Introduction: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA) related Interstitial Lung Disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. Methods: We used two-sample bidirectional Mendelian Randomisation (MR) to investigate the causal effects of RA on UIP and of UIP on RA, using variants from genome-wide association studies of RA (separately for seropositive and seronegative RA) and of IPF as genetic instruments. We conducted inverse-variance-weighted fixed-effect MR as a primary analysis and undertook sensitivity analyses to assess potential violations of the key MR assumption of no (horizontal) pleiotropy. Results: Seropositive RA showed a significant protective effect on IPF (Odds Ratio, OR = 0.93; 95% Confidence Interval, CI: 0.87-0.99; P=0.032), while the MR in the other direction showed a strongly significant causal effect of IPF on seropositive RA (OR = 1.06, 95% CI: 1.04-1.08, P=1.22x10-11). Conclusion: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between IPF and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The causal effect of IPF on seropositive RA suggests that patho-mechanisms involved in the development of UIP may promote RA and would suggest that screening for UIP in asymptomatic RA patients may be warranted and may influence therapy management of patients with RA-UIP.

LVW reports funding from GSK, Pfizer, Orion Pharma and Genentech, outside of the submitted work. LVW reports consultancy for Galapagos and Boehringer-Ingelheim. RB reports funding from Roche and Boehringer-Ingelheim and personal fees for meeting attendance/travel, speaking fees or consulting fees from Sanofi, Roche and Boehringer-Ingelheim outside the submitted work. PD reports funding from Bristol Myers Squibb, Pfizer, Galapagos and Chugai and personal fees for advisory board participation, speaking fees or consulting fees from Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, Abbvie, Pfizer, Novartis and Galapagos outside the submitted work. JKQ reports funding from MRC, HDR UK, GlaxoSmithKline, Bayer, BI, asthma+lung, Chiesi and AstraZeneca and consultancy fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Chiesi, Teva, Insmed and Bayer, outside the submitted work.

LVW holds a GSK / Asthma + Lung UK Chair in Respiratory Research (C17-1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. This research used the SPECTRE High Performance Computing Facility at the University of Leicester. LVW, JKQ and RGJ were supported by the Medical Research Council (MR/W014491/1, DEMISTIFI). For the purpose of open access, a CC BY or equivalent licence will be applied to any author accepted manuscript version arising from this submission.

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IPF GWAS data are available from: https://github.com/genomicsITER/PFgenetics RA GWAS data are available from: https://www.decode.com/summarydata/

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