitations of classification criteria, which insufficiently address the heterogeneity of LORA phenotypes. Patients with LORA often experience age-related geriatric syndromes, including frailty, cognitive decline, and malnutrition, in addition to comorbid cardiovascular disorders, pulmonary involvement, oncologic conditions, and osteoporosis. All these factors confound disease progression and treatment strategies, necessitating careful consideration of polypharmacy and modified drug metabolism. While the treatment principles largely align with those of Younge-Onset Rheumatoid Arthiritis (YORA), LORA management requires individualized approaches. Available evidence suggests that with proper monitoring, disease-modifying anti-rheumatic drugs (DMARDs) are safe and effective for older adults. Glucocorticoids should be minimized due to potential detrimental effects. Despite elevated baseline disease activity and functional deterioration, effectively managed LORA patients may achieve disease control similar to that of younger individuals. This review advocates for age-adjusted diagnostic strategies and patient-centered care models tailored to the needs of older RA patients. Addressing these unmet needs may enhance outcomes and quality of life for the growing population of LORA patients.

Interstitial lung disease (ILD) develops in 5-10% of patients with RA and contributes significantly to morbidity and mortality, particularly in those with a fibrotic phenotype. Yet, biomarkers to reliably identify RA patients with underlying pulmonary fibrosis are inadequate. Herein, we used sputum to identify lung-based biomarkers that distinguish RA patients with underlying pulmonary fibrosis and may better inform underlying pathogenesis in RA-ILD.

We included 37 RA patients with pulmonary fibrosis (RA-PF) and 30 RA patients without ILD (RA-no-ILD). Induced sputum and serum were tested for TGF-β levels by immunoassay. DNA was extracted to determine presence of the MUC5B ILD-risk allele ('T'). High-resolution CT (HRCT) and pulmonary function tests (PFTs) were completed within 3 months of sputum collection and quantified to determine lung disease severity.

Sputum TGF-β was significantly elevated in individuals with RA-PF compared with RA-no-ILD (P < 0.001) and correlated with more fibrosis on HRCT (P = 0.005) and lower forced vital capacity (P = 0.006) and diffusion capacity of carbon monoxide (P = 0.044) on PFTs. Within RA-PF patients, sputum TGF-β was higher in those with the MUC5B ILD-risk genotype (GT/TT) (P = 0.038). There were no differences in serum levels of TGF-β between groups.

We demonstrate that sputum levels of TGF-β are significantly elevated in individuals with RA-PF, correlate with lung disease severity, and are elevated in those with the MUC5B ILD-risk polymorphism. These findings could identify novel approaches to ILD screening in RA and potential targeted therapeutic strategies for RA-ILD.

Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities.

Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression.

We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18-1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52-2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10-8) but not RA. There were no statistically significant associations among Black/African American participants.

RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.

To evaluate the efficacy, safety, and tolerability of antifibrotic agents, nintedanib and pirfenidone, in the treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

A systematic literature review was conducted following PRISMA and MOOSE guidelines. Studies assessing nintedanib or pirfenidone in RA-ILD were included. A meta-analysis was performed using a random-effects model.

Six studies (2 randomized controlled trials and 4 observational) involving 270 RA-ILD patients met the inclusion criteria. In total, 148 received nintedanib and 122 received pirfenidone. Nearly 70 % had a usual interstitial pneumonia pattern. The pooled analysis revealed a mean FVC decline of -68.97 mL/year (95 % CI: -104.85 to -32.49; p < 0.001) and a mean difference of 1.15 % (p = 0.33; after excluding influential studies: -0.28, p = 0.54). Their impact on %pDLCO has been less extensively evaluated, with a mean difference of -1.76 % (p = 0.36; after excluding influential studies: effect size -3.78, p < 0.001). The changes in pulmonary function tests were comparable between nintedanib and pirfenidone. Mortality rates ranged from 15 % to 35 %, with respiratory-specific mortality reported at 44 % to 100 %. Lung transplantation rates were 4-5 %. Antifibrotic therapy was associated with a pooled adverse event (AE) rate of 73 % (95 % CI: 0.38-0.97; p < 0.001), with gastrointestinal symptoms and hepatotoxicity being the most frequently reported. Treatment discontinuation due to AEs occurred in nearly 24 % of patients (95 % CI: 0.16-0.40; p < 0.001).

Antifibrotic agents demonstrated stabilization of %pFVC, with less robust evidence for %pDLCO in RA-ILD. Nearly one quarter of patients discontinued therapy due to AEs.

In 2023, the Spanish Society of Rheumatology (SER) and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) proposed screening criteria for interstitial lung disease (ILD) in rheumatoid arthritis (RA) based on expert opinion, requiring validation. This study aimed to evaluate their sensitivity and specificity in a cohort of early RA patients.

This cross-sectional study retrospectively assessed the SER/SEPAR criteria in 146 early RA patients screened for ILD at diagnosis. Screening included medical history, respiratory auscultation, chest X-ray (CXR), and complete pulmonary function tests (PFTs). Thoracic high-resolution computed tomography (HRCT) was performed only in the presence of symptoms, velcro crackles, or abnormalities on CXR or PFTs.

