Lung involvement in rheumatologic diseases has a broad spectrum of clinical and radiological presentations, from acute and inflammatory predominance to chronic and fibrotic lung disorders. Therapy has to be guided by the type of rheumatologic disease, the kind of lung involvement and the risk associated with the clinical state of the patient and prognostic factors. Although several therapeutic approaches have been used, the best treatment is still not certain; clinical trials are mandatory, which would require a better knowledge of the pulmonary pathogenesis of immunologic diseases. The following review is focused on the therapeutic options for those rheumatologic disorders that could present as a predominant interstitial lung disease which may confer a bad or life-threatening prognosis.

1.
Bouros D, Wells AU, Nicholson AG, et al: Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165:1581-1586.
2.
Antoniou KM, Margaritopoulos G, Economidou F, et al: Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J 2008;33:882-896.
3.
Tashkin DP, Elashoff R, Clements PJ, et al; Scleroderma Lung Study Research Group: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666.
4.
Hoyles RK, Ellis RW, Wellsbury J, 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;54:3962-3970.
5.
Nadashkevich O, Davis P, Fritzler M, et al: A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006;25:205-212.
6.
Nannini C, West CP, Erwin PJ, et al: Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther 2008;10:R124.
7.
Guillevin L, Cordier JF, Lhote F, et al: A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum 1997;40:2187-2198.
8.
Kowal-Bielecka O, Landewé R, Avouac J, et al; EUSTAR Co-Authors: EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR). Ann Rheum Dis 2009;68:620-628.
9.
Poormoghim H, Rezaei N, Sheidae Z, et al: Systemic sclerosis: comparison of efficacy of oral cyclophosphamide and azathioprine on skin score and pulmonary involvement - a retrospective study. Rheumatol Int 2014;34:1691-1699.
10.
Iudici M, Cuomo G, Vettori S, et al: Low-dose pulse cyclophosphamide in interstitial lung disease associated with systemic sclerosis (SSc-ILD): efficacy of maintenance immunosuppression in responders and non-responders. Semin Arthritis Rheum 2015;44:437-444.
11.
Bérezné A, Ranque B, Valeyre D, et al: Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J Rheumatol 2008;35:1064-1072.
12.
Paone C, Chiarolanza I, Cuomo G, et al: Twelve-month azathioprine as maintenance therapy in early diffuse systemic sclerosis patients treated for 1 year with low dose of cyclophosphamide pulse therapy. Clin Exp Rheumatol 2007;25:613-616.
13.
Tzouvelekis A, Galanopoulos N, Bouros E, et al: Effect and safety of mycophenolate mofetil or sodium in systemic sclerosis-associated interstitial lung disease: a meta-analysis. Pulm Med 2012;2012:143637.
14.
Fischer A, Brown KK, Du Bois RM, et al: Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013;40:640-646.
15.
Yilmaz N, Can M, Kocakaya D, et al: Two-year experience with mycophenolate mofetil in patients with scleroderma lung disease: a case series. Int J Rheum Dis 2014;17:923-928.
16.
Walker KM, Pope J; Participating Members of the Scleroderma Clinical Trials Consortium; Canadian Scleroderma Research Group: Treatment of systemic sclerosis complications: what to use when first-line treatment fails - a consensus of systemic sclerosis experts. Semin Arthritis Rheum 2012;42:42-55.
17.
Panopoulos ST, Bournia VK, Trakada G, et al: Mycophenolate versus cyclophosphamide for progressive interstitial lung disease associated with systemic sclerosis: a 2-year case control study. Lung 2013;191:483-489.
18.
Daoussis D, Liossis SN, Tsamandas AC, et al: Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology 2010;49:271-280.
19.
Daoussis D, Liossis SN, Tsamandas AC, et al: Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol 2012;30(suppl 71):S17-S22.
20.
Bosello S, De Santis M, Lama G, et al: B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther 2010;12:R54.
21.
