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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 87-91

Management of connective tissue disease-associated interstitial lung disease


Department of Rheumatology, Yashoda Hospitals, Secunderabad, Telangana, India

Date of Submission01-Aug-2021
Date of Acceptance21-Sep-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Keerthi Talari
Yashoda Hospitals, Secunderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.332982

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  Abstract 


The management of connective tissue diseases (CTD)-associated interstitial lung disease (ILD) is challenging considering its myriad presentations and variable course. Evidence to guide treatment is insufficient with very few randomized trials reported till date. This review discusses the current evidence guiding management of CTD-ILD with a specific focus on corticosteroids, cyclophosphamide, mycophenolate, azathioprine, calcineurin inhibitors, and pirfenidone. Corticosteroids (except in systemic sclerosis [SSc]-ILD) in combination with immunosuppressants form the mainstay of therapy in CTD-ILD. Cyclophosphamide and mycophenolate mofetil are backed by randomised trials-Scleroderma lung study I and II respectively for SSc-ILD, while calcineurin inhibitors with or without cyclophosphamide have emerged as a promising initial therapy in myositis associated ILD. Rituximab is probably beneficial for all forms of CTD-ILD even as randomized trial data are awaited. General measures such as lifestyle modification, pulmonary rehabilitation, vaccination, prophylaxis, supplemental oxygen, palliative care are also of paramount importance. Future research should focus on long-term efficacy, safety and head-to-head comparison of drugs, role of upfront combination therapies, supportive and palliative care.

Keywords: Cyclophosphamide, connective tissue disease, Interstitial lung disease, mycophenolate mofetil, treatment


How to cite this article:
Talari K. Management of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol 2021;16, Suppl S1:87-91

How to cite this URL:
Talari K. Management of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol [serial online] 2021 [cited 2022 May 28];16, Suppl S1:87-91. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/5/87/332982




  Introduction Top


The management of interstitial lung disease (ILD) in connective tissue diseases (CTD) has taken a giant stride over the last 15 years with no controlled trials in 2005 to many clinical trials that have been completed or are ongoing today. Yet, we can state that the treatment of CTD-ILD is poorly defined. Most data are adapted from systemic sclerosis (SSc)-ILD trials and the unmet needs are umpteen. ILD continues to remain a major cause of morbidity and mortality in CTD-ILD especially in SSc, idiopathic inflammatory myositis, and rheumatoid arthritis (RA). In this review, the current management of CTD-ILD in routine clinical practice and the evidence backing the same shall be discussed. The purview of this topic would be limited to corticosteroids, cyclophosphamide, mycophenolate, rituximab, azathioprine, calcineurin inhibitors, pirfenidone, general measures, and vaccination while the rest would be discussed later. A literature search was hence made on the same lines in PUBMED and MEDLINE with the keywords – interstitial lung disease, systemic sclerosis, rheumatoid arthritis, connective tissue disease, inflammatory myositis, polymyositis (PM), dermatomyositis (DM), anti-MDA 5, Sjogren's, systemic lupus erythematosus, vaccines, oxygen, and rehabilitation. A total of 2378 articles have been screened. The following articles have been excluded – duplicates, not published in English, case reports, not pertaining to the purview of this topic, small observational studies in an area where randomized trials are available, reviews. A total of 22 articles – randomized trials, observational studies, systematic reviews, and meta-analysis were then included in this narrative review [Table 1].
Table 1: Completed and ongoing trials in connective tissue disease-associated interstitial lung disease

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  Systemic Sclerosis–Interstitial Lung Disease (Systemic Sclerosis-Interstitial Lung Disease) Top


Fifty percent of SSc patients have ILD at first assessment and 90% over time on high-resolution computed tomography (HRCT), while only 30% of these progress in the following year.[1] Although all patients with SSc should be screened for ILD at baseline with HRCT and pulmonary function tests, the decision on whom to initiate treatment for, usually depends on the disease severity and the rate of progression. Often, a >20% involvement on HRCT chest, forced vital capacity (FVC) <70% of predicted, decrease in FVC by >10% ordiffusion capacity of the lung for carbon monoxide by >15% or both are considered as indicators for initiating treatment.[2]