Among the 146 patients included, 28 (19.2 %) developed ILD, all confirmed by HRCT. Of these, 12 (43 %) had clinically evident ILD preceding or coinciding with joint symptoms, while the remaining 16 (57 %) were identified after applying the screening protocol. At diagnosis, 90 patients (61.6 %) met the screening criteria, with ILD confirmed in 26 cases (28.9 %). Conversely, among 56 patients (38.4 %) not meeting the criteria, ILD was ultimately identified in 2 cases (3.5 %). The SER/SEPAR screening criteria demonstrated a sensitivity of 92.9 % (95 % CI: 76.5-99.1), specificity of 45.8 % (95 % CI: 36.6-55.2), LR+ of 1.71 (95 % CI: 1.41-2.08), LR- of 0.16 (95 % CI: 0.04-0.60), PPV of 28.9 % (95 % CI: 25.1-33.1), NPV of 96.4 % (95 % CI: 87.5-99.1), and diagnostic accuracy of 54.8 % (95 % CI: 46.4-63.1).

The SER/SEPAR criteria for ILD screening demonstrated high sensitivity in recent-onset RA patients, supporting their utility as a tool for early detection in this scenario.

To develop a prediction model for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression.

We investigated predictors of RA-ILD progression in the Korean RA-ILD (KORAIL) cohort, a prospective study that enrolled patients with RA meeting ACR/EULAR criteria and ILD on chest computed tomography (CT) scans and followed for 3 years. Pulmonary function tests (PFTs) and chest CT scans were conducted annually. RA-ILD progression was defined as both physiological and radiological worsening, adapted from the 2023 ATS/ERS/JRS/ALAT definition of progressive pulmonary fibrosis. Baseline factors included clinical factors and biomarkers (autoantibodies, inflammatory markers, and pulmonary damage markers).

We analyzed 138 RA-ILD patients (mean age 66.4 years, 30.4 % male, 60.1 % usual interstitial pneumonia [UIP] pattern). During a median follow-up of 2.9 years, 34.8 % (n = 48) had RA-ILD progression. Baseline associations with progression included: UIP pattern, ILD extent >10 %, DLCO %pred., anti-cyclic citrullinated peptide (anti-CCP), Krebs von den Lungen-6 (KL-6), and human surfactant protein D. We developed prediction models using UIP pattern, ILD extent, DLCO % pred., and anti-CCP titer with or without serum KL-6 levels. The models had areas under the curve (AUCs) of 0.73 and 0.75, respectively. The high-risk group had a positive predictive value for progression of 85.7 %, while the low-risk group had a negative predictive value of 94.7 %.

In this prospective cohort, UIP pattern, ILD extent, lower DLCO, RA disease activity, anti-CCP levels, and pulmonary damage biomarkers were associated with RA-ILD progression. We developed prediction models that may be clinically useful to risk stratify once externally validated.

We aimed to describe the incidence of RA-ILD in various countries worldwide, and to explore its association with RA disease activity.

In 5 countries, data on RA-ILD (clinical diagnosis based on chest X-ray or CT) were collected RA patients of two observational databases (METEOR, EAC). We investigated a possible association between disease activity over time and RA-ILD.

16,663 patients with RA with variable disease duration were evaluated. At the first visit recorded in the database, 1/1077 (0.09 %) patients from The Netherlands, 63/11,787 (0.53 %) from India, 8/629 (1.27 %) from South Africa, 6/424 (1.42 %) from Mexico and 17/2728 (0.62 %) from Colombia had an RA-ILD diagnosis. The incidence rate of RA-ILD in patients with newly diagnosed RA was 3.8 (95 % CI 1.6 to 9.1) per 1000 patient years in The Netherlands, 1.6 (95 % CI 1.0 to 2.5) in India and 6.6 (95 % CI 2.5-17.5) in South Africa. The OR for RA-ILD development, per point increase in DAS28 over time was 1.19 (95 % CI 0.34 to 4.22). Disease activity after the RA-ILD diagnosis or a matched timepoint was statistically significantly higher in patients with RA-ILD than in controls (β 0.56 (95 % CI 0.18 to 0.93). There were no clear differences in DMARD use between the two groups.

Despite slight differences in RA-ILD prevalence and incidence between countries, the incidence of RA-ILD in daily practice is low in our RA population from different continents. Patients with RA-ILD had a higher disease activity than patients without RA-ILD, and were more often ACPA positive and/or (former) smokers.

Management of rheumatic conditions associated with interstitial lung disease (r-ILD) requires expertise, often occurring in tertiary referral centers. We set up a combined rheumatology and respiratory service in a district general hospital (DGH) to avoid long patient journeys and improve experience. We evaluated the outcomes of 104 patients managed in this pilot service model. Referrals were triaged in monthly ILD multidisciplinary team meetings, and appropriate patients were booked into the clinic. All data were recorded electronically with full access to demographics, disease parameters, investigations, and drug management. Of the patients who attended follow-up, 51 (51%) had stable or improved symptoms, 58 (67%) had stable or improved computed tomography imaging, 50 (78%) had stable or improved forced vital capacity, and 40 (77%) had stable or improved diffusing capacity of the lungs for carbon monoxide. There were similar improvements in 6-minute walk tests. A total of 27 patients died, with 33% of these deemed as a direct result of their ILD. Our report confirms that r-ILD can be successfully managed in a DGH setting, with a large cohort obtaining good comparable clinical outcomes. We show that r-ILD services can be established locally to help overstretched tertiary care while developing local expertise in the management of r-ILD.

