https://doi.org/10.4081/reumatismo.2025.1754
Janus kinase inhibitors in rheumatoid arthritis-associated interstitial lung disease: where do we stand and what may be the future?
Submitted: 13 June 2024
Accepted: 25 August 2024
Published: 29 January 2025
Accepted: 25 August 2024
Abstract Views: 162
PDF: 54
SUPPLEMENTARY MATERIAL: 10
SUPPLEMENTARY MATERIAL: 10
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Objective. Interstitial lung disease (ILD) is rare, but it is one of the most frequent extra-articular manifestations and a relevant cause of morbidity and mortality in rheumatoid arthritis (RA). Over the past few years, Janus kinase inhibitors (JAKis) have been reported to have promising efficacy in the treatment of active RA, but recent concerns have been raised about their safety profile, namely malignancy and cardiovascular disease, limiting their use to certain patient categories.
Methods. The objective of this narrative review is to summarize the current evidence of the efficacy and safety of JAKis in RA-ILD management, investigating a possible emerging role for this drug class in such subset of patients.
Results. Current studies focusing on JAKis in RA-ILD are scarce, but they globally report an overall stabilization of respiratory symptoms, functional data, and radiographic extension of ILD. In some cohorts, JAKis determined even an encouraging improvement in lung disease, and few reports presented good tolerability of JAKis in combination with antifibrotics. Concerning the safety profile, no significant increased risk of pulmonary infection has been reported.
Conclusions. Thus far, evidence regarding the role of JAKis in the treatment of RA-ILD remains relatively limited, and additional prospective studies are needed to better understand the place of JAKis, if any, in preventing/stabilizing ILD in RA patients.
Wang D, Zhang J, Lau J, Wang S, Taneja V, Matteson EL, et al. Mechanisms of lung disease development in rheumatoid arthritis. Nat Rev Rheumatol 2019; 15: 581-96.
DOI: https://doi.org/10.1038/s41584-019-0275-x
Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am 2015; 41: 225-36.
DOI: https://doi.org/10.1016/j.rdc.2014.12.004
Olson AL, Swigris JJ, Sprunger DB, Fischer A, Fernandez-Perez ER, Solomon J, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183: 372-8.
DOI: https://doi.org/10.1164/rccm.201004-0622OC
Hyldgaard C, Hilberg O, Pedersen AB, Ulrichsen SP, Løkke A, Bendstrup E, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis 2017; 76: 1700-6.
DOI: https://doi.org/10.1136/annrheumdis-2017-211138
Norton S, Koduri G, Nikiphorou E, Dixey J, Williams P, Young A. A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology 2013; 52: 99-110.
DOI: https://doi.org/10.1093/rheumatology/kes262
Kim D, Cho SK, Choi CB, Choe JY, Chung WT, Hong SJ, et al. Impact of interstitial lung disease on mortality of patients with rheumatoid arthritis. Rheumatol Int 2017; 37: 1735-45.
DOI: https://doi.org/10.1007/s00296-017-3781-7
Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 2010; 62: 1583-91.
DOI: https://doi.org/10.1002/art.27405
Albrecht K, Strangfeld A, Marschall U, Callhoff J. Interstitial lung disease in rheumatoid arthritis: incidence, prevalence and related drug prescriptions between 2007 and 2020. RMD Open 2023; 9: e002777.
DOI: https://doi.org/10.1136/rmdopen-2022-002777
Esposito AJ, Chu SG, Madan R, Doyle TJ, Dellaripa PF. Thoracic manifestations of rheumatoid arthritis. Clin Chest Med 2019; 40: 545-60.
DOI: https://doi.org/10.1016/j.ccm.2019.05.003
Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev 2015; 24: 1-16.
DOI: https://doi.org/10.1183/09059180.00008014
Sparks JA, He X, Huang J, Fletcher EA, Zaccardelli A, Friedlander HM, et al. Rheumatoid arthritis disease activity predicting incident clinically apparent rheumatoid arthritis-associated interstitial lung disease: a prospective cohort study. Arthritis Rheumatol 2019; 71: 1472-82.
DOI: https://doi.org/10.1002/art.40904
Wang T, Zheng XJ, Liang BM, Liang ZA. Clinical features of rheumatoid arthritis-associated interstitial lung disease. Sci Rep 2015; 5: 14897.
DOI: https://doi.org/10.1038/srep14897
Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63: v1-58.
DOI: https://doi.org/10.1136/thx.2008.101691
ACR. 2023 Interstitial Lung disease guidelines. Available from: https://rheumatology.org/interstitial-lung-disease-guideline.
Narváez J, Díaz Del Campo Fontecha P, Brito García N, Bonilla G, Aburto M, Castellví I, et al. SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 2: treatment. Reumatol Clin 2022; 18: 501-12.
