Long Term Effects of Cyclophosphamide Treatment on Lung Function and Survival in Scleroderma Patients with Interstitial Lung Disease

Background:Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a class of refractory diseases.Non-specific treatment with hormone and immunosuppressive agents is mostly used at present, but the effect is limited and the long-term survival rate is not improved [1],while anti-fibrosis treatments (such as Pirfenidone and Nintedanib) have only recently been approved, the long-term efficacy is still unknown.Tofacitinib(TOFA), a JAK inhibitor, has recently been used to treat patients with severe dermatomyositis related interstitial pulmonary disease, with significantly improved survival rate [2-4].A basic study showed that TOFA improved interstitial pulmonary disease in mice by promoting the proliferation of myelogenic inhibitory cells [5].However, whether TOFA can affect the migration and invasion of human lung fibroblasts and further research to reveal the mechanism of its inhibition of pulmonary fibrosis has not been reported.Objectives:To investigate the anti - fibrosis effect of TOFA in CTD-ILD.Methods:Cell migration and invasion AssaysHLFs were incubated with TOFA for 72h, followed by TGF- β1 for 24h.DMEM serum-free medium was used to determine the cell density to 5. 0 × 107/L, 600 uL medium containing 10% fetal bovine serum was added to the lower compartment of Transwell chamber, and 200 uL cell suspension was added to the upper compartment.Incubate in incubator for 12 h.After fixation, staining and sealing, the cells were observed and counted under a microscope. At least 5 random field transmembrane cells were counted in each hole, and the mean value was taken.For the invasion assays, Transwell chamber coated with matrigel was used, and the cell incubation time was 16 h.Results:1. Effect of TOFA on HLFs migration function (Figure 1)Figure 1.Effect of TOFA on HLFs migration function(×200).Mean ± SEM. n = 5.The number of cells passing through the biofilm in the three groups was counted.It can be seen that TGF-β1 group significantly increased compared with control group (*P < 0.0001), and TOFA group significantly decreased compared with TGF- β1 group (#P < 0.0001), suggesting that TOFA can significantly inhibit TGF-β1- induced HLFs migration.2. Effect of TOFA on HLFs invasion function (Figure 2)Figure 2.Effect of TOFA on HLFs invasion function(×200).Mean ± SEM. n = 5.The number of cells passing through the matrigel in the three groups was counted.It can be seen that TGF-β1 group was significantly higher than the control group (*P < 0.0001), and TOFA group was significantly lower than TGF-β1 group(#P < 0.001), suggesting that TOFA can significantly inhibit the invasion function of HLFs induced by TGF-β1.Conclusion:TOFA can effectively inhibit the function of HLFs migration and invasion. Although further studies are needed to elucidate the mechanism by which TOFA inhibit the function of HLFs migration and invasion, our study suggests that TOFA has a potential therapeutic effect for CTD-ILD.References:[1]Aparicio, I.J. and J.S. Lee, Connective Tissue Disease-Associated Interstitial Lung Diseases: Unresolved Issues. Semin Respir Crit Care Med, 2016. 37(3): p. 468-76.[2]Kato, M., et al., Successful Treatment for Refractory Interstitial Lung Disease and Pneumomediastinum With Multidisciplinary Therapy Including Tofacitinib in a Patient With Anti-MDA5 Antibody-Positive Dermatomyositis. J Clin Rheumatol, 2019.[3]Kurasawa, K., et al., Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis. Rheumatology (Oxford), 2018. 57(12): p. 2114-2119.[4]Chen, Z., X. Wang, and S. Ye, Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung Disease. N Engl J Med, 2019. 381(3): p. 291-293.[5]Sendo, S., et al., Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice. Arthritis Res Ther, 2019. 21(1): p. 184Disclosure of Interests:None declared

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Management of Myositis-Associated Interstitial Lung Disease

Medicina ◽

10.3390/medicina57040347 ◽

2021 ◽

Vol 57 (4) ◽

pp. 347

Author(s):