In the Scleroderma lung study-1 (SLS-1), patients received oral cyclophosphamide (≤2 mg/kg body weight per day) or matching placebo for 1 year and were followed for an additional year. Oral cyclophosphamide improved FVC (2.53%) and total lung capacity significantly as compared to placebo, paralleled by improvement in dyspnoea, functional ability, skin tightening, and health-related quality of life, with improvement in FVC through 2nd year too. However, the improvement was small and improvement in other measures was not sustained at the end of 2 years.[3] In the Fibrosing Alveolitis in Scleroderma Trial (FAST), six doses of IV CYC (600 mg/m2/month) with 20 mg oral prednisolone on alternate day followed by AZA (2.5 mg/kg/d) versus placebo at 12 months showed a nonsignificant improvement in FVC with cyclophosphamide.[4] Although no randomized controlled trials (RCTs), prospective, and retrospective studies with CYC demonstrated a clinically relevant improvement in lung volumes, it is of note that none of the patients included in them were selected on the basis of progression of ILD (except SLS 1).

In the SLS II, Mycophenolate mofetil (MMF) for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in lung function over the 2-year course of the study. This was a negative trial as the primary endpoint was to prove the superiority of MMF over CYC. MMF however was better tolerated with less leukopenia and thrombocytopenia, less premature withdrawals (20 vs. 32) with lesser deaths (mostly due to progressive ILD) (5 vs. 11).[5] The better tolerability of MMF over cyclophosphamide has made it the first-line choice of therapy in the treatment algorithms suggested by experts.[6] In a study by Naidu et al., MMF did not result in significant improvement in lung function in SSc-ILD with minimally impaired lung function (FVC >70%).[7]

In an open-label prospective comparative study, rituximab was found to improve FVC over a 7 year follow-up period as against other conventional therapies while a retrospective study has shown stabilization with no further deterioration in SSc ILD.[8],[9] The role of rituximab in SSc ILD warrants further studies. EvER-ILD and RECITAL are ongoing randomized trials trying to establish the role of rituximab in CTD ILD.[10]

Other immunosuppressives have not been found to have adequate evidence to support their use. Azathioprine is commonly used as a maintenance agent with evidence from the FAST trial. A randomized, unblinded study has suggested deterioration in lung function when used as an induction agent compared to cyclophosphamide.[10] The role of corticosteroids in SSc-ILD is not well defined with about 40% not using it at all and the majority of the rest preferring low doses only.[6] The role of antifibrotics in SSc-ILD is gaining importance with the recent approval of nintedanib for SSc-ILD.[11] Pirfenidone has been shown to be safe and tolerable in the Phase II LOTUSS trial and its role in SSc-ILD in combination with MMF is being evaluated in the ongoing Phase III trial SLS III.[12] In a short-term 6-month placebo-controlled RCT pirfenidone was not found effective in SSc-ILD.[13] In the RELIEF trial conducted in progressive fibrotic ILD patients which included CTD-ILD patients, pirfenidone showed a significantly lower decline in FVC. This trial was prematurely terminated as the recruitment was very slow.[14]


  Rheumatoid Arthritis–Interstitial Lung Disease (Rheumatoid Arthritis-Interstitial Lung Disease) Top


Randomized trials are lacking in RA-ILD in guiding treatment and in addition to this certain disease-modifying agents (traditional and biologic) have been implicated in pulmonary toxicity/worsening of ILD.

The most common patterns of RA-ILD are usual interstitial pneumonia (UIP) and Nonspecific interstitial pneumonia (NSIP). Corticosteroids have been found to have a beneficial role in NSIP and organizing pneumonia. Corticosteroids at 0.5–1 mg/kg prednisolone and pulse steroids along with immunosuppression are used in the treatment of RA-ILD.[15] The immunosuppressives most commonly used are cyclophosphamide, mycophenolate, and rituximab. Intravenous pulse cyclophosphamide has been found to be beneficial in RA-ILD with better survival rates.[16] The use of MMF is extrapolated from SSc-ILD trials with only few case series demonstrating benefit in RA-ILD. The role of rituximab in the treatment of RA-ILD was controversial initially with some case series suggesting progression or development of ILD. However, two retrospective observational studies and the data from the Spanish NEREA registry showed that rituximab is beneficial in RA-ILD with lesser chances of functional impairment, with clinical and radiologic stability in most.[17] Methotrexate and tumor necrosis factor inhibitors are usually avoided in the treatment of RA-ILD due to the fear of worsening of ILD, though this apprehension is unbacked by evidence.[15]