DOI: https://doi.org/10.1016/j.reumae.2022.03.004
McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet 2021; 398: 803-16.
DOI: https://doi.org/10.1016/S0140-6736(21)00438-4
Kaneko Y. Efficacy and safety of peficitinib in rheumatoid arthritis. Mod Rheumatol 2020; 30: 773-8.
DOI: https://doi.org/10.1080/14397595.2020.1794103
FDA. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death.
EMA. EMA’s Safety Committee (PRAC). Janus Kinase Inhibitors—PRAC Recommendation. 2022. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhibitors-jaki.
Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 2011; 31: 1409-17.
DOI: https://doi.org/10.1007/s00296-011-1999-3
Kalyoncu U, Bilgin E, Erden A, Satis H, Tufan A, Tekgoz E, et al. Efficacy and safety of tofacitinib in rheumatoid arthritis-associated interstitial lung disease: tReasure real-life data. Clin Exp Rheumatol 2022; 40: 2071‐7.
DOI: https://doi.org/10.21203/rs.3.rs-903223/v1
Saldarriaga-Rivera LM, López-Villegas VJ. Janus kinase inhibitors as a therapeutic option in rheumatoid arthritis and associated interstitial lung disease. Report of four cases. Rev Colomb Reumatol 2019; 26: 137-9.
DOI: https://doi.org/10.1016/j.rcreue.2018.02.003
Valero Jaimes JA, De Diego Sola A, Alcorta Lorenzo N, Egües Dubuc CA, Belzunegui Otano JM, Uriarte Isacelaya E, et al. Experience in the current practice with baricitinib in patients with rheumatoid arthritis and intersticial lung disease of the donostia university hospital. Ann Rheum Dis 2022; 81: 1289.
DOI: https://doi.org/10.1136/annrheumdis-2022-eular.269
Venerito V, Manfredi A, Carletto A, Gentileschi S, Atzeni F, Guiducci S, et al. Evolution of rheumatoid-arthritis-associated interstitial lung disease in patients treated with JAK inhibitors: a retrospective exploratory study. J Clin Med 2023; 12: 957.
DOI: https://doi.org/10.3390/jcm12030957
Tardella M, Di Carlo M, Carotti M, Ceccarelli L, Giovagnoni A, Salaffi F. A retrospective study of the efficacy of JAK inhibitors or abatacept on rheumatoid arthritis-interstitial lung disease. Inflammopharmacology 2022; 30: 705-12.
DOI: https://doi.org/10.1007/s10787-022-00936-w
Bejarano MV, Tamborenea MN, Goñi M, Saldarriaga L, Pisoni C, Salinas RG, et al. Interstitial lung disease in patients with rheumatoid arthritis treatedwith tofacitinib. J Clin Rheumatol 2020; 78: 12-S3.
DOI: https://doi.org/10.1136/annrheumdis-2019-eular.4896
Tsujii A, Isoda K, Yoshimura M, Nakabayashi A, Kim DS, Tamada T, et al. Janus kinase inhibitors vs. abatacept about safety and efficacy for patients with rheumatoid arthritis-associated interstitial lung disease: a retrospective nested case-control study. BMC Rheumatol 2024; 8: 4.
DOI: https://doi.org/10.1186/s41927-024-00374-x
Vacchi C, Manfredi A, Cassone G, Cerri S, Della Casa G, Andrisani D, et al. Tofacitinib for the treatment of severe interstitial lung disease related to rheumatoid arthritis. Case Rep Med 2021; 2021: 6652845.
DOI: https://doi.org/10.1155/2021/6652845
Nishii Y, Okamoto M, Zaizen Y, Kojima T, Nouno T, Naitou-Nishida Y, et al. Successful treatment of a patient with drug-refractory rheumatoid arthritis-associated interstitial lung disease with upadacitinib: a case report. Medicina 2023; 59: 1960.
DOI: https://doi.org/10.3390/medicina59111960
D'Alessandro M, Perillo F, Metella Refini R, Bergantini L, Bellisai F, Selvi E, et al. Efficacy of baricitinib in treating rheumatoid arthritis: modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting. Int Immunopharmacol 2020; 86: 106748.
DOI: https://doi.org/10.1016/j.intimp.2020.106748
Charaja HJM, Luza ME, Leon DP. Interstitial lung disease improvement in patients with rheumatoid arthritis and tofacitinib. J Clin Rheumatol 2019; 25: S48.
Kodera T, Tsutsumi T, Oka Y, Takeda T, Shirota Y, Kameoka J. Two cases of rheumatoid arthritis complicated by organising pneumonia successfully treated with tofacitinib therapy. Mod Rheumatol Case Rep 2021; 5: 218-25.