Jordan S, Distler JHW, Maurer B, et al: Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis 2015;74:1188-1194.
22.
Bosello S, De Luca G, Rucco M, et al: Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum 2015;44:428-436.
23.
Papiris SA, Kagouridis K, Papadaki G, Kolilekas L, Manali ED: Treating CTDs related fibrotic ILDs by immunosuppressants: ‘facts and faults'. Lung 2014;192:221-223.
24.
Ryerson CJ, Cottin V, Brown KK, Collard HR: Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J 2015;46:512-520.
25.
Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, et al; EUSTAR (EULAR Scleroderma Trials and Research Group): Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis 2013;72:1217-1220.
26.
McMahan ZH, Wigley FM: Novel investigational agents for the treatment of scleroderma. Expert Opin Investig Drugs 2014;23:183-198.
27.
Burt RK, Shah SJ, Dill K, et al: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label randomized phase 2 trial. Lancet 2011;378:498-506.
28.
van Laar MJ, Farge D, Sont JK, et al: The ASTIS trial: autologous stem cell transplantation versus iv pulse cyclophosphamide in poor prognosis systemic sclerosis, first results. EULAR, Annual Congress of the European League against Rheumatism. Ann Rheum Dis 2012;71(suppl 3):51.
29.
Barnett AJ: Scleroderma (progressive systemic sclerosis): progress and course based on a personal series of 118 cases. Med J Aust 1978;2:129-134.
30.
Greidinger EL, Flaherty KT, White B, et al: African-American race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998;114:801-807.
31.
Plastiras SC, Karadimitrakis SP, Ziakas PD, et al: Scleroderma lung: initial forced vital capacity as predictor of pulmonary function decline. Arthritis Rheum 2006;55:598-602.
32.
Khanna D, Tseng CH, Farmani N, et al: Clinical course of lung physiology in patients with scleroderma and interstitial lung disease. Arthritis Rheum 2011;63:3078-3085.
33.
Hallowell RW, Horton MR: Interstitial lung disease in patients with rheumatoid arthritis: spontaneous and drug induced. Drugs 2014;74:443-450.
34.
Song J-W, Lee H-K, Lee CK, et al: Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis 2013;30:103-112.
35.
Ogawa D, Hashimoto H, Wada J, et al: Successful use of cyclosporine A for the treatment of acute interstitial pneumonitis associated with rheumatoid arthritis. Rheumatology (Oxford) 2000;39:1422-1424.
36.
Chang HK, Park W, Ryu DS: Successful treatment of progressive rheumatoid interstitial lung disease with cyclosporine: a case report. J Korean Med Sci 2002;17:270-273.
37.
Puttick MP, Klinkhoff AV, Chalmers A, et al: Treatment of progressive rheumatoid interstitial lung disease with cyclosporine. J Rheumatol 1995;22:2163-2165.
38.
Saketkoo LA, Espinoza LR: Rheumatoid arthritis interstitial lung disease: mycophenolate mofetil as antifibrotic and disease-modifying antirheumatic drug. Arch Intern Med 2008;168:1718-1719.
39.
Braun-Moscovici Y, Butbul-Aviel Y, Guralnik L, et al: Rituximab: rescue therapy in life-threatening complications or refractory autoimmune diseases: a single center experience. Rheumatol Int 2013;33:1495-1504.
40.
Braun MG, Wagener P: Regression of peripheral and pulmonary rheumatoid nodules under therapy with rituximab (in German). Z Rheumatol 2013;72:166-171.
41.
Matteson E: Rituximab in rheumatoid arthritis lung disease. NCT00588565. https://www.clinicaltrials.gov/ct2/show/study/NCT00578565?term=NCT00578565&rank=1&sect=Xcba9870156 (updated September 25, 2012).
42.
Lioté H, Lioté F, Séroussi B, et al: Rituximab-induced lung disease: a systematic literature review. Eur Respir J 2010;35:681-687.
43.
Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-1400.
44.