Psoriatic arthritis (PsA) is anatomically much more heterogeneous than rheumatoid arthritis, as, beyond synovitis, it often also involves enthesitis, peritendinitis, tenosynovitis, osteitis and periostitis. This heterogeneity currently precludes a gold standard for objectively defining resolution of inflammation following treatment, with enthesitis posing a particular challenge. Despite these difficulties, we apply lessons learned from rheumatoid arthritis to describe how patients with PsA and an inadequate response to therapy can be designated within two patient subgroups, characterized by persistent inflammatory PsA (PIPsA) and non-inflammatory PsA (NIPsA), respectively. The NIPsA phenotype is defined by the lack of ongoing joint inflammation, as confirmed through clinical assessment and imaging, along with normalized inflammatory marker levels. NIPsA might be associated with obesity, biomechanical-related pain, osteoarthritis, fibromyalgia, secondary post-inflammatory damage and central pain mechanisms. In this article, we frame PsA composite outcomes measures in relationship to the PIPsA and NIPsA phenotypes and propose that this approach might help to minimize unnecessary or ineffective cycling of PsA therapy in patients who acquire dominant non-inflammatory mechanisms and might also inform future trial design.

To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression.

In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders.

We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (∆KL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels.

In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

Connective tissue disease (CTD), comprising a range of autoimmune disorders, is often accompanied by lung involvement, which can lead to life-threatening complications. The primary types of CTDs that manifest as interstitial lung disease (ILD) include rheumatoid arthritis, systemic sclerosis, Sjögren's syndrome, mixed CTD, idiopathic inflammatory myopathies, and systemic lupus erythematosus. CTD-ILD presents a significant challenge in clinical diagnosis and management due to its heterogeneous nature and variable prognosis. Early diagnosis through clinical, serological, and radiographic assessments is crucial for distinguishing CTD-ILD from idiopathic forms and for implementing appropriate therapeutic strategies. Hence, we have reviewed the multiple clinical manifestations and diagnostic approaches for each type of CTD-ILD, acknowledging the diversity and complexity of the disease. The importance of a multidisciplinary approach in optimizing the management of CTD-ILD is emphasized by recent therapeutic advancements, which include immunosuppressive agents, antifibrotic therapies, and newer biological agents targeting specific pathways involved in the pathogenesis. Therapeutic strategies should be customized according to the type of CTD, the extent of lung involvement, and the presence of extrapulmonary manifestations. Additionally, we aimed to provide clinical guidance, including therapeutic recommendations, for the effective management of CTD-ILD, based on patient, intervention, comparison, outcome (PICO) analysis.

Patients with rheumatoid arthritis (RA) are at an increased risk of osteoporosis and vertebral fractures. We investigated the risk factors for vertebral fractures and severe vertebral fractures in patients with RA, including comorbidities and urinary pentosidine levels.

This study included 637 patients with available clinical data on urinary pentosidine levels, vertebral fractures, and comorbidities. Vertebral fractures were evaluated using plain X-ray imaging. Comorbidities considered relevant to osteoporosis were type 2 diabetes mellitus, chronic kidney disease, and lung diseases.

The prevalence of vertebral fractures in this cohort was 30.1%. Patients with vertebral fracture Patients with vertebral fractures were significantly more likely to be older [odds ratio (OR) 1.075; 95% confidence interval (CI) 1.049-1.1.03], had higher prevalence of comorbidities (OR 1.770; 95% CI 1.138-2.753), higher urinary pentosidine levels (OR 1.028; 95% CI 1.013-1.044), higher history of non-vertebral fractures (OR 2.084; 95% CI 1.222-3.557), and lower total hip T-score (OR 0.526; 95% CI 0.329-0.841) than patients without vertebral fractures. Among patients with vertebral fractures, 54.2% had severe vertebral fractures. Patients with severe vertebral fractures were more likely to have lower lumbar spine T-scores (OR 0.768; 95% CI 0.622-0.949) than patients with non-severe vertebral fractures.

This study identified factors associated with vertebral fractures and severe vertebral fractures in patients with RA. Notably, vertebral fractures were associated with comorbidities and urinary pentosidine levels. In patients with RA and vertebral fractures, low BMD in the lumbar spine was a significant factor associated with severe vertebral fractures.

Uncertainty exists regarding patient outcomes when using TNF inhibitors versus other biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis-associated interstitial lung disease (ILD). We compared survival and respiratory hospitalisation outcomes following initiation of TNF-inhibitor or non-TNF inhibitor biological or targeted synthetic DMARDs for treatment of rheumatoid arthritis-associated ILD.

We did a retrospective, active-comparator, new-user, observational cohort study with propensity score matching following the target trial emulation framework using US Department of Veterans Affairs (VA) electronic and administrative health records. VA health-care enrollees with rheumatoid arthritis-associated ILD and no previous receipt of ILD-directed therapies (eg, antifibrotics) who initiated a TNF inhibitor or non-TNF inhibitor between Jan 1, 2006, and Dec 31, 2018, were included. Propensity score matching was performed using demographics, health-care use, health behaviours, comorbidity burden, rheumatoid arthritis-related severity factors, and ILD-related severity factors, including baseline forced vital capacity. Study outcomes were respiratory hospitalisation, all-cause mortality, and respiratory-related death over follow-up of up to 3 years, from VA, Medicare, and National Death Index data. People with lived experience of rheumatoid arthritis-associated ILD were not involved in the design or conduct of this study.