DOI: https://doi.org/10.1080/24725625.2021.1899372
Jeong E, Hong H, Lee YA, Kim KS. Potential rheumatoid arthritis-associated interstitial lung disease treatment and computational approach for future drug development. Int J Mol Sci 2024; 25: 2682.
DOI: https://doi.org/10.3390/ijms25052682
Citera G, Mysler E, Madariaga H, Cardiel MH, Castañeda O, Fischer A, et al. Incidence rates of interstitial lung disease events in tofacitinib-treated rheumatoid arthritis patients: post hoc analysis from 21 clinical trials. J Clin Rheumatol 2021; 27: e482-e90.
DOI: https://doi.org/10.1097/RHU.0000000000001552
ClinicalTrials.gov. Effects of tofacitinib vs methotrexate on rheumatoid arthritis interstitial lung disease (PULMORA). ClinicalTrials.gov. Identifier: NCT04311567. Available from: https://clinicaltrials.gov/ct2/show/NCT04311567.
ClinicalTrials.gov. Tofacitinib in the treatment of rheumatoid arthritis-related interstitial lung disease. (RAILDTo). ClinicalTrials.gov Identifier: NCT05246293. Available from: https://clinicaltrials.gov/ct2/show/NCT05246293.
Tardella M, Di Carlo M, Carotti M, Giovagnoni A, Salaffi F. Abatacept in rheumatoid arthritis-associated interstitial lung disease: short-term outcomes and predictors of progression. Clin Rheumatol 2021; 40: 4861-7.
DOI: https://doi.org/10.1007/s10067-021-05854-w
Barbero MAN, Font CV, Alcala MC, Urgelles JF, Bobillo JR, Nuñez DF, et al. Rituximab improves interstitial lung disease in rheumatoid arthritis patients. Eur Respir J 2017; 50: PA893.
DOI: https://doi.org/10.1183/1393003.congress-2017.PA893
Manfredi A, Cassone G, Furini F, Gremese E, Venerito V, Atzeni F, et al. Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicentre retrospective study. Intern Med J 2020; 50: 1085-90.
DOI: https://doi.org/10.1111/imj.14670
He C, Li W, Xie Q, Yin G. Rituximab in the treatment of interstitial lung diseases related to anti-melanoma differentiation-associated gene 5 dermatomyositis: a systematic review. Front Immunol 2021; 12: 820163.
DOI: https://doi.org/10.3389/fimmu.2021.820163
Khoo JK, Barnes H, Key S, Glaspole IN, Östör AJ. Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis. Rheumatology 2020; 59: 2217-25.
DOI: https://doi.org/10.1093/rheumatology/keaa117
Salvarani C, Sebastiani M, Dieude P, Garcia M, Deberdt W, Rogai V, et al. Baricitinib and the risk of incident interstitial lung disease: a descriptive clinical case report from clinical trials. Rheumatol Ther 2021; 8: 1435-41.
DOI: https://doi.org/10.1007/s40744-021-00332-w
Mimori T, Harigai M, Atsumi T, Kuwana M, Takei S, Tamura N, et al. Post-marketing surveillance of tofacitinib in Japanese patients with rheumatoid arthritis: an interim report of safety data. Arthritis Rheumatol 2017; 69: 431.
DOI: https://doi.org/10.1136/annrheumdis-2017-eular.1420
Balanescu AR, Citera G, Pascual-Ramos V, Bhatt DL, Connell CA, Gold D, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis 2022; 81: 1491-503.
DOI: https://doi.org/10.1136/ard-2022-222405
Chopra A, Shobha V, Chandrashekara S, Veeravalli SCM, Sharma R, Rao UR, et al. Tofacitinib in the treatment of Indian patients with rheumatoid arthritis: a post hoc analysis of efficacy and safety in phase 3 and long-term extension studies over 7 years. Int J Rheum Dis 2020; 23: 882-97.
DOI: https://doi.org/10.1111/1756-185X.13853
Cohen S, Curtis JR, DeMasi R, Chen Y, Fan H, Soonasra A, et al. Worldwide, 3-year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis. Rheumatol Ther 2018; 5: 283-91.
DOI: https://doi.org/10.1007/s40744-018-0097-3
Montero P, Milara J, Roger I, Cortijo J. Role of JAK/STAT in interstitial lung diseases; molecular and cellular mechanisms. Int J Mol Sci 2021; 22: 6211.
DOI: https://doi.org/10.3390/ijms22126211
Cronin O, McKnight O, Keir L, Ralston SH, Hirani N, Harris H. A retrospective comparison of respiratory events with JAK inhibitors or rituximab for rheumatoid arthritis in patients with pulmonary disease. Rheumatol Int 2021; 41: 921-8.
