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Background: Rheumatoid arthritis (RA) is associated with an increased risk for malignancies, with differences regarding specific cancer types [1]. Dealing with cancer and a chronic inflammatory disease at the same time is challenging for both patients and physicians. Based on the data available to date, the risk of new malignancies does not appear to be increased in RA patients with a history of malignancy treated with biological (b) disease-modifying anti-rheumatic drugs (DMARDs) compared to conventional synthetic (cs) DMARDs. There is some evidence that tumour necrosis factor inhibitors (TNFi) may have a lower malignancy risk than csDMARDs [2, 3]. However, for some of the DMARD therapies there are no data on cancer development after a previous cancer e.g. for Interleukin-6 inhibition (IL6i) or Janus Kinase inhibition (JAKi).
Objectives: To estimate and compare the effects of JAKi, TNFi, abatacept (ABA), rituximab (RTX), IL6i and csDMARDs on the risk of new incident or recurrent malignancies in patients with RA and previous malignancy in routine care.
Methods: Data from patients with a history of malignancies enrolled in the RABBIT register between 11/2006 and 12/2021 with the start of a DMARD treatment were analysed. Incidence rates (IR) of new incident or recurrent malignancies (without non-melanoma skin cancer) per 1000 patient-years (PY) with 95% confidence intervals (CI) were calculated. Relative risk was estimated as hazard ratios (HR) by Cox regression, adjusted by stabilized and winsorized inverse probability weights, taking into account age, sex, smoking, concomitant therapies with glucocorticoids and csDMARDs, disease duration, disease activity, number of prior DMARD therapies, rheumatoid factor/ACPA positivity and cancer-relevant comorbidities as covariates. A 6-month latency period after treatment start and multiple imputation of missing data were applied, events were assigned to therapies by the “once exposed, always at risk” rule.
Results: 118 JAKi, 278 TNFi, 87 ABA, 202 RTX, 104 IL6i and 413 csDMARD treatment episodes were documented from a total of 706 patients. JAKi patients were older on average and more frequently smokers than others, while patients receiving ABA, RTX and IL6i on average had a longer disease duration and were more frequently seropositive than other patients. Patients receiving ABA and RTX were more frequently enrolled in a clinic. Patients under TNFi were slightly more often male and had received considerably less prior DMARD therapies, particularly less TNFi and IL6i (Table 1). 127 malignancies were reported, with 14, 40, 9, 34, 17 and 70 occurring under JAKi, TNFi, ABA, RTX, IL6i and csDMARDs, respectively. IRs ranged from 23 to about 40 under csDMARDs and JAKi (Tble 2). However, when adjusted for differing patient characteristics, no DMARD modes of action showed a significantly altered risk for malignancies compared to TNFi (Table 2).
Conclusion: We found no statistical evidence of an increased risk of new incident or recurrent malignancies for any DMARD mode of action compared to TNFi in RA patients with a history of malignancies. However, the numbers of cancer events under some modes of action were limited and further analyses are needed.
REFERENCES: [1] PMID: 31427060.
[2] PMID: 27550304.
[3] PMID: 31620795.
Baseline characteristics for patients with prior malignancies at treatment start.
