Abstract
Anti-synthetase syndrome (ASS) is an idiopathic inflammatory myopathy (IIM). In comparison to interstitial lung disease (ILD) in polymyositis and dermatomyositis (PM/DM), ILD in ASS is more frequent, has a more aggressive phenotype, a greater involvement of the lungs, and a more rapid onset of pulmonary symptoms. Continuous declines in predicted forced vital capacity (FVC) and dyspnea were the main features of patients who developed end-stage ILD. The severity of ASS at diagnosis dictates when and which immunosuppressant will be started. There is an experience for the usage of RTX in the first, second, and subsequent lines, as well as for reintroduction and salvage therapies. Not all ASS patients will develop severe illness and require intense immunosuppression. Some features associated with poor prognosis include older age, acute or subacute onset, lack of response to steroids, and lower baseline values for FVC and DLCO. Here we hypothesize that RTX should be the first line of treatment for high-risk ILD in ASS to preserve lung function and then maintenance therapy should be continued with the same or another drug depending on the recovery of lung function.
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Witt LJ, Curran JJ, Strek ME (2016) The diagnosis and treatment of antisynthetase syndrome. Clin Pulm Med 23:218–226. https://doi.org/10.1097/CPM.0000000000000171
Lundberg IE, Tjärnlund A, Bottai M et al (2017) 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis 76:1955–1964. https://doi.org/10.1136/annrheumdis-2017-211468
Betteridge Z, McHugh N (2016) Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. J Intern Med 280:8–23. https://doi.org/10.1111/joim.12451
Pinal-Fernandez I, Casal-Dominguez M, Huapaya JA et al (2017) A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. Rheumatology 56:999–1007. https://doi.org/10.1093/rheumatology/kex021
Shi J, Li S, Yang H et al (2017) Clinical profiles and prognosis of patients with distinct antisynthetase autoantibodies. J Rheumatol 44:1051–1057. https://doi.org/10.3899/jrheum.161480
Wilfong EM, Young-Glazer JJ, Sohn BK et al (2022) Anti-tRNA synthetase syndrome interstitial lung disease: a single center experience. Respir Med 191:106432. https://doi.org/10.1016/j.rmed.2021.106432
Trallero-Araguás E, Grau-Junyent JM, Labirua-Iturburu A et al (2016) Clinical manifestations and long-term outcome of anti-Jo1 antisynthetase patients in a large cohort of Spanish patients from the GEAS-IIM group. Semin Arthritis Rheum 46:225–231. https://doi.org/10.1016/j.semarthrit.2016.03.011
Gasparyan AY, Ayvazyan L, Mukanova U et al (2019) Scientific hypotheses: writing, promoting, and predicting implications. J Korean Med Sci 34:e300. https://doi.org/10.3346/jkms.2019.34.e300
Marie I, Hatron PY, Dominique S et al (2011) Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients. Arthritis Rheum 63:3439–3447. https://doi.org/10.1002/art.30513
Korsten P, Rademacher J-G, Riedel L et al (2020) Antisynthetase syndrome-associated interstitial lung disease: monitoring of immunosuppressive treatment effects by chest computed tomography. Front Med 7:609595. https://doi.org/10.3389/fmed.2020.609595
American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646–664. https://doi.org/10.1164/ajrccm.161.2.ats3-00
Waseda Y, Johkoh T, Egashira R et al (2016) Antisynthetase syndrome: pulmonary computed tomography findings of adult patients with antibodies to aminoacyl-tRNA synthetases. Eur J Radiol 85:1421–1426. https://doi.org/10.1016/j.ejrad.2016.05.012
De Zorzi E, Spagnolo P, Cocconcelli E et al (2022) Thoracic involvement in systemic autoimmune rheumatic diseases: pathogenesis and management. Clin Rev Allergy Immunol 63:472–489. https://doi.org/10.1007/s12016-022-08926-0