The role of Pirfenidone in RA-ILD seems promising, but the randomized trial evaluating the safety and efficacy of pirfenidone in RA-ILD, TRAIL 1 was terminated as an adequate number of patients could not be recruited in the time frame due to the COVID 19 pandemic.[15]


  Myositis-Associated Interstitial Lung Disease (Polymyositis/Dermatomyositis/Clinically Amyopathic Dermatomyositis-interstitial Lung Disease) Top


ILD is a frequent manifestation of idiopathic inflammatory myopathies with a prevalence rate of 40%-and 5-year survival rates ranging from 52% to 84% in acute to chronic-myositis associated ILD.[18] Anti-tRNA synthetases and anti-MDA5 antibodies are most commonly associated with ILD. No consensus guidelines exist regarding the treatment of myositis-associated ILD, and treatment is mostly guided by case series and retrospective studies with few prospective studies recently being published.

Glucocorticoids (pulse in acute forms, and 0.5–1 mg/kg prednisolone in chronic forms) are the mainstay of therapy and should be given in combination with immunosuppressants for sparing high doses to avoid long-term toxicity and at the same time prevent the relapse of ILD. Calcineurin inhibitors are becoming the first line of therapy for PM/DM/clinically amyopathic DM (CADM)–ILD. Retrospective studies have shown stabilization, efficacy, and safety of cyclosporine A in DM/CADM-ILD including anti Jo1 associated ILD. A systematic review has shown survival benefit at 3 months with cyclosporine A in rapidly progressive ILD.[19] Tacrolimus has been found to improve pulmonary function and progression-free survival in PM/DM/CADM-ILD based on few retrospective studies, a single-arm prospective study, and a systematic review even in those who do not respond to conventional treatment.[20] In a prospective, randomized trial comparing tacrolimus to cyclosporine A, tacrolimus showed a trend toward better survival rates compared to cyclosporine A (87% vs. 71%) at 52 weeks.[21] Tacrolimus has been found to be effective in anti-MDA5 associated myositis when used in combination with cyclophosphamide as discussed below.

Cyclophosphamide (iv) has been found to be effective in improving lung volumes and HRCT scores in a systematic review of 12 studies which included an open-label prospective study.[22] Fifty percent of patients with rapidly progressive DM-ILD had improvement up to 2 years with a combination of corticosteroids, cyclosporine A and iv cyclophosphamide. Tsuji et al. conducted a single-arm prospective trial in patients with anti MDA5 ILD with corticosteroids, tacrolimus (trough levels of 10–12 ng/ml), and iv cyclophosphamide (q 2 weeks for 6 doses followed by q 6–8 weeks) and compared the survival rates with historical cohort receiving conventional step-up immunosuppressive therapy. The 12-month survival rates were 85% versus 33% in the combination therapy compared to the historical cohort respectively.[23] MMF has been found useful in DM/PM-ILD in several case series. Both MMF and azathioprine have been found useful for long-term maintenance and in reduction of glucocorticoid dose in myositis-associated ILD including those with antisynthetase and anti-MDA 5 antibodies.[24] In retrospective studies rituximab has been found to be useful in DM/PM/CADM-ILD including antisynthetase syndrome and in anti-MDA5-ILD who either have refractory or severe disease. Results of the randomized trials RECITAL and EvER-ILD may provide more information.[17] In a small prospective study, pirfenidone has shown a trend towards better survival in rapidly progressive CADM-ILD especially those with subacute onset, but the results were only numerically superior and not statistically significant.[25]


  Other Connective Tissue Diseases-Associated Interstitial Lung Disease Top


Other forms of CTD-ILD have not been individually addressed in trials, but few studies in CTD-ILD exist. Azathioprine was less well tolerated than mycophenolate but resulted in equal stabilisation of disease.[24] MMF has shown stabilization (in UIP) or improvement (in non-UIP) in CTD-ILD with some case series in systemic lupus erythematosus ILD showing benefit.[26] There are few prospective randomized studies with cyclophosphamide but historically it has been the drug of choice for progressive ILD. Rituximab has shown benefit in Sjogrens' syndrome-related ILD and the RECITAL study results are awaited. The completed and ongoing trials in CTD-ILD has been summarised in [Table 1].


