Animal models for connective tissue disease-associated interstitial lung disease: Current status and future directions.

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

Introduction Interstitial lung disease (ILD) associated with connective tissue disease (CTD) carries significant morbidity and mortality. In mixed connective tissue disease (MCTD), ILD is reported in 40–78% of cases. For patients with progressive ILD despite conventional DMARD therapy, rituximab has demonstrated non-inferiority to cyclophosphamide. However, its use in CTD-ILD is not currently supported by routine clinical commissioning. We present a case of a 26-year-old patient with RNP-positive CTD-ILD who experienced disease progression despite treatment with mycophenolate, highlighting the current gap in therapeutic options for patients with MCTD. Case description We present the case of a 26-year-old woman referred to Rheumatology in 2021 with severe Raynaud’s phenomenon. Investigations revealed strongly positive ANA and anti-RNP antibodies, abnormal nailfold capillaries, puffy fingers, mild skin thickening, rash, arthralgia, elevated CK (509 U/L), proximal muscle weakness, and myoedema on MRI thighs. A diagnosis of mixed connective tissue disease (MCTD) was made, with overlapping systemic sclerosis and myositis features. Baseline high-resolution CT (HRCT) showed early interstitial lung disease (ILD), with pulmonary function tests (PFTs) showing FEV1 88%, FVC 94%, and DLCO 100% predicted. Multidisciplinary review confirmed a mixed cellular and fibrotic non-specific interstitial pneumonia (NSIP) pattern involving approximately 10% of lung parenchyma. Echocardiogram was normal. Methotrexate and hydroxychloroquine were initiated. In May 2023, she developed breathlessness, worsening Raynaud’s, and muscle weakness. DLCO declined to 80%. Methotrexate was switched to mycophenolate mofetil, and a weaning course of prednisolone. She also developed chest pain and palpitations; cardiac MRI excluded myocarditis but revealed a small pericardial effusion. Symptoms improved with increased steroids. Despite treatment, by early 2024, breathlessness and muscle weakness worsened. MMT-8 score was 121/150, CK rose to 800 U/L, FVC declined to 72%, and DLCO dropped to 64%. Repeat HRCT showed progression of fibrotic changes. Echocardiography remained normal with no evidence of pulmonary hypertension. Following review in the joint specialty CTD-ILD clinic, treatment with rituximab was advocated, in preference to cyclophosphamide given her age and potential fertility concerns. Rituximab is not currently commissioned for CTD-ILD so discussion with the regional specialist commissioning panel led to rituximab approval as per the NHS England commissioning policy for myositis. She met criteria for active disease based on CK, MMT 8, HAQ score, MDAAT and ILD Post-infusion, the patient reported significant improvement in breathlessness, proximal muscle strength, arthralgia, and Raynaud’s. PFTs improved markedly (FVC 85%, DLCO 84%). Discussion Connective tissue disease-associated interstitial lung disease (CTD-ILD) presents a significant therapeutic challenge, particularly in younger patients of childbearing age where treatment options may be limited by concerns around fertility. In this context, the RECITAL trial provides valuable evidence supporting the use of rituximab, demonstrating non-inferiority to cyclophosphamide in patients with CTD-ILD, including those with MCTD. Rituximab therefore represents an important addition to the therapeutic armamentarium for CTD-ILD, offering a steroid-sparing option with a more favourable safety profile in selected populations. Despite this, rituximab is not currently commissioned for use in CTD-ILD outside of clinical trials or specialist pathways. In our case, access to rituximab was achieved through the commissioning policy for idiopathic inflammatory myopathies (IIM) with associated ILD, rather than through a CTD-ILD indication. This underscores the challenges clinicians face in navigating prescribing frameworks that do not fully reflect evolving evidence or the heterogeneity of CTD presentations. This case also highlights the value of multidisciplinary collaboration, particularly between Rheumatology, Respiratory, and specialist commissioning teams. The use of structured disease activity scoring tools, including the manual muscle testing score (MMT-8) also played a critical role in objectively demonstrating disease progression and securing access to treatment. Such tools are vital in standardising assessment and advocating for appropriate therapy. Furthermore, it reinforces the importance of regular ILD surveillance in patients with CTD, as early progression may occur even in the context of stable systemic disease. Finally, this case illustrates the role of specialist commissioning as a mechanism not only for accessing high-cost therapies, but also for identifying policy gaps that may disadvantage patients with overlapping or less clearly defined disease subsets such as MCTD. Key learning points 1. Rituximab is an effective alternative to cyclophosphamide in CTD-ILD The RECITAL trial supports rituximab as non-inferior to cyclophosphamide for CTD-ILD, making it a valuable option, particularly in young patients where fertility preservation is a concern. 2. Current prescribing and commissioning policies may not reflect emerging evidence Despite robust clinical data, rituximab is not routinely commissioned for CTD-ILD, requiring clinicians to navigate alternative pathways to access appropriate care. 3. Multidisciplinary collaboration is essential Effective management of complex CTD-ILD cases depends on coordinated input from Rheumatology, Respiratory, and Specialist Commissioning teams to ensure timely diagnosis, treatment, and access to advanced therapies. 4. Ongoing surveillance of ILD in CTD is vital ILD progression may occur even in the absence of worsening systemic symptoms, highlighting the need for regular pulmonary function testing and imaging in patients with CTD.