Doyle TJ, Dhillon N, Madan R et al (2018) Rituximab in the treatment of interstitial lung disease associated with antisynthetase syndrome: a multicenter retrospective case review. J Rheumatol 45:841–850. https://doi.org/10.3899/jrheum.170541
Baratella E, Marrocchio C, Cifaldi R et al (2021) Interstitial lung disease in patients with antisynthetase syndrome: a retrospective case series study. Jpn J Radiol 39:40–46. https://doi.org/10.1007/s11604-020-01030-3
Ha Y-J, Lee YJ, Kang EH (2018) Lung involvements in rheumatic diseases: update on the epidemiology, pathogenesis, clinical features, and treatment. Biomed Res Int 2018:6930297. https://doi.org/10.1155/2018/6930297
Debray M-P, Borie R, Revel M-P et al (2015) Interstitial lung disease in anti-synthetase syndrome: initial and follow-up CT findings. Eur J Radiol 84:516–523. https://doi.org/10.1016/j.ejrad.2014.11.026
Langlois V, Gillibert A, Uzunhan Y et al (2020) Rituximab and cyclophosphamide in antisynthetase syndrome-related interstitial lung disease: an observational retrospective study. J Rheumatol 47:1678–1686. https://doi.org/10.3899/jrheum.190505
Mehta P, Aggarwal R, Porter JC, Gunawardena H (2022) Management of interstitial lung disease (ILD) in myositis syndromes: a practical guide for clinicians. Best Pract Res Clin Rheumatol 36:101769. https://doi.org/10.1016/j.berh.2022.101769
Kurita T, Yasuda S, Oba K et al (2015) The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology 54:39–44. https://doi.org/10.1093/rheumatology/keu166
Kotani T, Takeuchi T, Makino S et al (2011) Combination with corticosteroids and cyclosporin-A improves pulmonary function test results and chest HRCT findings in dermatomyositis patients with acute/subacute interstitial pneumonia. Clin Rheumatol 30:1021–1028. https://doi.org/10.1007/s10067-011-1713-6
Zhao N, Jiang W, Wu H et al (2022) Clinical features, prognostic factors, and survival of patients with antisynthetase syndrome and interstitial lung disease. Front Immunol 13:872615. https://doi.org/10.3389/fimmu.2022.872615
Li X, Zhou Q, Wu P et al (2022) A prognostic analysis of antisynthetase syndrome-related interstitial lung disease. Int J Rheum Dis 25:1368–1375. https://doi.org/10.1111/1756-185X.14428
Huapaya JA, Silhan L, Pinal-Fernandez I et al (2019) Long-Term treatment with azathioprine and mycophenolate mofetil for myositis-related interstitial lung disease. Chest 156:896–906. https://doi.org/10.1016/j.chest.2019.05.023
Cassone G, Sebastiani M, Vacchi C et al (2021) Efficacy and safety of mycophenolate mofetil in the treatment of rheumatic disease-related interstitial lung disease: a narrative review. Drugs Context. https://doi.org/10.7573/dic.2020-8-8
Fujisawa T, Hozumi H, Kamiya Y et al (2021) Prednisolone and tacrolimus versus prednisolone and cyclosporin A to treat polymyositis/dermatomyositis-associated ILD: a randomized, open-label trial. Respirology 26:370–377. https://doi.org/10.1111/resp.13978
Sharma N, Putman MS, Vij R et al (2017) Myositis-associated interstitial lung disease: predictors of failure of conventional treatment and response to tacrolimus in a US cohort. J Rheumatol 44:1612–1618. https://doi.org/10.3899/jrheum.161217
Kourkouni E, Mitsogiannis G, Simopoulou T et al (2019) Interstitial lung disease in anti-synthetase syndrome. Mediterr J Rheumatol 30:186–189. https://doi.org/10.31138/mjr.30.3.186
Keir GJ, Maher TM, Hansell DM et al (2012) Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur Respir J 40:641–648. https://doi.org/10.1183/09031936.00163911
Keir GJ, Maher TM, Ming D et al (2014) Rituximab in severe, treatment-refractory interstitial lung disease. Respirology 19:353–359. https://doi.org/10.1111/resp.12214