DOI: https://doi.org/10.1007/s00296-021-04835-1
Matsuno H, Atsumi T, Takei S, Tamura N, Harigai M, Fujii T, et al. Safety of baricitinib under clinical settings in patients with rheumatoid arthritis, using data from all-case post-marketing surveillance and spontaneous reports. Arthritis Rheumatol 2019; 71: 4197-8.
Moreno Herrera A, Garcia Marin J, Fages M, Martinez-Echevarria Gil-Delgado Z, Luna Reina RM. Effectiveness and safety of baricitinib and tofacitinib in rheumatoid arthritis in clinical practice. Eur J Hospital Pharm 2022; 29: A76.
DOI: https://doi.org/10.1136/ejhpharm-2022-eahp.160
Azadeh N, Limper AH, Carmona EM, Ryu JH. The role of infection in interstitial lung diseases: a review. Chest 2017; 152: 842-52.
DOI: https://doi.org/10.1016/j.chest.2017.03.033
Farooqui H, Jit M, Heymann DL, Zodpey S. Burden of severe pneumonia, pneumococcal pneumonia and pneumonia deaths in Indian states: modelling based estimates. PLoS One 2015; 10: e0129191.
DOI: https://doi.org/10.1371/journal.pone.0129191
Choi WI, Lee DY, Choi HG, Lee CW. Lung cancer development and mortality in interstitial lung disease with and without connective tissue diseases: a five-year Nationwide population-based study. Respir Res 2019; 20: 117.
DOI: https://doi.org/10.1186/s12931-019-1094-y
Curtis JR, Yamaoka K, Chen YH, Bhatt DL, Gunay LM, Sugiyama N, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis 2023; 82: 331-43.
DOI: https://doi.org/10.1136/ard-2022-222543
Cornet L, Khouri C, Roustit M, Guignabert C, Chaumais MC, Humbert M, et al. Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance-pharmacodynamic study. Eur Respir J 2019; 53: 1802472.
DOI: https://doi.org/10.1183/13993003.02472-2018
Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1382-92.
DOI: https://doi.org/10.1183/09031936.00198013
Veeravalli V, Dash RP, Thomas JA, Babu RJ, Madgula LMV, Srinivas NR. Critical assessment of pharmacokinetic drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib, the three approved janus kinase inhibitors for rheumatoid arthritis treatment. Drug Saf 2020; 43: 711-25.
DOI: https://doi.org/10.1007/s40264-020-00938-z
Alim K, Bruyère A, Lescoat A, Jouan E, Lecureur V, Le Vée M, et al. Interactions of janus kinase inhibitors with drug transporters and consequences for pharmacokinetics and toxicity. Expert Opin Drug Metab Toxicol 2021; 17: 259-71.
DOI: https://doi.org/10.1080/17425255.2021.1862084
Carrasco Cubero C, Chamizo Carmona E, Vela Casasempere P. Systematic review of the impact of drugs on diffuse interstitial lung disease associated with rheumatoid arthritis. Reumatol Clin 2020; S1699-258X(20)30111-X.
Lee SK, Shin K, Jung JY, Suh CH, Kim JW, Kim HA. Retention rate and safety of biologic and targeted synthetic DMARDs in patients with RA-associated interstitial lung disease: a KOBIO registry study. BioDrugs 2023; 37: 247-57.
DOI: https://doi.org/10.1007/s40259-023-00578-6
Xie F, Annapureddy N, Chen L, Lobo JL, Oates JC, Shah A, et al. Rheumatoid arthritis and the risk for interstitial lung disease: a comparison of risk associated with biologic and conventional DMARDs. Arthritis Rheumatol 2017; 69: 137.
Takagi M, Atsumi T, Matsuno H, Tamura N, Fujii T, Okamoto N, et al. Safety and effectiveness of baricitinib for rheumatoid arthritis in Japanese clinical practice: 24-week results of all-case post-marketing surveillance. Mod Rheumatol 2023; 33: 647-56.
DOI: https://doi.org/10.1093/mr/roac089
Baker MC, Liu Y, Lu R, Lin J, Melehani J, Robinson WH. Incidence of interstitial lung disease in patients with rheumatoid arthritis treated with biologic and targeted synthetic disease-modifying antirheumatic drugs. JAMA Netw Open 2023; 6: e233640.
DOI: https://doi.org/10.1001/jamanetworkopen.2023.3640
How to Cite
Maranini, B., Foti, R., Taha, M., Venturelli, V., Lo Monaco, A., & Govoni, M. (2025). Janus kinase inhibitors in rheumatoid arthritis-associated interstitial lung disease: where do we stand and what may be the future?. Reumatismo. https://doi.org/10.4081/reumatismo.2025.1754
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