  General Measures Top


Lifestyle modification measures such as quitting smoking, exercising regularly, eating a healthy diet, adequate sleep, stress management should be encouraged in all patients with CTD-ILD. Associated symptoms such as cough, fatigue, depression should be addressed. Supplemental oxygen, pulmonary rehabilitation, antibiotic prophylaxis, palliative care, vaccination should be a part of comprehensive care. Multidisciplinary team's coordination and involvement are necessary in managing comorbidities such as pulmonary arterial hypertension, osteoporosis, gastroesophageal reflux, premature atherosclerosis, and others.


  Supplemental Oxygen Top


Resting and exertional hypoxia may contribute to dyspnoea, fatigue, depression, and poor functional status. Small studies suggest that supplemental oxygen improves quality of life and hence most national guidelines suggest oxygen to maintain a saturation of over 90%.[27] However, no trials exist on the usage, mode of delivery of oxygen in ILD patients, though a randomized trial in IPF is underway.[28]


  Pulmonary Rehabilitation Top


This includes exercise training, behavioral interventions, and education. In a prospective observational study, a 12-week pulmonary rehabilitation program for 2 hours a day, led to significant improvements in the 6-minute walking distance test, the modified Borg Scale, modified Medical research council scores, and in the health status measures.[29] Educational sessions on self-management by medical doctors, psychologists, physiotherapists, dieticians and respiratory nurses was also found to be useful.


  Prophylaxis Top


Although no guidelines specifically recommend it, it is prudent to give Pneumocystis carinii pneumonia prophylaxis in ILD patients on immunosuppression. Prophylaxis against cytomegalovirus has also been proposed in anti-MDA 5 ILD.[30]


  Vaccination Top


All patients with ILD who are on immunosuppression should receive vaccination. Yearly influenza vaccine should be given. The pneumococcal conjugate vaccine (PCV13) followed by pneumococcal polysaccharide vaccine (PPSV 23) eight weeks later is preferred. Zoster vaccine (preferably the inactivated recombinant one) can be given 2 weeks prior to starting immunosuppression.[27] As per the American College of Rheumatology (ACR) guidance statement, all patients with autoimmune rheumatic diseases should be vaccinated for COVID 19 as a priority with adjustments in immunomodulatory therapy as suggested.[31]


  Conclusion Top


The course of ILD in CTD is unforeseeable with varying patterns, severity, progression, and outcomes in individual patients. There is paucity of evidence in guiding when to initiate, how long to continue and when to taper drugs. Most trials are short-term with modest improvement in lung function. Future research should focus on long-term efficacy, safety, and head-to-head comparison of drugs. The role of upfront combination therapies needs further analysis. Structured research on the best outcome measures, supportive and palliative care remains a pressing priority.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-66.  Back to cited text no. 3
    
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Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54:3962-70.  Back to cited text no. 4
    
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Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016;4:708-19.  Back to cited text no. 5
    
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Fernández-Codina A, Walker KM, Pope JE; Scleroderma Algorithm Group. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol 2018;70:1820-8.  Back to cited text no. 6
    
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Naidu GS, Sharma SK, Adarsh MB, Dhir V, Sinha A, Dhooria S, et al. Effect of mycophenolate mofetil (MMF) on systemic sclerosis-related interstitial lung disease with mildly impaired lung function: A double-blind, placebo-controlled, randomized trial. Rheumatol Int 2020;40:207-16.  Back to cited text no. 7
    
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Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum 2017;46:625-31.  Back to cited text no. 8
    