Maher TM, Tudor VA, Saunders P et al (2023) Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med 11:45–54. https://doi.org/10.1016/S2213-2600(22)00359-9
Sem M, Molberg O, Lund MB, Gran JT (2009) Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatology 48:968–971. https://doi.org/10.1093/rheumatology/kep157
Aggarwal R, Bandos A, Reed AM et al (2014) Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol 66:740–749. https://doi.org/10.1002/art.38270
Andersson H, Sem M, Lund MB et al (2015) Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease. Rheumatology 54:1420–1428. https://doi.org/10.1093/rheumatology/kev004
Oldroyd AGS, Lilleker JB, Amin T et al (2022) British Society for Rheumatology guideline on management of paediatric, adolescent and adult patients with idiopathic inflammatory myopathy. Rheumatology 61:1760–1768. https://doi.org/10.1093/rheumatology/keac115
Fujisawa T (2021) Management of myositis-associated interstitial lung disease. Medicina. https://doi.org/10.3390/medicina57040347
Sacco KA, Abraham RS (2018) Consequences of B-cell-depleting therapy: hypogammaglobulinemia and impaired B-cell reconstitution. Immunotherapy 10:713–728. https://doi.org/10.2217/imt-2017-0178
Roberts DM, Jones RB, Smith RM et al (2015) Immunoglobulin G replacement for the treatment of infective complications of rituximab-associated hypogammaglobulinemia in autoimmune disease: a case series. J Autoimmun 57:24–29. https://doi.org/10.1016/j.jaut.2014.11.004
López J, Merino L, Piris L et al (2019) Rituximab induces a lasting, non-cumulative remodelling of the B-cell compartment. Clin Exp Rheumatol 37:615–622
Duarte AC, Cordeiro A, Fernandes BM et al (2019) Rituximab in connective tissue disease-associated interstitial lung disease. Clin Rheumatol 38:2001–2009. https://doi.org/10.1007/s10067-019-04557-7
Oddis CV, Aggarwal R (2018) Treatment in myositis. Nat Rev Rheumatol 14:279–289. https://doi.org/10.1038/nrrheum.2018.42
Robles-Perez A, Dorca J, Castellví I et al (2020) Rituximab effect in severe progressive connective tissue disease-related lung disease: preliminary data. Rheumatol Int 40:719–726. https://doi.org/10.1007/s00296-020-04545-0
Xu L, Wang F, Luo F (2022) Rituximab for the treatment of connective tissue disease-associated interstitial lung disease: a systematic review and meta-analysis. Front Pharmacol 13:1019915. https://doi.org/10.3389/fphar.2022.1019915
Atienza-Mateo B, Remuzgo-Martínez S, Prieto-Peña D et al (2020) Rituximab in the treatment of interstitial lung disease associated with autoimmune diseases: experience from a single referral center and literature review. J Clin Med Res. https://doi.org/10.3390/jcm9103070
Hervier B, Uzunhan Y (2019) Inflammatory myopathy-related interstitial lung disease: from pathophysiology to treatment. Front Med 6:326. https://doi.org/10.3389/fmed.2019.00326
Jeganathan N, Sathananthan M (2020) Connective tissue disease-related interstitial lung disease: prevalence, patterns, predictors, prognosis, and treatment. Lung 198:735–759. https://doi.org/10.1007/s00408-020-00383-w
Cyclophosphamide and azathioprine vs tacrolimus in antisynthetase syndrome-related interstitial lung disease—full text view—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03770663. Accessed 14 Mar 2023
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Zekić, T. Rituximab as the first-line therapy in anti-synthetase syndrome-related interstitial lung disease. Rheumatol Int 43, 1015–1021 (2023). https://doi.org/10.1007/s00296-023-05302-9
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DOI: https://doi.org/10.1007/s00296-023-05302-9