Tomoyuki Fujisawa

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Current Knowledge ◽

Strong Predictor ◽

Calcineurin Inhibitors ◽

Pulmonary Involvement ◽

Trna Synthetase ◽

Evidence Based Guidelines ◽

Substantial Heterogeneity

Idiopathic inflammatory myopathies, including polymyositis (PM), dermatomyositis (DM), and clinically amyopathic DM (CADM), are a diverse group of autoimmune diseases characterized by muscular involvement and extramuscular manifestations. Interstitial lung disease (ILD) has major pulmonary involvement and is associated with increased mortality in PM/DM/CADM. The management of PM-/DM-/CADM-associated ILD (PM/DM/CADM-ILD) requires careful evaluation of the disease severity and clinical subtype, including the ILD forms (acute/subacute or chronic), because of the substantial heterogeneity of their clinical courses. Recent studies have highlighted the importance of myositis-specific autoantibodies’ status, especially anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl tRNA synthetase (ARS) antibodies, in order to evaluate the clinical phenotypes and treatment of choice for PM/DM/CADM-ILD. Because the presence of the anti-MDA5 antibody is a strong predictor of a worse prognosis, combination treatment with glucocorticoids (GCs) and calcineurin inhibitors (CNIs; tacrolimus (TAC) or cyclosporin A (CsA)) is recommended for patients with anti-MDA5 antibody-positive DM/CADM-ILD. Rapidly progressive DM/CADM-ILD with the anti-MDA5 antibody is the most intractable condition, which requires immediate combined immunosuppressive therapy with GCs, CNIs, and intravenous cyclophosphamide. Additional salvage therapies (rituximab, tofacitinib, and plasma exchange) should be considered for patients with refractory ILD. Patients with anti-ARS antibody-positive ILD respond better to GC treatment, but with frequent recurrence; thus, GCs plus immunosuppressants (TAC, CsA, azathioprine, and mycophenolate mofetil) are often needed in order to achieve favorable long-term disease control. PM/DM/CADM-ILD management is still a therapeutic challenge for clinicians, as evidence-based guidelines do not exist to help with management decisions. A few prospective clinical trials have been recently reported regarding the treatment of PM/DM/CADM-ILD. Here, the current knowledge on the pharmacologic managements of PM/DM/CADM-ILD was mainly reviewed.

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POS0645 RITUXIMAB THERAPY IN THE INTERSTITIAL LUNG DISEASE OF RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4192 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 560.3-561

Author(s):

E. F. Vicente-Rabaneda ◽

J. De la Macorra ◽

J. P. Baldivieso ◽

F. Gutiérrez-Rodríguez ◽

A. García-Vadillo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Interstitial Lung Disease ◽

Lung Function ◽

Adverse Events ◽

Lung Disease ◽

Statistical Significance ◽

Connective Tissue Diseases ◽

Case Series ◽

Original Research ◽

Case Control Studies

Background:Interstitial lung disease (ILD) is a severe manifestation of rheumatoid arthritis (RA), linked to increased mortality. There is still no consensus on the best therapeutic strategy as there aren’t yet randomized controlled trials.Objectives:To analyze the available scientific evidence on the efficacy and safety of rituximab (RTX) treatment of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).Methods:A systematic search was carried out in PubMed until April 2020 following the PRISMA recommendations. Studies were selected according to the following inclusion criteria: (1) original research, including case series, case/control studies, cohort studies, and clinical trials; (2) population with RA and associated ILD, either monographically or together with other connective tissue diseases (CTD), provided that individualized data on patients with RA were provided; (3) patients treated with RTX; (4) objective and quantifiable results on the evolution of ILD after treatment with available data of FVC, DLCO and/or HRCT.Results:Of the 64 papers identified, 9 articles were selected. The studies showed great heterogeneity in design, both in the sample selection criteria and in the objectives of the analysis. Most were observational, retrospective (n = 6) or prospective (n = 2) studies, with only one open prospective experimental study. Those focused on RA predominated, but 3 of them also included patients with other CTDs. The mean age of the patients in the different studies ranged between 52 and 70 years, predominantly women. 40-79% had a history of smoking and were mostly positive for rheumatoid factor (83-100%) and anti-CCP (82-100%). The most frequent radiological patterns were NSIP, UIP and undefined. The outcome measures were diverse: changes in respiratory function tests (LTF) and HRCT, incidence of pulmonary dysfunction, mortality rates, effect on glucocorticoid deprivation, delay in inclusion in the lung transplant list and/or serious adverse events. The initiation of RTX was motivated by pulmonary and/or joint pathology, in patients with failure to other synthetic or biological DMARDs. A total of 393 treatment cycles were collected in 114 patients, with a mean of 3.45 cycles per patient. The RTX regimen was 2 infusions of 1g 2 weeks apart in all patients, except for 1 who received the lymphoma-like regimen. With regard to the efficacy of the treatment with RTX, improvement and especially stabilization of HRCT and LFT predominated, with numerically greater improvement for DLCO than for FVC. There was also a favorable trend in the evolution of patients treated with RTX compared to controls, although it did not reach statistical significance, and a lower risk of deterioration of lung function in patients treated with RTX versus those who had received other DMARDs. The mortality rate found at 5 years was lower than that previously described for the disease and half for the patients treated with RTX compared to those treated with anti-TNF. The adverse events described in the studies did not show additional safety alerts to those already described for RTX.Conclusion:RTX seems to be postulated as a promising therapy for patients with ILD associated with RA, showing a stabilizing effect on the lung function, with an acceptable safety profile. However, further research of higher methodological quality prospective studies is needed to confirm these favorable preliminary results.Disclosure of Interests:None declared

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AB0796 THE EVALUATION OF LUNG DIAGNOSTIC PROCEDURE AT THE ONSET OF INFLAMMATORY RHEUMATIC DISEASES WITH INTERSTITIAL LUNG DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3119 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1422.3-1423

Author(s):

T. Hoffmann ◽

P. Oelzner ◽

F. Marcus ◽

M. Förster ◽

J. Böttcher ◽

...