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Lepri G, Avouac J, Airò P, Anguita Santos F, Bellando-Randone S, Blagojevic J, et al. Effects of rituximab in connective tissue disorders related interstitial lung disease. Clin Exp Rheumatol 2016;34 Suppl 100:181-5.  Back to cited text no. 9
    
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Nadashkevich O, Davis P, Fritzler M, Kovalenko W. A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006;25:205-12.  Back to cited text no. 10
    
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Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019;380:2518-28.  Back to cited text no. 11
    
12.
Goos T, De Sadeleer LJ, Yserbyt J, Verleden GM, Vermant M, Verleden SE, et al. Progression in the management of non-idiopathic pulmonary fibrosis interstitial lung diseases, where are we now and where we would like to be. J Clin Med 2021;10:1330.  Back to cited text no. 12
    
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Acharya N, Sharma SK, Mishra D, Dhooria S, Dhir V, Jain S. Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease – A randomised controlled trial. Rheumatol Int 2020;40:703-10.  Back to cited text no. 13
    
14.
Behr J, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): A double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med 2021;9:476-86.  Back to cited text no. 14
    
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Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: Manifestations and current concepts in pathogenesis and management. Eur Respir Rev 2021;30:210011.  Back to cited text no. 15
    
16.
Kelly C, Palmar E, Gordon J, Woodhead F, Nisar M, Arthanari S, et al. on behalf of BRILL Network, OP0037 Pulsed Cyclophosphamide in the Treatment of Rheumatoid Arthritis-Related Interstitial Lung Disease (RA-ILD) Annals of the Rheumatic Diseases 2014;73:74.  Back to cited text no. 16
    
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Vacchi C, Manfredi A, Cassone G, Erre GL, Salvarani C, Sebastiani M. Efficacy and safety of rituximab in the treatment of connective tissue disease-related interstitial lung disease. Drugs Context 2021;10:2020-8-7.  Back to cited text no. 17
    
18.
Fujisawa T, Hozumi H, Kono M, Enomoto N, Hashimoto D, Nakamura Y, et al. Prognostic factors for myositis-associated interstitial lung disease. PLoS One 2014;9:e98824.  Back to cited text no. 18
    
19.
Barba T, Fort R, Cottin V, Provencher S, Durieu I, Jardel S, et al. Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis. Autoimmun Rev 2019;18:113-22.  Back to cited text no. 19
    
20.
Ge Y, Zhou H, Shi J, Ye B, Peng Q, Lu X, et al. The efficacy of tacrolimus in patients with refractory dermatomyositis/polymyositis: A systematic review. Clin Rheumatol 2015;34:2097-103.  Back to cited text no. 20
    
21.
Fujisawa T, Hozumi H, Kamiya Y, Kaida Y, Akamatsu T, Kusagaya H, et al. Prednisolone and tacrolimus versus prednisolone and cyclosporin A to treat polymyositis/dermatomyositis-associated ILD: A randomized, open-label trial. Respirology 2021;26:370-7.  Back to cited text no. 21
    
22.
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23.
Tsuji H, Nakashima R, Hosono Y, Imura Y, Yagita M, Yoshifuji H, et al. Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid, tacrolimus, and cyclophosphamide in interstitial lung diseases accompanied by anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Arthritis Rheumatol 2020;72:488-98.  Back to cited text no. 23
    
24.
Huapaya JA, Silhan L, Pinal-Fernandez I, Casal-Dominguez M, Johnson C, Albayda J, et al. Long-term treatment with azathioprine and mycophenolate mofetil for myositis-related interstitial lung disease. Chest 2019;156:896-906.  Back to cited text no. 24
    
25.
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26.
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31.
Curtis JR, Johnson SR, Anthony DD, Arasarathnam RJ, Baden LR, Bass AR, et al. American college of rheumatology guidance for COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases: Version 2. Arthritis Rheumatol 2021;73:e30-45.  Back to cited text no. 31
    



 
 
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Abstract
Introduction
Systemic Scleros...
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Myositis-Associa...
Other Connective...
General Measures
Supplemental Oxygen
Pulmonary Rehabi...
Prophylaxis
Vaccination
Conclusion
References
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