Of 1047 patients with rheumatoid arthritis-associated-ILD who initiated biological or targeted synthetic DMARDs, we matched 237 patients who had initiated TNF inhibitors and 237 who had initiated non-TNF inhibitors (mean age 68 years [SD 9]); 434 (92%) of 474 were male and 40 (8%) were female. Death and respiratory hospitalisation did not significantly differ between groups (adjusted hazard ratio 1·21 [95% CI 0·92-1·58]). Respiratory hospitalisation (1·27 [0·91-1·76]), all-cause mortality (1·15 [0·83-1·60]), and respiratory mortality (1·38 [0·79-2·42]) did not differ between groups. Secondary, sensitivity, and subgroup analyses supported the primary findings.

In US veterans with rheumatoid arthritis-associated ILD, no difference in outcomes were seen between those who started TNF inhibitors compared to those starting non-TNF biological or targeted synthetic DMARDs. These data do not support systematic avoidance of TNF inhibitors in all people with rheumatoid arthritis-associated ILD. Comparative efficacy trials in patients with rheumatoid arthritis-associated ILD are needed given the potential for residual confounding and selection bias in observational studies.

US Department of Veterans Affairs.

Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) is linked to high mortality. Currently, effective screening tools are lacking. We assessed the role of symptoms and lung ultrasound (LUS) as potential screening tools.

116 adult patients with RA presenting to the rheumatology outpatient clinic underwent high-resolution CT (HRCT) scans, pulmonary function tests, LUS (72 zones) and completed a Visual Analogue Scale (VAS) for cough and modified Medical Research Council dyspnoea scale (mMRC). Kruskal-Wallis (KW) tests evaluated the correlation between clinical-radiological HRCT score (no ILD, non-specific abnormalities, subclinical ILD or ILD) and the B-lines on LUS, diffusion capacity (DLCO%pred), forced vital capacity (FVC%pred), VAS Cough and mMRC. Sensitivity and specificity analyses were performed to assess symptom-based questionnaires and the number of B-lines to detect RA-ILD. Area under the receiver operating characteristics (AUROC) for detecting clinical ILD and subclinical ILD were calculated.

In 11.8% of patients, an ILD was detected on HRCT. Additionally, in 5%, a diagnosis of subclinical interstitial lung changes was made. The number of B-lines was most strongly associated with the clinical-radiological score (KW χ²=41.2, p=<0.001). DLCO%pred was also significantly correlated with the clinical-radiological score (KW χ²=27.4, p=<0.001), but FVC%pred, mMRC and VAS cough were not. Cough and dyspnoea only weakly predicted the ILD score in the sensitivity-specificity analyses, while B-lines showed AUROCs>0.9 for predicting subclinical and clinical ILD.

LUS is a promising tool for early detection of RA-ILD, outperforming symptom-based questionnaires or the presence of dyspnoea or cough.

Interstitial lung disease (ILD) leads to worse outcomes in subjects with rheumatoid arthritis (RA). Few large-scale longitudinal studies have provided comprehensive data on the incidence and risk of ILD in RA compared with non-RA populations. We compare the risk of incident ILD in subjects with RA and matched controls, while also evaluating the impact of RA serologic status. Using the Korean National Health Insurance Service Data between 2010 and 2017, we identified 52,325 individuals with RA and 261,625 without RA. During a median follow-up period of 4.4 years, 3.7% of the RA cohort and 0.5% of the matched cohort developed ILD, with incidence rates of 8.30 and 1.01 per 1,000 person-years. Compared to controls, the risk of incident ILD was significantly higher in the RA cohort (adjusted hazard ratio [aHR] 7.84 [7.29-8.44]), and seropositive and seronegative RA exhibited aHRs of 9.00 (8.34-9.72) and 4.81 (4.25-5.44). Although the risk of ILD was higher in seropositive RA than seronegative RA, the risk of developing ILD was also higher in subjects with seronegative RA than in matched controls, suggesting that close monitoring for ILD should be performed in this population.

Controlling disease activity and improving physical function would be more difficult in patients with late-onset rheumatoid arthritis (LORA) who have chronic lung disease (CLD) at baseline. Our aim was to evaluate 5-year outcomes of following a treat-to-target (T2T) strategy targeting low disease activity (LDA) in LORA with CLD.

Data from 197 methotrexate (MTX)-naïve LORA patients (mean age 74.4 years) from a prospective, monocentric registry were analyzed. Patients were treated with MTX if they had one or more poor prognostic features. If they had interstitial lung disease (ILD), tacrolimus could be administered instead of MTX at the discretion of the attending physician. If patients exhibited no response according to the European League Against Rheumatism criteria at week 12 or had not achieved LDA by week 24, biological disease-modifying antirheumatic drugs (bDMARDs) were started targeting LDA. The primary outcomes were the 5-year simplified disease activity index (SDAI) remission and Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 by non-responder imputation analysis. Secondary outcomes were serious adverse events (SAEs).

Of the 197 LORA patients, 47 had CLD at baseline. The proportion of patients using MTX at baseline was significantly lower in those with than without CLD. Tacrolimus was initiated in 25.5% of the CLD group. The proportion of patients on bDMARDs was higher in those with CLD at year 5. Achievement of SDAI remission at year 5 was 29.8% in patients with CLD and 44.0% in those without CLD (p = 0.555). Achievement of HAQ-DI ≤ 0.5 at year 5 was 36.2% and 45.3% in patients with and without CLD, respectively (p = 0.939). Non-adherence to T2T due to comorbidities or adverse events was observed in 34.0% and 18.7% of the patients with and without CLD, respectively (p = 0.027). Infections requiring hospitalization, deterioration of extra-articular manifestations and fractures were more frequently reported as SAEs in patients with CLD, and multivariable analysis showed that patients with CLD had a higher risk of developing these SAEs (adjusted hazard ratio:2.53, 95% CI 1.60-4.00, p < 0.001).