| JAKi
| TNFi
| ABA
| RTX
| IL6i
| csDMARDs
|
|
|---|---|---|---|---|---|---|
| age, years | 69.9 (16.9) | 66.1 (15.0) | 64.5 (16.7) | 65.1 (13.0) | 64.1 (15.0) | 66.1 (14.5) |
| male sex | 26 (22.0) | 90 (32.4) | 22 (25.3) | 56 (27.7) | 29 (27.9) | 110 (26.6) |
| ever smoker | 69 (58.5) | 144 (51.8) | 44 (50.6) | 112 (55.4) | 51 (49.0) | 210 (50.8) |
| disease duration, years | 9.1 (12.3) | 8.1 (11.0) | 11.1 (12.5) | 12.5 (15.0) | 11.6 (13.3) | 8.5 (12.0) |
| rheumatoid factor/ ACPA positive | 86 (74.8) | 187 (71.9) | 72 (85.7) | 173 (89.6) | 81 (86.2) | 304 (77.2) |
| no glucocorticoids | 50 (42.7) | 116 (42.2) | 37 (43) | 64 (32.5) | 38 (38) | 186 (45.9) |
| glucocorticoids
| 45 (38.5) | 92 (33.5) | 28 (32.6) | 52 (26.4) | 36 (36) | 130 (32.1) |
| glucocorticoids
| 17 (14.5) | 48 (17.5) | 15 (17.4) | 68 (34.5) | 19 (19.0) | 73 (18.0) |
| glucocorticoids
| 5 (4.3) | 19 (6.9) | 6 (7.0) | 13 (6.6) | 7 (7.0) | 16 (4.0) |
| DAS28-ESR | 4.3 (2.3) | 5.2 (2.0) | 4.5 (2.2) | 5.4 (2.1) | 5.0 (1.8) | 4.5 (1.9) |
| no prior b/tsDMARDs | 34 (28.8) | 214 (77.0) | 24 (27.6) | 74 (36.6) | 28 (26.9) | 186 (45.0) |
| # prior TNF/IL6i, mean (SD) | 1.1 (1.1) | 0.2 (0.6) | 1.1 (1.0) | 0.8 (0.9) | 1.0 (0.9) | 0.6 (0.8) |
| # prior other b/tsDMARDs, mean (SD) | 0.4 (0.7) | 0.2 (0.5) | 0.4 (0.5) | 0.3 (0.5) | 0.5 (0.7) | 0.4 (0.6) |
| concomitant csDMARDs | 39 (33.1) | 170 (61.2) | 62 (71.3) | 138 (68.3) | 41 (39.4) | NA |
| any cancer-relevant comorbidity | 62 (52.5) | 152 (54.7) | 37 (42.5) | 108 (53.5) | 47 (45.2) | 209 (50.6) |
| enrolled in clinic (vs. practice) | 37 (31.4) | 61 (21.9) | 35 (40.2) | 82 (40.6) | 33 (31.7) | 104 (25.2) |
Results are based on treatment episodes without missing values and given as median (interquartile range) for continuous variables and number (percentage) for categorical variables unless defined otherwise.
Abbreviations: DAS28-ESR, Disease Activity Score based on erythrocyte sedimentation rate and 28 joints; NA, not available; SD, standard deviation.
Raw incidence rates and hazard ratios for new incident or recurrent malignancies.
| # episodes | # PY | # events | IR (95% CI) | HR (95% CI) | |
|---|---|---|---|---|---|
| TNFi | 278 | 1193.9 | 40 | 33.5 (23.9, 45.6) | reference |
| JAKi | 118 | 344.1 | 14 | 40.7 (22.2, 68.3) | 0.85 (0.38, 1.88) |
| ABA | 87 | 386.7 | 9 | 23.3 (10.6, 44.2) | 0.49 (0.20, 1.21) |
| RTX | 202 | 1025.7 | 34 | 33.1 (23.0, 46.3) | 1.12 (0.69, 1.81) |
| IL6i | 104 | 429.2 | 17 | 39.6 (23.1, 63.4) | 1.07 (0.52, 2.18) |
| csDMARDs | 413 | 1734.8 | 70 | 40.3 (31.5, 51.0) | 1.20 (0.77, 1.85) |
Abbreviations: CI, confidence interval; IR, incidence rate; PY, patient years.
Acknowledgements: RABBIT is supported by a joint, unconditional grant from AbbVie, Alfasigma, Amgen, Biocon, Bristol Myers Squibb, Fresenius Kabi, Hexal, Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, and UCB, and previously from Celltrion and Roche.
Disclosure of Interests: Martin Schaefer Unconditional grant paid to my institution for the RABBIT register with equal parts from AbbVie, Alfasigma, Amgen, Biocon, Bristol Myers Squibb, Fresenius Kabi, Hexal, Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, and UCB, and previously from Celltrion and Roche, Helge Wernitzsch Grant/research support from Galapagos Biopharma Germany GmbH, Norbert Blank Research support from SOBI and Novartis, Bernd Müller: None declared, Bernhard Manger Speakers bureau: Janssen, Novartis, AbbVie, Pfizer, Alexion, Lilly, MSD, Consultant for Vifor, Pharming, Astra-Zeneca, Anne Regierer Speakers bureau: Amgen, Pfizer, LAWG, TMF, Unrestricted grant from AbbVie, Amgen, BioCon, Biogen, Celltrion, Hexal, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, and UCB to my institution, Anja Strangfeld Speakers bureau: AbbVie, AlfaSigma/Galapagos, Janssen, Lilly, Pfizer, Takeda, UCB, Unconditional grant paid to my institution for the RABBIT register with equal parts from AbbVie, Alfasigma, Amgen, Biocon, Bristol Myers Squibb, Fresenius Kabi, Hexal, Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, and UCB, and previously from Celltrion and Roche.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (