Abstract Background The increased lymphoma risk in IBD has been traditionally attributed to immunosuppressive therapy. Previous studies lacked power to explore whether the risk is confounded by disease severity. In this two nationwide cohort study, we aimed to estimate lymphoma rates among patients exposed to different treatments, and to adjust for disease severity. Methods Federated learning methods were used to enable multi-center analyses from Israel and Sweden (2005-2023) without sharing individual-level data; the models run from a shared server as if using a single combined dataset while preserving patient privacy. Treatment exposure was classified as naïve, thiopurines, anti-TNF, or combotherapy with anti-TNF+thiopurines. Lymphoma incidence-rates with age and sex adjusted hazard-ratios (aHR) were calculated by treatment group using a once-exposed-always-exposed approach. Disease load was assessed using hierarchical-clustering of laboratory tests annually. Time-varying Cox models, adjusted for age, sex, and year of IBD diagnosis evaluated the impact of disease severity and treatments on lymphoma. Results We included 97,464 patients with IBD and 644,556 non-IBD matched controls, with a median follow-up of 7.6 years (IQR 3.7-11.9). Overall, 304 IBD patients (0.32%; incidence rates 3.97/10,000) and 1,246 controls (0.19%; 2.42/10,000) developed lymphoma (aHR 2.18 95%CI 1.9-2.5). The risk was higher for both non-Hodgkin lymphoma (aHR 2.1 95%CI 1.8-2.4) and Hodgkin disease (aHR 2.9 2.1-4.1; Figure 1). Treatment-naïve patients had higher hazard of lymphoma than non-IBD controls (aHR 1.5195%CI 1.26–1.81). Among IBD patients, anti-TNF-monotherapy (aHR 1.6195%CI 1.17–2.42), and combotherapy (aHR1.86 1.13–3.07) had increased risk of lymphoma vs. naïve patients. Separately, higher disease severity over time was independently associated with an increased risk of lymphoma (HR 1.36 1.14-1.63). In a combined model including treatments and disease severity, adjusted for age and sex, the only independent variables were combotherapy (HR 2.22 1.28-3.85) and disease severity (HR 1.36 1.13-1.62, while treatment with thiopurines and anti-TNF alone were not associated with lymphoma (Table 1). Conclusion IBD was associated with higher risk of lymphoma compared with controls even in untreated patients. The associations of thiopurines and anti-TNF with lymphoma were confounded by disease severity, whereas combotherapy remained independently associated with higher risk. Conflict of interest: Mrs. Lujan, Rona: No conflict of interest Atia, Ohad: No conflict of interest Everhov, Åsa H: No conflict of interest Friss, Chagit: No conflict of interest Focht, Gili: Other: Received in the past 3 years consultation fee from Lilly Sokolik, Menachem: No conflict of interest Voghera, Siri: No conflict of interest Söderling, Jonas: No conflict of interest Osooli, Mehdi: No conflict of interest Ludvigsson, Jonas: No conflict of interest Ben-Tov, Amir: No conflict of interest Zacay, Galia: No conflict of interest Matz, Eran: No conflict of interest Zekaria, Shir: No conflict of interest Waterman, Matti: Personal Fees: Consultant and speaker fees from Abbvie, Janssen, Neopharm, Takeda, Pfizer Paid advisory board participation: Janssen, Takeda, BMS, Abbvie, Pfizer Consultant: Medtronic Turner, Dan: Consultation fee: Janssen, Pfizer, Ferring, Abbvie, Takeda, Prometheus Biosciences, Lilly, SorrisoPharma, Boehringer Ingelheim, Galapagos, BMS, AlfaSigma, Merck, Gentech Research support: Janssen, Abbvie, Takeda, Pfizer Royalties: Shaare Zedek Medical Center, Hospital for Sick Children Olen, Ola: Karolinska Institutet has received research grants from Pfizer, Janssen, AbbVie, Takeda, Ferring, Bristol Myers Squibb, and Alfasigma for projects led by Olén. Ola Olén has also received fees for lectures from Pfizer, Janssen, Bristol Myers Squibb, and Takeda.
Lujan et al. (Thu,) studied this question.