For LORA patients with CLD, the T2T strategy is effective, but comorbidities and SAEs make the implementation of the T2T more difficult.

The purpose of this review is to outline considerations for treating older adults with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) as it relates to infection, comorbidities, cancer, and quality of life.

The recent 2023 American College of Rheumatology/American College of Chest Physicians guideline conditionally recommended specific disease-modifying antirheumatic drugs (DMARDs), antifibrotics, and short-term glucocorticoids to treat RA-ILD. Since RA-ILD often affects older adults, we contextualize these pharmacologic options related to infection, gastrointestinal (GI) effects, cancer, cardiovascular disease, and quality of life. Nearly all DMARDs and glucocorticoids are immunosuppressive and increase infection risk. Rituximab, mycophenolate, cyclophosphamide, and glucocorticoids may have particularly high infection risk. Many therapies recommended for treating RA-ILD have potential GI side effects. Antifibrotics have a high rate of nausea and diarrhea. Janus kinase inhibitors may increase risk of cancer and cardiovascular disease in older people. In older individuals, decisions must weigh the risks and benefits of drug options while considering clinical and social factors such as polypharmacy, adherence, cost, convenience, and social support. Management of RA-ILD in older individuals is complex and should consider risks and benefits, while optimizing quality and quantity of life through a shared decision-making process.

Overdiagnosis occurs when patients are diagnosed with a disease that would otherwise never have affected the quality or duration of their lives. This often happens unintentionally through well-meaning screening programmes that aim to detect diseases during so-called subclinical stages. Recently, it has been suggested that patients with polymyalgia rheumatica should be screened for giant cell arteritis to identify those at higher risk of relapse or vascular complications. Screening for interstitial lung disease for patients with rheumatoid arthritis has also been recommended to identify patients who could benefit from pulmonary interventions. These potential benefits must be weighed against foreseeable harms. Such harms include the uncovering of incidental findings that necessitate additional medical follow-up, the financial costs associated with screening initiatives, the risk of overtreatment through increased immunosuppression in patients who might not have otherwise required it, and the psychosocial burden of a new diagnosis. Randomised clinical trials and prospective cohort studies of screening interventions should be conducted to establish the risks and benefits and identify patients most likely to benefit from them. This Viewpoint covers risks that overdiagnosis presents to the field of rheumatology, with focus on rheumatoid arthritis and polymyalgia rheumatica.

This study is aimed at identifying key risk factors associated with the onset of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and developing and validating a novel risk prediction model for RA-ILD.

This is a hospital-based retrospective cohort study. A total of 459 RA patients were selected from Longhua Hospital Affiliated with Shanghai University of Traditional Chinese Medicine between 2015 and 2020 as observation subjects. Demographic and clinical data were collected through the hospital's medical record system. The analysis involved evaluating demographic factors, joint clinical characteristics, traditional Chinese medicine (TCM) syndrome classification, laboratory indicators, medication history, and their associations with RA-ILD. Subsequently, a machine learning model was applied to create and validate a novel risk prediction model for the onset of RA-ILD.

The overall frequency of RA-ILD was 42.70%. Advanced age, smoking, elevated rheumatoid DAS28 score, higher radiographic joint staging (Phases II and III), strong positive CCP status (above 200), and methotrexate therapy were identified as independent risk factors for RA-ILD. Conversely, hormone therapy was found to be a protective factor against RA-ILD development. The RA-ILD prediction model, formulated based on these risk factors, exhibited superior predictive performance compared to existing models, with an AUC of 0.8914 (95% CI 0.8593-0.9234), a sensitivity of 74.5%, and a specificity of 89.7%.

The study results highlighted the risk factors for the onset of RA-ILD and underscored the utility of the established RA-ILD nomogram model for early identification of RA-ILD patients and predicting the future risk of RA-ILD in individuals with rheumatoid arthritis.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) includes multiple subtypes with varying histopathology, prognosis, and potential treatments. Limited research has investigated risk factors for different RA-ILD subtypes. Therefore, we examined demographic, serologic, and lifestyle associations with RA-ILD subtypes.

We systematically identified RA-ILD cases and RA controls without ILD (RA-noILD) in the Brigham RA Sequential Study and Mass General Brigham Biobank RA cohort. We determined RA-ILD subtype (usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], and other/indeterminate) through chest high-resolution computed tomography imaging pattern. We investigated associations of demographic, lifestyle, and serologic factors with major RA-ILD subtypes using multivariable logistic regression.

Among 3,328 patients with RA, we identified 208 RA-ILD cases and 547 RA-noILD controls. RA-UIP was associated with older age (odds ratio [OR] 1.03 per year, 95% confidence interval [95% CI] 1.01-1.05), male sex (OR 2.15, 95% CI 1.33-3.48), and seropositivity (OR 2.08, 95% CI 1.24-3.48), whereas RA-NSIP was significantly associated only with seropositive status (OR 3.21, 95% CI 1.36-7.56). Nonfibrotic ILDs were significantly associated with smoking (OR 2.81, 95% CI 1.52-5.21). Having three RA-ILD risk factors (male, seropositive, smoking) had an OR of 6.89 (95% CI 2.41-19.7) for RA-UIP compared with having no RA-ILD risk factors.

