Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

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Abstract

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease affecting 0.5–1% of the population worldwide. Interstitial lung disease (ILD) is a serious pulmonary complication of RA and it is responsible for 10–20% of mortality, with a mean survival of 5–8 years. However, nowadays there are no therapeutic recommendations for the treatment of RA-ILD. Therapeutic options for RA-ILD are complicated by the possible pulmonary toxicity of many disease modifying anti-rheumatic drugs (DMARDs) and by their unclear efficacy on pulmonary disease. Therefore, joint and lung involvement should be evaluated independently of each other for treatment purposes. On the other hand, some similarities between RA-ILD and idiopathic pulmonary fibrosis and the results of the recent INBIULD trial suggest a possible future role for antifibrotic agents. From this perspective, we review the current literature describing the pulmonary effects of drugs (immunosuppressants, conventional, biological and target synthetic DMARDs and antifibrotic agents) in patients with RA and ILD. In addition, we suggest a framework for the management of RA-ILD patients and outline a research agenda to fill the gaps in knowledge about this challenging patient cohort.

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Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

Kevin R. Flaherty, Athol Wells, Vincent Cottin … (2019)

Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.

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Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.

Roy Fleischmann, Joel Kremer, John M Cush … (2012)

Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity). At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts. In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).

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Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.

Ronald van Vollenhoven, Roy Fleischmann, Stanley Cohen … (2012)

Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).

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Journal

Journal ID (nlm-ta): J Clin Med

Journal ID (iso-abbrev): J Clin Med

Journal ID (publisher-id): jcm

Title: Journal of Clinical Medicine

Publisher: MDPI

ISSN (Electronic): 2077-0383

Publication date (Electronic): 10 April 2020

Publication date Collection: April 2020

Volume: 9

Issue: 4

Electronic Location Identifier: 1082

Affiliations

[1 ]Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41124 Modena, Italy; giulia.cassone@ 123456unimore.it

[2 ]Rheumatology Unit, IRCCS Arcispedale Santa Maria Nuova, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42100 Reggio Emilia, Italy

[3 ]Chair and Rheumatology Unit, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Policlinico di Modena, 41124 Modena, Italy; andreina.manfredi@ 123456gmail.com (A.M.); carlo.salvarani@ 123456ausl.re.it (C.S.)

[4 ]Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41124 Modena, Italy; caterina.vacchi@ 123456unimore.it

[5 ]Respiratory Unit, University of Milano Bicocca, S. Gerardo Hospital, 20900 Monza, Italy; fabrizio.luppi@ 123456unimib.it

[6 ]Department of Cardiology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Univesitaria Policlinico di Modena, 41124 Modena, Italy; coppi.francesca@ 123456aou.mo.it

Author notes

[* ]Correspondence: marco.sebastiani@ 123456unimore.it ; Tel.: +39-059-4225636; Fax: +39-059-4223007

Author information

Giulia Cassone https://orcid.org/0000-0002-3454-401X

Fabrizio Luppi https://orcid.org/0000-0001-5775-5947

Marco Sebastiani https://orcid.org/0000-0002-1294-6421

Article

Publisher ID: jcm-09-01082

DOI: 10.3390/jcm9041082

PMC ID: 7230307

PubMed ID: 32290218

SO-VID: f5574924-d899-49ce-acc4-5a5750b6e880

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

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Most cited references 212

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.

Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.

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