Commentary: Interstitial Lung Disease, Onset Time, and RA, January 2023

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.