Towards clinical significance of the MUC5B promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease

While rheumatoid arthritisassociated interstitial lung disease (RAILD) has been known to be a serious extraarticular rheumatoid arthritis (RA) manifestation for decades, RAILD and other pulmonary sequelae of RA have been of intense interest in recent years. Patients with RA have excess respiratory mortality of RA compared with the general population. 2 This respiratory burden of RA seems to be specific for patients with seropositive RA, and RAILD is likely a key contributor to the respiratory burden of RA. Median survival after clinical RAILD detection is poor, ranging from 3 years to 8 years in previous studies. Unlike nearly all other outcomes in RA, prevalence of RAILD does not seem to be decreasing over calendar time. This may be explained by several factors that include increased longevity of patients, improved articular disease activity unmasking symptoms of dyspnoea on exertion, increased awareness by clinicians of RAILD, greater ease in obtaining advanced chest imaging, or perhaps by medications used to treat RAILD. Thus, RAILD is a serious public health condition for patients with RA. Establishing the risk and identifying risk factors for RAILD are therefore of utmost importance. In Annals of the Rheumatic Diseases, Palomäki and colleagues investigate the lifetime risk of RAILD related to the MUC5B promoter variant. RAILD is a heterogeneous condition that is notoriously difficult to diagnose. Usual interstitial pneumonia (UIP) is the most common RAILD, considered to be fibrotic and progressive. A recent metaanalysis found that the UIP subtype had worse prognosis compared with other RAILD subtypes. Idiopathic pulmonary fibrosis (IPF) shares many of the same clinical and imaging features of UIP in RAILD. A common promoter variant of MUC5B (G>T at the rs35705950 singlenucleotide polymorphism) was identified as an important genetic risk factor for IPF. Subsequently, the MUC5B promoter variant was associated with overall RAILD risk, specifically the UIP subtype, compared with patients with RA without ILD as well as general population controls. However, in that previous study, there was no association of the MUC5B promoter variant with RA risk or serostatus, and there was no genesmoking interaction for RAILD risk. People with the MUC5B promoter variant produce higher quantities of mucin 5B in lung parenchyma and airways. While the exact mechanisms linking the MUC5B promoter variant with IPF and UIP risk are still being elucidated, the relative overabundance of the mucin 5B protein may lead to local recruitment of immune cells that eventually leads to longterm damage and fibrosis that presents clinically as fibrotic lung disease. The parallels between IPF and UIP have led some to speculate that these may be the same entity, the latter in a patient that just happens to also have RA. However, the prevalence of UIP is generally reported to be higher than would be expected by chance alone, considering the independent prevalence of IPF and RA. Previous studies have also identified RAspecific characteristics, such as RArelated autoantibodies and articular disease activity, as risk factors for RAILD. Thus, there may be a synergistic relationship between the MUC5B promoter variant and RA for RAILD risk. Other established RAILD risk factors include older age at RA onset, male sex, cigarette smoking and longer RA duration, among others. Palomäki and colleagues used FinnGen to study the relationship of the MUC5B promoter variant with the lifetime risk of RAILD. FinnGen was assembled from other prospective studies and linked to nationwide registers in Finland to link genetic and clinical data with up to 50 years of followup. They analysed 293 972 individuals to determine presence and dates of RA and ILD, identified using medication reimbursement codes and diagnoses from hospital inpatient and outpatient registries. They then stratified by presence or absence of the MUC5B promoter variant and also performed separate analyses among men and women. In the entire population, about 20% had at least one copy of the MUC5B promoter variant. Overall, the estimated risk of ILD was 1.5% by 80 years of age (considered as a surrogate for lifetime risk). Within RA, the lifetime risk of RAILD was higher, at 6.1%. Presence of the MUC5B promoter variant was strongly associated with ILD risk within RA compared with absence of the variant (HR 2.27, 95% CI 1.75 to 2.95). The lifetime risk of ILD in RA for those with the MUC5B promoter variant was 16.8% (compared with 4.4% in the general population) and seemed to specifically emerge after age of 65 years. Consistent with other studies, men with RA had a higher lifetime risk of ILD than women with RA. However, the lifetime risk for RAILD among those with the MUC5B promoter variant was quite high for both men (20.9%) and women (14.5%). Considering that the MUC5B promoter variant is relatively common, this means that many patients with RA may be harbouring this genetic variation that could dramatically alter their lifetime risk for RAILD. Beyond risk for RAILD, there was also some evidence that the MUC5B promoter variant could also impact overall RA risk. Those with the variant had slightly increased risk for RA in FinnGen, which was also replicated in the UK Biobank. The relationship persisted when eliminating patients from the analysis who developed ILD prior to RA. A possible mechanism for this observation could be that the MUC5B promoter variant could impact RArelated autoantibody production, perhaps by leading to pulmonary mucosal inflammation and immune tolerance loss prior to articular RA onset. However, large genetic studies have not identified a relationship of MUC5B with overall or seropositive RA risk, so these findings should be considered preliminary. Some limitations need to be considered. Most notably, cigarette smoking was not measured and so could not be considered in the analysis. Smoking likely mediates the relationships between MUC5B, RA, and RAILD. It would be Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA 02115, USA Department of Medicine, Harvard Medical School, Boston, MA, USA