Older age, seropositivity, and male sex were strongly associated with RA-UIP, whereas RA-related autoantibodies were associated with RA-NSIP. These findings suggest RA-ILD sex differences may be driven by RA-UIP and emphasize the importance of further studies to clarify RA-ILD heterogeneity and optimize screening and treatment approaches.

Interstitial lung disease (ILD) is a potential severe complication of various rheumatic diseases, typically connective tissue diseases (CTD), associated with significant morbidity and mortality. ILD may occur during the course of the disease but may also be its first manifestation. Several cell types are involved in ILD's pathogenesis, and if not controlled, pulmonary inflammation may lead to pulmonary fibrosis.

We searched PubMed, Medline, and the Cochrane Library for papers published between 1995 and February 2017 in the first version, and between 2017 and April 2023 using combinations of words. The most frequent systemic rheumatic diseases associated with ILD are systemic sclerosis (SSc), rheumatoid arthritis (RA), and idiopathic inflammatory myositis. Treatment and monitoring guidelines are still lacking, and current treatment strategies have been extrapolated from the literature on SSc and established treatments for non-pulmonary systemic rheumatic manifestations.

Given the complexity of diagnosis and the paucity of treatment trials, managing CTD patients with ILD is challenging. It requires the skills of multidisciplinary CTD-ILD clinics including at least rheumatologists and lung specialists.

Interstitial lung disease (ILD) is an extra-articular manifestation of rheumatoid arthritis (RA) that causes substantial morbidity and mortality. Effective, evidence-based strategies to screen for, and manage, RA-ILD are lacking.

Highlight recent research advances in, and further opportunities to improve, the identification and management of RA-ILD.

The goals of RA-ILD screening are early disease detection while avoiding unnecessary testing. Such an approach requires the ability to accurate risk stratify RA patients. With only a few recognized clinical risk factors for RA-ILD, a growing body of evidence on peripheral biomarkers for RA-ILD appears well suited to support a precision medicine approach. There is a paucity of evidence to guide management after RA-ILD diagnosis. While initial trials of antifibrotics have been conducted in RA-ILD and show the potential to slow the rate of pulmonary function decline, there have been no randomized trials of immunomodulatory therapies in RA-ILD. Supporting such trials, and addressing the barriers to conducting them, is a high priority.

Robust characterization of peripheral biomarkers in large, RA populations is essential to inform a precision medicine approach to RA-ILD identification. Randomized trials of treatments and treatment strategies that consider the systemic nature of RA-ILD are necessary to inform evidence-based RA-ILD treatment.

Interstitial lung disease (ILD) is rare, but it is one of the most frequent extra-articular manifestations and a relevant cause of morbidity and mortality in rheumatoid arthritis (RA). Over the past few years, Janus kinase inhibitors (JAKis) have been reported to have promising efficacy in the treatment of active RA, but recent concerns have been raised about their safety profile, namely malignancy and cardiovascular disease, limiting their use to certain patient categories.

The objective of this narrative review is to summarize the current evidence of the efficacy and safety of JAKis in RA-ILD management, investigating a possible emerging role for this drug class in such subset of patients.

Current studies focusing on JAKis in RA-ILD are scarce, but they globally report an overall stabilization of respiratory symptoms, functional data, and radiographic extension of ILD. In some cohorts, JAKis determined even an encouraging improvement in lung disease, and few reports presented good tolerability of JAKis in combination with antifibrotics. Concerning the safety profile, no significant increased risk of pulmonary infection has been reported.

Thus far, evidence regarding the role of JAKis in the treatment of RA-ILD remains relatively limited, and additional prospective studies are needed to better understand the place of JAKis, if any, in preventing/stabilizing ILD in RA patients.

Risk factors and screening strategies for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have received limited evaluation in patients with early RA. We investigated RA-ILD prevalence, risk factors, and the performance of proposed RA-ILD screening methodologies in a multicenter, prospective study of patients with early RA.

Participants with early RA, defined as being within two years of RA diagnosis, were enrolled at five US sites and assessed with high-resolution computed tomography (HRCT) chest imaging, pulmonary function tests, and autoantibodies. RA-ILD presence was determined through independent HRCT review by thoracic radiologists. We investigated RA-ILD risk factors using multivariable logistic regression and reported the predictive performance of RA-ILD screening strategies (ANCHOR-RA, 2023 ACR/CHEST, Four Factor Score, and ESPOIR).

Among 172 participants (74% female, 82% seropositive, median RA duration 0.79 years, mean age 55.3 years), 19 (11%) had ILD on HRCT. Moderate/high RA disease activity by DAS28ESR (OR 7.00 [1.95, 25.1]) and age ≥60 years (OR 3.87 [1.33, 11.3]) were associated with RA-ILD. Sensitivity and specificity of screening strategies ranged from 0.32-0.95 and 0.32-0.81, respectively. The number of early RA patients needing screening to detect one ILD case ranged from 3.6 to 6.4.

In this prospective, multicenter study, ILD prevalence in early RA was 11%. Disease activity and older age were strongly associated with ILD in early RA, and several proposed ILD screening strategies performed showed promise for enabling ILD screening in early RA.

The clinical manifestations and course of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) exhibits considerable heterogeneity. In this study, we aimed to explore radiographic progression over a defined period, employing the Warrick score as a semi-quantitative measure in early RA-ILD, and to assess the associated risk factors for progression.