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A Clue to Diagnosing Connective Tissue Disease-Associated Interstitial Lung Disease

OBJECTIVE:Our study aimed to evaluate clinical, functional, and prognostic features and to determine the prognosis of idiopathic pulmonary fibrosis, connective tissue disease-associated interstitial lung diseases, and interstitial pneumonia with autoimmune features.MATERIAL AND METHODS:Sixty-nine cases with interstitial lung diseases were recruited in this study prospectively. Demographic features, symptoms, radiological findings, functional measurements, and immunological markers were recorded twice (at the time of initial admission and in the 12th month). Twenty-four of 69 cases were idiopathic pulmonary fibrosis, 32 were connective tissue disease-associated interstitial lung diseases, and 13 were interstitial pneumonia with autoimmune features . Results:Most of the patients with idiopathic pulmonary fibrosis were male, while there were more female patients in connective tissue disease-associated interstitial lung diseases and interstitial pneumonia with autoimmune features groups. Female patients (65.0%) predominated in connective tissue disease-associated interstitial lung diseases group (P < .001). There was no significant difference in the mean ages of the disease groups, yet connective tissue disease-associated interstitial lung diseases patients were generally younger (min–max: 34–82 years). In the idiopathic pulmonary fibrosis group, only low titers of antinuclear antibody positivity were found. Antinuclear antibody positivity in the connective tissue disease-associated interstitial lung diseases group and interstitial pneumonia with autoimmune features group was high (P = .001). The long-term survival of idiopathic pulmonary fibrosis, connective tissue disease-associated interstitial lung diseases, and interstitial pneumonia with autoimmune features patients were 37%, 40 months (median) (95% CI, 5.193-74.807), 48.6%, 80 months (median) (95% CI, 57.032-102.968), 30.8%, 46 months (median) (95% CI, 26.624-65.376), respectively.Conclusion:Although a consensus report describing interstitial lung diseases with autoimmune features has been published, diagnostic criteria for this group are still vague. Since the interstitial pneumonia with autoimmune features group had the worst results in terms of functional loss and survival rates, the follow-up parameters and follow-up algorithm should be established for this group. Clinical and immunological evaluation of the interstitial pneumonia with autoimmune features group should include detailed parameters because of follow-up and to estimate survival.

Connective tissue disease-associated interstitial lung disease is one of the most common subtypes of interstitial lung disease, which is a leading cause of morbidity and mortality in patients with these systemic autoimmune rheumatic diseases. A spectrum of disease trajectories exists within individual and across different connective tissue diseases. In individuals with connective tissue diseases who are at risk or at the early asymptomatic stage with interstitial lung changes, we have potential windows of opportunity for interventions to prevent the development of or progression to interstitial lung disease. In this perspective, we use systemic sclerosis and rheumatoid arthritis as sample cases to discuss emerging knowledge on disease pathogenesis, as well as to apply the preventative medicine concept for pharmacotherapeutic approaches at different disease stages of connective tissue disease-associated interstitial lung disease.

BackgroundInterstitial lung disease (ILD) includes a heterogeneous group of disorders that result in diffuse parenchymal lung disease, with overlapping clinical, radiographic, and physiologic manifestations. Several rheumatologic conditions are associated with...

To compare the characteristics of connective tissue disease-associated interstitial lung disease with idiopathic pulmonary fibrosis at a tertiary care hospital. The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised demographical, clinical and radiological data of patients with interstitial lung disease between October 2016 and October 2017 accessed through the outpatient data registry. Data was compared in terms of characteristics and key features of patients with connective tissue disease-associated interstitial lung disease with those of idiopathic pulmonary fibrosis. Statistical analysis was done using STATA 12. Of the 184 patients, 52(29.3%) had connective tissue disease-associated interstitial lung disease and 62(35%) had idiopathic pulmonary fibrosis. The most prevalent conditions among connective tissue disease-associated interstitial lung disease patients were rheumatoid arthritis 22(42.3%) and scleroderma 13(25%). Compared to patients with idiopathic pulmonary fibrosis, those with connective tissue disease-associated interstitial lung disease were predominantly younger (p<0.001) and female (p<0.001). History of gastroesophageal reflux disease was also significantly lower in connective tissue disease-associated interstitial lung disease (p=0.05). Connective tissue disease-associated interstitial lung disease patients were found to be younger and predominantly female compared to patients of idiopathic pulmonary fibrosis.

BackgroundLung imaging findings vary among subtypes of connective tissue disease-associated interstitial lung disease (CTD-ILD), leading to both diagnostic and therapeutic challenges.ObjectivesWe performed a comprehensive assessment of ILD morphology across CTD-ILD...