Keyword(s):

Carbon Monoxide ◽

Interstitial Lung Disease ◽

Lung Function ◽

Lung Disease ◽

Sensitivity And Specificity ◽

Lung Function Test ◽

Inflammatory Rheumatic Diseases ◽

X Ray ◽

Function Test ◽

Chest X Ray

Background:Interstitial lung disease (ILD) in inflammatory rheumatic diseases (IRD) is associated with increased mortality. Moreover, the lung is one of the most effected organs on IRD. Consequently, screening methods were required to the detect ILD in IRD.Objectives:The objective of the following study is to evaluate the diagnostic value of lung function test, chest x-ray and HR-CT of the lung in the detection of ILD at the onset of IRD.Methods:The study is designed as a case-control study and includes 126 patients with a newly diagnosed IRD. It was matched by gender, age and the performance of lung function test and chest x-ray. The sensitivity and specificity were verified by crosstabs and receiver operating characteristic (ROC) curve analysis. The study cohort was divided in two groups (ILD group: n = 63 and control group: n = 63). If possible, all patients received a lung function test and optional a chest x-ray. Patients with pathological findings in the screening tests (chest x-ray or reduced diffusing capacity for carbon monoxide (DLCO) < 80 %) maintained a high-resolution computer tomography (HR-CT) of the lung. Additionally, an immunological bronchioalveolar lavage was performed in the ILD group as gold standard for the detection of ILD.Results:The DLCO (< 80 %) revealed a sensitivity of 83.6 % and specificity of 45.8 % for the detection of ILD. Other examined parameter of lung function test showed no sufficient sensitivity as screening test (FVC = Forced Vital Capacity, FEV1 = Forced Expiratory Volume in 1 second, TLC = Total Lung Capacity, TLCO = Transfer factor of the Lung for carbon monoxide). Also, a combination of different parameter did not increase the sensitivity. The sensitivity and specificity of chest x-ray for the verification of ILD was 64.2 % versus 73.6 %. The combination of DLCO (< 80 %) and chest x-ray showed a sensitivity with 95.2 % and specificity with 38.7 %. The highest sensitivity (95.2 %) and specificity (77.4 %) was observed for the combination of DLCO (< 80 %) and HR-CT of the lung.Conclusion:The study highlighted that a reduced DLCO in lung function test is associated with a lung involvement in IRD. DLCO represented a potential screening parameter for lung manifestation in IRD. Especially patients with suspected vasculitis should receive an additional chest x-ray. Based on the high sensitivity of DLCO in combination with chest x-ray or HR-CT for the detection of ILD in IRD, all patients with a reduced DLCO (< 80%) should obtained an imaging of the lung.Disclosure of Interests:None declared

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FRI0442 Long-term treatment with rituximab in interstitial lung disease related to systemic sclerosis: our clinical experience

10.1136/annrheumdis-2018-eular.6052 ◽

2018 ◽

Author(s):

F. Lumetti ◽

A. Spinella ◽

A. Ariani ◽

E. Cocchiara ◽

M. Colaci ◽

...

Keyword(s):

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Clinical Experience ◽

Term Treatment ◽

Long Term Treatment

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Impact of Lung Function Decline on Time to Hospitalisation Events in Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD): a Joint Model Analysis

10.21203/rs.3.rs-562095/v1 ◽

2021 ◽

Author(s):

Michael Kreuter ◽

Francesco Del Galdo ◽

Corinna Miede ◽

Dinesh Khanna ◽

Wim A. Wuyts ◽

...

Keyword(s):

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Function ◽

Lung Disease ◽

Fold Increase ◽

Phase Iii ◽

Lung Function Decline ◽

Related Hospitalisation ◽

The Relationship ◽

Increase In Risk

Abstract Background: Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post-hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints.Methods: We used data from SENSCIS®, a Phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD.Results: There was a statistically significant association between FVC decline and the risk of all-cause (n=78) and SSc-related (n=42) hospitalisations or death (both P<0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n=75; P=0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®.Conclusions: The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints.Trial registration: Clinialtrials.gov, NCT02597933. Registered 8 October 2015, https://clinicaltrials.gov/ct2/show/study/NCT02597933.

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