RA-ILD patients underwent consecutive Warrick scoring based on initial high-resolution computed tomography (HRCT) at diagnosis and the first follow-up. Associations between Warrick scores, pulmonary function tests, and patient characteristics were analyzed. The ROC curve assessed the predictive performance of the Warrick score change rate for ILD progression, while multivariable logistic regression analysis identified risk factors for progression.

Significant correlations were found between Warrick scores and age at RA-ILD diagnosis, age at ILD diagnosis, and baseline DAS28-ESR. For the severity score, correlations were r = 0.359, r = 0.372, and r = 0.298 (p = 0.001, p < 0.001, p = 0.014, respectively); for the extent score, r = 0.364, r = 0.318, and r = 0.255 (p = 0.001, p = 0.005, p = 0.038, respectively); and for the total score, r = 0.376, r = 0.367, and r = 0.280 (p < 0.001, p = 0.001, p = 0.022, respectively). Annual changes in severity, extent, and total Warrick scores showed sensitivities of 91-97% and specificities of 98% for predicting progression over a 5-year follow-up. Cut-off values were 0.0278 for the severity score (AUC 0.954), 0.0227 for extent score (AUC 0.976), and 0.0694 for total score (AUC 0.946). Warrick severity, extent, and total scores increased significantly during follow-up. Age > 50 years (OR 7.7; p = 0.028) and baseline usual interstitial pneumonia (UIP) pattern (OR 3.1, p = 0.041) were identified as risk factors for progression.

Advanced age and UIP pattern were significant risk factors for progression. Warrick scoring may may help predict progression in RA-ILD, particularly through changes in severity, extent, and total scores. Due to the retrospective design and small sample size, further prospective studies with larger cohorts are needed to confirm these findings and validate Warrick scoring as a reliable marker for RA-ILD progression.

High-throughput technologies in human and animal studies have revealed novel molecular and cellular pathways involved in tissue inflammation of rheumatoid arthritis (RA). Fibroblasts have been in the forefront of research for several decades. Subpopulations with specific phenotypic and functional properties have been characterized both in mouse models and human disease. Data supporting the active involvement of fibroblasts in immune responses and tissue remodeling processes, as well as their central role in promoting clinical relapses and contributing to treatment resistance, have clearly reshaped their role in disease evolution. The lung is an important non-synovial component of RA both from a clinical and an immunopathogenic aspect. Interstitial lung disease (ILD) is a significant contributor to disease burden affecting morbidity and mortality. Although our knowledge of ILD has progressed, significant gaps in both basic and clinical science remain, posing hurdles to efficient diagnosis, prediction of disease course and its effective treatment. The specific role and contribution of fibroblasts to this process has not been clearly defined. The focus of this review is on fibroblasts and their contribution to RA and RA-ILD, presenting data on genetics and immune responses associated with RA-ILD in humans and animal models.

This study aims to review the literature and estimate the global pooled prevalence of interstitial lung disease among patients with rheumatoid arthritis (RA-ILD). The influence of risk factors like geography, socioeconomic status, smoking and DMARD use will be explored. A systematic review was performed according to the PRISMA and JBI guidelines. Studies published between January 1980 and February 2024 were sourced from 7 electronic databases and screened for eligibility. A random-effects meta-analysis model was used to produce pooled prevalences and the potential between-study heterogeneity was identified using sensitivity, subgroup, meta-regression and correlation analyses. 33 studies were included in this meta-analysis containing 14,281 RA patients. The global pooled prevalence of RA-ILD was 21.38% (CI: 0.1542-0.2886), with a high heterogeneity (I2) of 98%. The prevalence of usual interstitial pneumonia and non-specific interstitial pneumonia among RA patients were 11.01% and 6.86% respectively. Africa had the highest RA-ILD prevalence with an imprecise estimate of 38.15% (95% Confidence Interval [CI]: 2.29-94.2) and Europe had the lowest prevalence of 10.15% (CI: 2.86-30.23). Other risk factors associated with a higher prevalence of RA-ILD included living in low-income countries, smoking and DMARD use. The biggest limitation of this study is the high heterogeneity of results and underrepresentation of Oceania and low-income countries. This study has clarified the global prevalence of RA-ILD. The risk factors identified in this study can aid clinicians in identifying high-risk populations and highlight the need for screening these populations. Smoking cessation should also be encouraged.

