Peripheral Blood Biomarkers for Rheumatoid Arthritis–Associated Interstitial Lung Disease: A Systematic Review

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has garnered increasing attention because of reports of higher-than-expected prevalence with persistent excess mortality, despite the availability of antifibrotics as novel therapeutic options. [1][2][3][4] Although antifibrotics have only modest efficacy, emerging therapeutic options have bolstered efforts for risk stratification, early detection, and identifying risk factors for progression of RA-ILD. Chest high-resolution computed tomography (HRCT) scan is the gold standard for ILD diagnosis. Because of ionizing radiation, cost, and logistical barriers associated with chest HRCT scan, a risk-stratified screening approach to RA-ILD has been proposed. 5 Previous studies identified RA-ILD risk factors already available in daily practice, eg, male sex, older age, smoking, high articular RA disease activity, and elevated RA-related autoantibodies. [6][7][8] However, performance characteristics of these factors are not currently sufficient to risk stratify who should or should not receive a chest HRCT, and pulmonary function tests (PFTs) are not sensitive enough to detect early ILDs, so biomarkers may improve risk stratification in combination with clinical variables. 7,8 In addition to the potential for clinical risk stratification, biomarkers may also provide biologic insight into the pathogenesis of RA-ILD and, perhaps, other fibrotic diseases. The MUC5B promoter variant is the strongest genetic risk factor for usual interstitial pneumonia (UIP), the prototypic fibrotic RA-ILD subtype. 9,10 Peripheral blood biomarkers have been shown to predict RA-ILD. [11][12][13] Establishing biomarkers of pulmonary damage may be particularly helpful in identifying preclinical RA-ILD, even before changes in PFTs. Matrix metalloproteinases (MMPs) are responsible for regulation and degradation of the extracellular matrix and have been associated with RA-ILD previously, 14 so they may be a

Section: Figurementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Pulmonary Damage Biomarkers for Risk of Rheumatoid Arthritis–Associated Interstitial Lung Disease: Enabling Early Detection and Risk Stratification

Juge,

Dellaripa,

Sparks

2024

“…[5][6][7] In addition to autoantibodies and select genetic variants already mentioned, other categories of candidate biomarkers evaluated in RA-ILD to date have included extracellular matrix proteins, cytokines and chemokines, lung epithelial-related proteins, tumor markers, and growth factors. 8 Because these risk factors are not sufficient for clinical use to detect RA-ILD, 9 the discovery of novel biomarkers that can help stratify patients at risk for or with undiagnosed RA-ILD is needed.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical and epidemiologic studies have identified older age, male sex, cigarette smoking, higher RA disease activity, RA autoantibodies, and genetic risk alleles, including the gain‐of‐function MUC5B rs35705950 promoter variant, as risk factors for RA‐ILD 5–7 . In addition to autoantibodies and select genetic variants already mentioned, other categories of candidate biomarkers evaluated in RA‐ILD to date have included extracellular matrix proteins, cytokines and chemokines, lung epithelial–related proteins, tumor markers, and growth factors 8 . Because these risk factors are not sufficient for clinical use to detect RA‐ILD, 9 the discovery of novel biomarkers that can help stratify patients at risk for or with undiagnosed RA‐ILD is needed.…”

Section: Introductionmentioning

confidence: 99%

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort

Luedders,

Wheeler,

Ascherman

et al. 2024

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ObjectiveTo evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA).MethodsWithin a multicenter, prospective cohort of U.S. Veterans with RA, we performed a cross‐sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP‐1, ‐3, ‐7, and ‐9 concentrations were measured in plasma samples then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA‐ILD risk factors.ResultsAmong 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person‐years of follow‐up (crude incidence rate 7.5/1,000 person‐years). Participants with the highest quartile of MMP‐7 concentrations had a nearly four‐fold increased odds of prevalent ILD (aOR 3.78 [95% CI: 1.86‐7.65]) and over two‐fold increased risk of incident ILD (aHR 2.33 [1.35‐4.02]). Higher MMP‐9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r=‐0.30, p=0.005).ConclusionMMP‐7 and MMP‐9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA‐ILD risk factors. These population‐level findings further support a potential pathogenic role for MMPs in RA‐ILD and suggest that their measurement could facilitate RA‐ILD risk stratification.

Antibodies to Malondialdehyde‐Acetaldehyde Adduct Are Associated With Prevalent and Incident Rheumatoid Arthritis–Associated Interstitial Lung Disease in US Veterans

Aripova,

Thiele,

Duryee

et al. 2024

ObjectiveTo determine the associations of protein‐specific anti‐malondialdehyde acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis‐interstitial lung disease (RA‐ILD).MethodsWithin a multicenter, prospective cohort of U.S. Veterans with RA, RA‐ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA‐albumin, MAA‐collagen, MAA‐fibrinogen, and MAA‐vimentin (IgA, IgM, and IgG) were measured by a standardized ELISA. Associations of anti‐MAA antibodies with prevalent and incident RA‐ILD were assessed using multivariable regression models adjusting for established RA‐ILD risk factors.ResultsAmong 2,739 RA participants (88% male, mean age 64 years), there were 114 prevalent and 136 incident RA‐ILD cases (average time to diagnosis: 6.6 years). Higher IgM anti‐MAA‐collagen (per 1 SD: aOR 1.28 [1.02‐1.61]), IgA anti‐MAA‐fibrinogen (aOR 1.48 [1.14‐1.92]), and IgA (aOR 1.78 [1.34‐2.37]) and IgG (aOR 1.48 [1.14‐1.92]) anti‐MAA‐vimentin antibodies were associated with prevalent RA‐ILD. In incident analyses, higher IgA (per 1 SD: aHR 1.40 [1.11‐1.76]) and IgM (aHR 1.29 [1.04‐1.60]) anti‐MAA‐albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13 [1.16‐3.90]) or IgM (aHR 1.98 [1.08‐3.64]) anti‐MAA‐albumin antibody concentrations in the highest quartile had an approximate 2‐fold increased risk of incident RA‐ILD. Across all isotypes, anti‐MAA‐fibrinogen, ‐collagen, and ‐vimentin antibodies were not significantly associated with incident RA‐ILD.ConclusionsProtein‐specific anti‐MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA‐ILD. IgA and IgM anti‐MAA‐albumin antibodies were associated with a higher risk of incident RA‐ILD. These findings suggest that MAA‐modifications and resultant immune responses may contribute to RA‐ILD pathogenesis.