Methodological Concerns Regarding the Causal Relationship Between Methotrexate and COPD: The Missing Confounding by Indication [Letter]

Dear editor

We read with great interest the article by Xiang et al entitled “Causal Relationship Between Methotrexate and Chronic Obstructive Pulmonary Disease: A Study Based on Network Toxicology and Mendelian Randomization”.¹ The authors used an innovative dual-method framework merging network toxicology and Mendelian randomization (MR) to examine whether methotrexate (MTX) use increases the risk of developing chronic obstructive pulmonary disease (COPD). While we commend the authors for their new methodological approach and the combination of molecular docking with genetic epidemiology, we wish to raise a critical methodological concern that may substantially affect the interpretation of their findings—specifically, the failure to adequately address confounding by indication arising from rheumatoid arthritis (RA) itself.^2,3

RA as an Independent Risk Factor for COPD

The authors appropriately note in their introduction that “RA patients using MTX have a higher risk of developing COPD than the general population”. However, this observation shows a well-established epidemiological fact: RA itself is an independent risk factor for COPD, irrespective of MTX exposure.⁴ A recent systematic review and meta-analysis of 19 studies comprising 1,549,181 participants showed a significant bidirectional association between RA and COPD, with RA increasing COPD risk by 41% (OR = 1.41, 95% CI: 1.13–1.76, P = 0.003).⁴ A large-scale real-world cohort study from the TriNetX Research Network involving 136,820 propensity-matched pairs found that the 5-year cumulative probability of COPD was 7.36% in RA patients versus 5.97% in non-RA individuals (HR = 1.228, 95% CI: 1.186–1.272).⁵ Subgroup analyses, moreover, revealed that male RA patients faced even higher risk (HR = 1.300), and patients under 60 years of age had the most pronounced risk elevation (HR = 1.560).⁵ Analysis of NHANES 2007–2020 data (25,682 participants) confirmed that RA remained significantly associated with COPD even after comprehensive adjustment for demographic, socioeconomic, lifestyle, and health-related factors (adjusted OR = 1.52, 95% CI: 1.23–1.87, P < 0.001).⁶

Moreover, a bidirectional association exists: COPD itself may also increase RA risk. MR analysis has shown a causal relationship between COPD and increased odds of RA (OR = 1.072, P = 0.008).⁴ This bidirectional association underscores shared pathogenic mechanisms, including systemic inflammation, common genetic susceptibility, and the “lung–joint axis” hypothesis, in which citrullinated protein antibodies may initially form in the pulmonary mucosa before migrating to the synovium.⁴

The Core Issue: Confounding by Indication

The main challenge in the authors’ MR analysis is the inability to separate MTX effects from those of underlying RA.^2,3 This represents a standard case of confounding by indication—a bias that occurs when the indication for drug prescription (RA) is itself an independent risk factor for the outcome of interest (COPD).⁷ The authors briefly acknowledge “residual confounding where the instrumental variables affect COPD through non-MTX target pathways” but do not explicitly identify RA disease activity as the most likely source of this bias, nor do they propose or implement any analytical strategy to address it.

The validity of MR analysis rests on three core assumptions, the third of which—the exclusion restriction assumption—requires that the instrumental variables (SNPs) affect the outcome only through the exposure of interest (MTX use).⁸ However, the SNPs selected as instruments for MTX may also be associated with RA susceptibility, disease activity, or serological status (eg, rheumatoid factor or anti-CCP positivity), thereby violating this assumption through horizontal pleiotropy.⁹ If these genetic variants influence COPD risk via RA disease pathways rather than MTX exposure, the observed causal estimate would be biased by the very disease the drug is intended to treat.

Clinical Implications and Unresolved Questions

The clinical significance of this methodological-related concern reaches beyond statistical nuance. From a therapeutic perspective, the clinically relevant question is not simply “Does MTX increase COPD risk?” but rather: “In RA patients, does MTX, through its disease-modifying effects, alter the already elevated COPD risk associated with RA?”

A nationwide cohort study of 58,580 COPD outpatients found that MTX use was actually associated with a reduced risk of COPD exacerbation within 180 days of follow-up (HR = 0.66, 95% CI: 0.66–0.66, P < 0.001),¹⁰ suggesting that MTX’s anti-inflammatory properties might confer pulmonary benefits. This stands in apparent contradiction to the authors’ conclusion of increased COPD risk, and we would suggest that this variation may reflect, at least in part, the failure to separate drug effects from disease effects.

Conclusion

The authors’ integration of network toxicology with MR represents an admirable effort to bridge molecular and epidemiological evidence. However, we contend that the conclusion that MTX “increases the risk of developing COPD” requires more considered interpretation, as the observed association may be substantially confounded by the effect of RA itself. Until analytical strategies can accurately separate drug effects from disease effects, the clinical community should interpret these outcomes with appropriate circumspection and continue to weigh the well-established benefits of MTX in managing RA against its possible pulmonary risks in individual patients.

Disclosure

The author reports no conflicts of interest in this communication.