The objective of this study was to assess fibrinogen (FIB) comodified with citrulline (CIT) and/or malondialdehyde-acetaldehyde (MAA) initiates macrophage-fibroblast interactions, leading to extracellular matrix (ECM) deposition that characterizes rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Macrophages (Mϕ) were stimulated with native-FIB, FIB-CIT, FIB-MAA, or FIB-MAA-CIT. Supernatants (SNs) [Mϕ-SN (U-937-derived) or MϕP-SN (PBMC-derived)] or direct antigens were coincubated with human lung fibroblasts (HLFs). Gene expression was examined using RT-PCR. ECM deposition was quantified using immunohistochemistry and Western blot; cell signaling mechanisms were delineated. Platelet-derived growth factor (PDGF)-BB and TGF-β were measured in macrophage supernatants, and inhibition studies were performed using Su16f and SB431542, respectively. HLF gene expression of CD36, COL6A3, MMP-9, MMP-10, and MMP-12 was increased following stimulations with Mϕ-SN generated from modified FIB but not from direct antigens. HLF stimulated with MϕP-SNFIB-MAA-CIT derived from patients with RA-ILD resulted in 4- to 30-fold increases in COL6A3 and MMP12 expression; upregulation was greater in HLFs stimulated with MϕP-SN derived from RA-ILD versus controls. HLF exposure to Mϕ-SNFIB-MAA-CIT increased types I/VI collagen deposition versus all other Mϕ-SN groups and was greater than FIB-MAA-CIT stimulation. PDGF-BB and TGF-β signaling had the highest concentrations identified in Mϕ-SNFIB-MAA-CIT and MϕP-SNFIB-MAA-CIT, particularly from RA-ILD-derived cells. PDGF-BB and TGF-β inhibitors, alone and in combination, significantly reduced HLF-mediated ECM deposition from Mϕ-SN stimulations. These results show that comodified fibrinogen activates macrophages to produce PDGF-BB and TGF-β that promotes an aggressive HLF phenotype characterized by increased ECM deposition. These results suggest that targeting CIT and/or MAA modifications or downstream cellular signals could represent novel approaches to RA-ILD treatment.NEW & NOTEWORTHY This report demonstrates that fibrinogen simultaneously harboring two common posttranslational modifications activates macrophages to secrete platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β. Resulting cross talk between activated macrophages and human lung fibroblasts leads to marked increases in extracellular matrix deposition. These protein modifications are abundant and colocalize in lung tissues from patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), and the results suggest that agents targeting citrullination and/or malondialdehyde-acetaldehyde (MAA) adduct formation could represent novel therapeutic strategies.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is an increasingly recognized extra-articular manifestations (EAMs) in the RA, with highly morbidity and mortality. The identification of key molecules involved in RA-ILD has a high requirement in clinic, and the role of their transcriptional regulation in the etiology of RA-ILD is great significant for investigation. In this study, we collected the whole peripheral blood samples of RA-ILD and RA only patients to bulk RNA-sequence. Differential gene expression analysis was employed to identify key genes, common pathways, and potential drug targets for RA-ILD. Furthermore, RT-qPCR was conducted to verify potential biomarkers in RA-ILD. Four hundred seventy-eight differentially expressed genes (DEGs) were identified that related to chromatin-modifying enzymes. A robust correlation with immune and inflammation biological processes and pathways was indicated through enrichment analyses of these shared DEGs, like B cell receptor signaling pathway, complement activation, NF-kappa B signaling pathway. Protein-protein interaction network analysis further emphasized the significance of 12 hub genes, including CHD4, MUS81, CXCL8, NSUN6, RAD9A, CCL4, B3GAT1, KAT2A, TBX21, HDAC2, ERBB2, and ITGAL. Notably, NSUN6 expression was statistically significant in RA-ILD by the machine learning LASSO regression analysis and RT-qPCR. Our study provides novel insights into the molecular mechanisms of RA-ILD, identifies potential biomarkers, and lays the groundwork for future therapeutic strategies.

There have been limited investigations of the prevalence and mortality impact of quantitative CT (QCT) parenchymal lung features in RA. We examined the cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants.

We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbour quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1-3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features.

We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (β = 1.7 [0.5], P = 0.0008) but not emphysema (β = 1.3 [1.7], P = 0.44). Participants with RA and >75th percentile of emphysema had significantly higher mortality than non-RA participants (hazard ratio [HR] 5.86; 95% CI: 3.75, 9.13) as well as RA participants (HR 5.56; 95% CI: 2.71, 11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative P = 0.014; attributable proportion 0.53; 95% CI: 0.30, 0.70).

Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred >5-fold higher mortality.

To longitudinally assesses pulmonary involvement in newly diagnosed rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients over a 12-months follow-up. To identify biomarkers and establish a diagnostic algorithm for monitoring pulmonary changes.

Newly diagnosed RA and PsA patients were examined with clinical and laboratory assessments, pulmonary function tests (PFT), and chest radiography (CXR) at three-months intervals for one year.

The study enrolled 50 patients (26 RA, 24 PsA) and 26 controls. At baseline, 37.0% of arthritis patients (50.0% RA, 22.7% PsA) exhibited radiographic pulmonary involvement, with 64.7% being asymptomatic. No association was observed between CXR and PFTs. Reduced pathological breathing width was noted in 64.0% of patients (RA 69.2%, PsA 58.3%) and 23.1% of controls (p < .001). Thoracic excursion and lung auscultation showed no differences. During follow-up, PFT and physical examination findings remained stable. Mean CRP levels significantly decreased in RA patients from 23.5 mg/l (± 33.6; 95% CI: 9.9-37.1) to 2.7 mg/L (± 3.4; 95% CI: 1.0-4.3), and in PsA patients from 13.3 mg/L (± 18.0; 95% CI: 5.7-20.9) to 8.1 mg/L (± 16.2; 95% CI: 0.1-16.2) (p < .001). Additionally, significant reductions in disease activity scores and improvements in six-minute walking distance were observed (p < .001). No associations were identified between PFT outcomes, disease activity, or rheumatological medications throughout the disease course.

Our study underscores the prevalence of significant, predominantly asymptomatic pulmonary involvement in newly diagnosed RA and PsA patients. The lack of correlation between pulmonary function, disease activity, and medication during disease progression suggests that reducing arthritic disease activity does not necessarily mitigate the risk or severity of pulmonary involvement. Finally, our finding underscore the need for more sensitive biomarkers and optimized monitoring strategies.