Dass S, Atzeni F, Vital E, et al: Safety of rituximab in patients with rheumatoid arthritis and concomitant lung disease. Ann Rheum Dis 2011;70(suppl 3):71.
45.
Becerra G, Cambridge M: Safety and efficacy of rituximab in patients with rheumatoid arthritis and lung involvement. Ann Rheum Dis 2013;72(suppl 3):450.
46.
Roubille C, Haraoui B: Interstitial lung diseases induced or exacerbated by DMARDs and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum 2014;43:613-626.
47.
Doyle TJ, Hunninghake GM, Rosas IO: Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med 2012;185:1147-1153.
48.
Saravanan V, Kelly CA: Reducing the risk of methotrexate pneumonitis in rheumatoid arthritis. Rheumatology (Oxford) 2009;48:1065-1068.
49.
Saag KG, Teng GG, Patkar NM, et al; American College of Rheumatology: American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-784.
50.
Conway R, Low C, Coughlan RJ, et al: Methotrexate and lung disease in rheumatoid arthritis - a meta-analysis of randomized controlled trials. Arthritis Rheum 2014;66:803-812.
51.
Alarcon GS, Kremer JM, Macaluso M, et al: Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med 1997;127:356-364.
52.
Suissa S, Hudson M, Ernst P: Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum 2006;54:1435-1439.
53.
Chikura B, Lane S, Dawson JK: Clinical expression of leflunomide-induced pneumonitis. Rheumatology (Oxford) 2009;48:1065-1068.
54.
Sawada T, Inokuma S, Sato T, et al; Study Committee for Leflunomide-Induced Lung Injury, Japan College of Rheumatology: Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 2009;48:1069-1072.
55.
Panopoulos ST, Sfikakis PP: Biological treatments and connective tissue disease associated interstitial lung disease. Curr Opin Pulm Med 2011;17:362-367.
56.
Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al: Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum 2011;41:256-264.
57.
Dixon WG, Hyrich KL, Watson KD, et al: Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2010;69:1086-1091.
58.
Herrinton LJ, Harrold LR, Liu L, et al: Association between anti-TNF-α therapy and interstitial lung disease. Pharmacoepidemiol Drug Saf 2013;22:394-402.
59.
Robles-Perez A, Rodriguez-Sanchon B, Dorca J, et al: Preclinical lung disease in early rheumatoid arthritis. Chron Respir Dis 2015, in press.
60.
Imokawa S, Colby TV, Leslie KO, et al: Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000;15:373-381.
61.
Kreider M, Highland K: Pulmonary involvement in Sjögren syndrome. Semin Respir Crit Care Med 2014;35:255-264.
62.
Parambil JG, Myers JL, Lindell RM, et al: Interstitial lung disease in primary Sjögren syndrome. Chest 2006;130:1489-1495.
63.
Cha SI, Fessler MB, Cool CD, et al: Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J 2006;28:364-369.
64.
Deheinzelin D, Capelozzi VL, Kairalla RA, et al: Interstitial lung disease in primary Sjögren's syndrome. Clinical-pathological evaluation and response to treatment. Am J Respir Crit Care Med 1996;154:794-799.
65.
Gottenberg JE, Cinquetti G, Larroche C, et al; Club Rhumatismes et Inflammations and the French Society of Rheumatology: Efficacy of rituximab in systemic manifestations of primary Sjögren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann Rheum Dis 2013;72:1026-1031.
66.
Swartz MA, Vivino FB: Dramatic reversal of lymphocytic interstitial pneumonitis in Sjögren's syndrome with rituximab. J Clin Rheumatol 2011;17:454.
67.
Seror R, Sordet C, Guillevin L, et al: Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren's syndrome. Ann Rheum Dis 2007;66:351-357.
68.
Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-1277.
69.
Winslow WA, Ploss LN, Loitman B: Pleuritis in systemic lupus erythematosus: its importance as an early manifestation in diagnosis. Ann Intern Med 1958;49:70-88.
70.