Recently, the role of long non-coding RNA (lncRNA) in rheumatic immune diseases has attracted widespread attention. However, knowledge of lncRNA in connective tissue disease-associated interstitial lung disease (CTD-ILD) is limited. This study explored the expression profile and possible mechanisms of lncRNA and mRNA in peripheral blood mononuclear cells (PBMCs) of CTD-ILD patients, especially systemic sclerosis (SSc)-ILD and rheumatoid arthritis (RA)-ILD. LncRNA microarray analysis identified 240 diferentially expressed lncRNAs and 218 diferentially expressed mRNA in the CTD-ILD group and the connective tissue disease without associated interstitial lung disease (CTD-NILD) group. The bioinformatics analysis of diferential genes has identified several important biological processes and signal pathways, including nuclear factor kappa B (NF-kappa B) signaling pathway, interleukin 17 (IL-17) signaling pathway, B cell receptor signaling pathway. Relative expression levels of five diferentially expressed lncRNAs and one mRNA in 120 SSc and RA patients with or without ILD were detected by quantitative reverse-transcription (PCR). The ENST00000604692 expression level was significantly higher in the ILD than the without interstitial lung disease (NILD) group; T311354 and arginase-1 were significantly higher in SSc than RA group. These data suggest that the specific profile of lncRNA in PBMCs of CTD-ILD patients and the potential signal pathways related to the pathogenesis of CTD-ILD, which may provide newfound insights for the diagnosis and treatment of CTD-ILD patients.

Interstitial lung disease (ILD) induces overwhelming morbidity and kills more patients with connective tissue disease (CTD) than any other CTD-related manifestation.1–5 Because of this, there is a keen and growing...

BackgroundRecently, the role of long noncoding RNA (lncRNA) in rheumatic immune diseases has attracted widespread attention1. However, knowledge of lncRNA in connective tissue disease-associated interstitial lung disease (CTD-ILD) is limited.ObjectivesTo...

Objective To compare the characteristics of connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis(IPF). Methods Patients with a diagnosis of ILD from June 2014 to December 2015 were selected in this study and patients with known other causes of ILD were excluded. The clinical manifestation, autoantibody, high resolution chest computed tomography (CT) and blood gas analysis were retrospectively analyzed. Results Six hundred and twenty-eight patients were included in this study. The prevalence of CTD-ILD and IPF were 459 (73.09%) and 169(26.91%) respectively. The age in IPF group was higher than that in CTD-ILD group: (67.10 ± 13.13) years vs. (52.10 ± 14.23) years, and there was significant difference (t = -10.092, P = 0.000). The rate of male in IPF group was higher than that in CTD-ILD group: 75.15% (127/169) vs. 28.32%(130/459), and there was significant difference (P = 0.000). Autoantibodies were commonly seen in CTD-ILD group and only antinuclear antibody, and anti-SSA antibody and anti-Ro-52 antibody were seen in IPF group. The most common chest images were honeycombing, bullae of lung and pneumonectasis in CTD-ILD group, while the presence of consolidation and small nodular shadow were more common in IPF group. The concurrence of respiratory failure was higher in IPF group compared with that in CTD-ILD group: 49.11%(83/169) vs. 13.07%(60/459), and there was significant difference (P <0.01). Conclusions Patients with CTD-ILD and IPF possess distinct characteristics. Overall assessment of clinical manifestation, autoantibody serology, high resolution chest CT and other indicator will be conducive to the differential diagnosis and treatment of ILD. Key words: Connective tissue disease; Idiopathic pulmonary fibrosis; Interstitial lung diseases

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is an important underlying cause of morbidity and mortality in patients with connective tissue disease (CTD). Serum Krebs von den Lungen-6 (KL-6) is an immune factor that has been related to the severity of interstitial lung disease (ILD). This systematic review and meta-analysis aimed to evaluate the association between serum KL-6 and mortality of patients with CTD-ILD. Longitudinal studies relevant to the aim of the meta-analysis were retrieved by search of electronic databases including PubMed, Web of Science, and Embase. A random-effects model was used to combine the data by incorporating the influence of between-study heterogeneity. Fifteen cohorts involving 1737 patients with CTD-ILD were included. During a mean follow-up of 35.3 months, 430 (24.8%) patients died. Compared to those with a lower KL-6 at admission, patients with a higher KL-6 were associated with a higher mortality risk during follow-up (risk ratio: 2.18, 95% confidence interval: 1.66–2.87, P < 0.001; I2 ═ 20%). Subgroup analysis showed a significant association in studies from Asian countries, but not in those from non-Asian countries; in studies with a cutoff of KL-6 derived in receiver operating characteristic (ROC) curve analysis, but not in those derived from other methods; in studies with multivariate analysis, but not in those with univariate analysis (P for subgroup difference all < 0.05). The association was not significantly affected by different CTDs or methods for measuring serum KL-6. In conclusion, a high serum KL-6 may be a risk factor for increased mortality in patients with CTD-ILD.

Safety and efficacy of rituximab in connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis