Patients with RA have an elevated risk of interstitial lung disease (ILD), but methotrexate does not accen- tuate that risk and may in fact beprotective, new data show. These wereamong key findings of a pair of studiesreported at the congress.
Although a guideline-recommendedcornerstone in the management of RA,methotrexate hasbeen associatedwith both hypersensitivity pneumonitisand diffuse lung disease. However, itsinvolvement in thedevelopment of ILDamong patients withRA is unclear.
A Danish studyof more than 30,000 RA patients reportedat the congress found that their risk of ILDwas about three to five times that of thegeneral population. However, risk did notdiffer significantly whether they had filleda methotrexate prescription or not.
In addition, a multinational case-controlstudy of more than 1,000 RA patients alsoreported at the congress found that, compared with never-users of methotrexate,ever-users actually had a 59% lower likelihood of developing ILD.
However, both studies were limited bytheir retrospective design, Dr. ElizabethR. Volkmann, codirector of the connectivetissue disease–related interstitial lungdisease program at the University of California, Los Angeles, cautioned in an interview. Hence, there was likely systematicbias and confounding.
“I would interpret the conclusions of
both studies with caution,” she main-
tained. “To understand how a particular
intervention, such as methotrexate use,
affects the outcome of ILD development, a
prospective design is needed, which ade-
quately adjusts for known ILD risk factors,
such as male sex and smoking.”
As to whether the new findings are
practice-changing and how they might
affect patient counselling, “the answers
to these questions are not straightforward
and depend on other patient-related fac-
tors,” according to Dr. Volkmann.
Danish nationwide study
Dr. René Cordtz, a clinical research assistant at the Center for Rheumatology andSpine Diseases, Rigshospitalet‐Gentofte,Copenhagen, and colleagues conducted anationwide population-based cohort studyusing 1997-2015 registry data to assesslung disease among patients with RA byprescriptions filled.
Results based on 30,512 RA patientsshowed that, compared with peers fillingno methotrexate prescriptions, patientsfilling at least one did not have a significantly elevated risk of ILD at either 1 yearof follow-up (hazard ratio, 1.03) or 5 yearsof follow-up (HR, 1.00).
In addition, patients with RA had a similarly sharply elevated 5-year risk of ILD relativeto the general population regardless ofwhether they had filled neither methotrexatenor sulfasalazine prescriptions (standardisedincidence ratio, 3.38) or had filled prescriptions for methotrexate only (SIR, 3.63), sulfasalazine only (SIR, 4. 12), or both (SIR, 5.45).
“RA patients have an increased risk of ILD,compared to the general population, whichwas not surprising, but very importantly, thatrisk was not further exacerbated in thosetreated with methotrexate,” Dr. Cordtz concluded. “We do acknowledge that purchasing your medicine is different from takingyour medicine, which is why we found itextra reassuring that when requiring at leasttwo methotrexate prescriptions to be considered exposed, it did not change our results.”
Dr. Pierre-Antoine Juge, a rheumatologist atBichat-Claude Bernard Hospital, Paris, andcolleagues performed a case-control studyamong 482 RA patients with ILD and 741
RA patients without ILD in three cohorts: aFrench discovery cohort, a multinational (Brazil, Italy, Mexico, United Kingdom, and UnitedStates) replication cohort, and a combinedcohort. Those with methotrexate hypersensitivity pneumonitis were excluded.
Results showed that relative to peers
without ILD, patients with ILD had a lower
prevalence of ever having used methotrex-
ate and had received a lower cumulative
methotrexate dose, findings that were
consistent across all three cohorts.
Methotrexate ever-use was associated
with a significantly lower adjusted likelihood
of ILD in the discovery cohort (odds ratio,
0.46), the replication cohort (OR, 0.38), and
the combined cohort (OR, 0.41). Furthermore,
ever-users were less
ed among patients
with ILD regardless
of chest high-resolu-
tion CT pattern (usual
pattern vs. not).
ate use appeared to
delay the adjusted
time to onset of ILD by 3. 5 years in the
discovery cohort (P = .001), by 3. 2 years
in the replication cohort (P < .0001), and
by 3. 5 years in the combined cohort (P <
“Outside of methotrexate hypersensi-
tivity pneumonitis, methotrexate was not
a risk factor for RA-associated ILD in our
study. We observed an inverse relationship
that was similar whatever the high-reso-
lution CT pattern,” Dr. Juge commented.
“But this possible protective effect should
be confirmed through a dedicated prospec-
tive, randomised, controlled trial.
“Methotrexate should not be consideredas a causal factor for RA-associated ILD,and its [discontinuation] should be discussedthrough a multidisciplinary discussion,” herecommended. In addition, “this study doesnot investigate the impact of methotrexateuse on RA-associated ILD prognosis.”
The Danish study did not receive anyspecific funding, and none of its authorsreported having any financial disclosures.The multinational study did not receive anyspecific funding. Dr. Juge disclosed that hehad no relevant conflicts of interest, butmany of his coauthors reported financialrelationships with industry. Dr. Volkmanndisclosed consulting for Boehringer Ingel-heim and Forbius, and receiving grant support from Corbus and Forbius.
No link seen between methotrexate and
interstitial lung disease in rheumatoid arthritis
DR. VOLKMANN DR. JUGE