Muangchan C, van Vollenhoven RF, Bernatsky SR, et al: Treatment algorithms in systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2015, Epub ahead of print.
71.
Colby TV: Pulmonary pathology in patients with systemic autoimmune diseases. Clin Chest Med 1998;19:587-612.
72.
Gutsche M, Rosen GD, Swigris JJ: Connective tissue disease-associated interstitial lung disease: a review. Curr Respir Care Rep 2012;1:224-232.
73.
Martínez-Martínez MU, Abud-Mendoza C: Recurrent diffuse alveolar haemorrhage in a patient with systemic lupus erythematosus: long-term benefit of rituximab. Lupus 2012;21:1124-1127.
74.
Al Rashidi A, Alajmi M, Hegazi MO: Mycophenolate mofetil as a maintenance therapy for lupus-related diffuse alveolar hemorrhage: a case report. Lupus 2011;20:1551-1553.
75.
Claridge S, Das P, Dorling A, et al: Plasmapheresis as a rescue therapy for systemic lupus erythematosus-associated diffuse alveolar haemorrhage. BMJ Case Rep 2011;2011:bcr0220113893.
76.
Carmier D, Diot E, Diot P: Shrinking lung syndrome: recognition, pathophysiology and therapeutic strategy. Expert Rev Respir Med 2011;5:33-39.
77.
Calderaro DC, Ferreira GA: Presentation and prognosis of shrinking lung syndrome in systemic lupus erythematosus: report of four cases. Rheumatol Int 2012;32:1391-1396.
78.
Carmier D, Marchand-Adam S, Diot P, et al: Respiratory involvement in systemic lupus erythematosus. Rev Mal Respir 2010;27:e66-e78.
79.
Peñacoba Toribio P, Córica Albani ME, Myos Pérez M, et al: Rituximab in the treatment of shrinking lung syndrome in systemic lupus erythematosus. Rheumatol Clin 2013;10:325-327.
80.
Connors GR, Christopher-Stine L, Oddis CV, et al: Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest 2010;138:1464-1474.
81.
Cottin V, Thivolet-Béjui F, Reynaud-Gaubert M, et al: Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis. Eur Respir J 2003;22:245-250.
82.
Marie I, Hatron PY, Dominique S, et al: Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients. Arthritis Rheum 2011;63:3439-3447.
83.
Mukae H, Ishimoto H, Sakamoto N, et al: Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis. Chest 2009;136:1341-1347.
84.
Schnabel A, Reuter M, Biederer J, et al: Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum 2003;32:273-284.
85.
Marie I, Josse S, Hatron PY, et al: Interstitial lung disease in anti-Jo-1 patients with antisynthetase syndrome. Arthritis Care Res (Hoboken) 2013;65:800-808.
86.
Lega JC, Reynaud Q, Belot A, et al: Idiopathic inflammatory myopathies and the lung. Eur Respir Rev 2015;24:216-238.
87.
Kurita T, Yasuda S, Oba K, et al: The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology 2015;54:39-44.
88.
Mira-Avendano IC, Parambil JG, Yadav R, et al: A retrospective review of clinical features and treatment outcomes in steroid-resistant interstitial lung disease from polymyositis/dermatomyositis. Respir Med 2013;107:890-896.
89.
Sem M, Molberg O, Lund MB, et al: Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatology (Oxford) 2009;48:968-971.
90.
Vij R, Strek ME: Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest 2013;143:814-824.
91.
Simeon-Aznar CP, Fonollosa-Pla V, Tolosa-Vilella C, et al: Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol 2011;30:1393-1398.
92.
Meiners PM, Vissink A, Kroese FG, et al: Abatacept treatment reduces disease activity in early primary Sjögren's syndrome (open-label proof of concept ASAP study). Ann Rheum Dis 2014;73:1393-1396.
93.
Buch MH, Vital EM, Emery P: Abatacept in the treatment of rheumatoid arthritis. Arthritis Res Ther 2008;10(suppl 1):S5.
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