Impact of Medications on COVID-19 Outcomes in Inflammatory Bowel Disease: Analysis of More Than 6000 Patients From an International Registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) database, an international, collaborative database created to monitor COVID-19 outcomes in patients with inflammatory bowel disease (IBD), has previously reported that corticosteroids and mesalamine or sulfasalazine are associated with an increased risk of severe COVID-19 and tumor necrosis factor (TNF) antagonists do not impact risk. A follow-up report observed that patients on combination therapy with TNF antagonists and thiopurines appeared to be at higher risk of severe COVID-19. However, at that time, the number of reported cases was too low to fully evaluate the risk of other IBD therapies. As the cases reported to SECURE-IBD have increased substantially, more granular analyses evaluating other IBD medication classes (including combination therapies) and adjusting for more covariates are possible. In this study, we compared associations between multiple medication classes and adverse COVID-19 outcomes in the SECURE-IBD database.

We analyzed reports to SECURE-IBD from inception (March 13, 2020) through May 21, 2021. Details regarding data and analysis are provided in the Supplementary Material.

Demographic and clinical characteristics of 6144 included reports stratified by medication type are provided in Supplementary Table 1. Figure 1 summarizes the independent associations of medication classes on adverse COVID-19 outcomes among all cases reported to SECURE-IBD. Systemic corticosteroids were associated and methotrexate was marginally associated with an increased odds of hospitalization or death or both. Medications associated with a decreased odds of COVID-19–related hospitalization or death or both included TNF, interleukin-12/23, and integrin antagonists. Systemic corticosteroids were significantly associated with increased odds of severe COVID-19, and TNF and interleukin-12/23 antagonists were associated with a decreased odds of severe COVID-19. Systemic corticosteroids were associated with increased odds of death due to COVID-19, and biologics were not. Notably, there were no statistically significant associations between mesalamine or sulfasalazine and any adverse COVID-19 outcome. We also observed that TNF antagonist and thiopurine combination therapy was associated with a significantly increased risk of hospitalization or death (adjusted odds ratio [aOR], 1.82; 95% confidence interval [CI], 1.26–2.62), but not severe COVID-19 (aOR, 1.63; 95% CI, 0.87–3.10). In contrast, a combination of TNF antagonist and methotrexate was not significantly associated with risk of either adverse COVID-19 outcome (aOR, 0.82; 95% CI, 0.42–1.60 and OR, 2.44; 95% CI, 0.55–10.74).

Supplementary Table 1

Patient Population Characteristics Stratified by Medication Type

Characteristics	Overall	Sulfasalazine/ mesalamine	P value	6-mercaptopurine/ azathioprine	P value	TNF antagonists	P value
Total no. of patients	6144	1818	—	1072	—	2620	—
Age			<.001				<.001
Mean (SD)	40.0 (17.2)	44.0 (17.7)		39.6 (15.7)	.511	35.9 (16.1)
Median (IQR)	38.0 (26.0–52.0)	43.0 (30.0–56.0)		38.0 (28.0–50.0)		33.0 (23.0–47.0)
Sex
Female	3097 (50)	909 (50)	.679	515 (48)	.088	1271 (49)	.010
Disease type			<.001		.006		<.001
Crohn’s disease	3514 (57)	476 (26)		657 (61)		1839 (70)
Ulcerative colitis	2472 (40)	1287 (71)		398 (37)		735 (28)
IBD unspecified	118 (2)	48 (3)		13 (1)		32 (1)
IBD disease activity			<.001		.149		<.001
Remission	3385 (55)	895 (49)		616 (57)		1590 (61)
Mild	1326 (22)	463 (25)		216 (20)		515 (20)
Moderate/severe	1142 (19)	396 (22)		200 (19)		386 (15)
Unknown	291 (5)	64 (4)		40 (4)		129 (5)
Current smoker	238 (4)	52 (3)	.008	46 (4)	.436	112 (4)	.160
No. of comorbidities			<.001		.205		<.001
0	4377 (71)	1196 (66)		789 (74)		2008 (77)
1	1229 (20)	418 (23)		193 (18)		474 (18)
2	324 (5)	107 (6)		58 (5)		100 (4)
3+	214 (3)	97 (5)		32 (3)		38 (1)

NOTE. The n (%) from each subcategory may not add up to the exact number of total reported cases due to missing values or non-mutually exclusive variables. P values compare those taking drug class of interest with those not taking drug class.

IL, interleukin; IQR, interquartile range; SD, standard deviation.

Figure 1

Associations between medication class and COVID-19 outcomes. Each multivariable model included country (as a random effect), days from first case reported, age, sex, race (White vs non-White), ethnicity (Hispanic vs non-Hispanic), disease type (Crohn’s disease vs ulcerative colitis or inflammatory bowel disease-unclassified), disease activity by physician global assessment (active vs nonactive), smoking, body mass index (≥30 kg/m2 vs others), number of comorbidities, and calendar month. Final model was selected using backward selection. IL, interleukin. Right column: N and % represent number and proportion of patients with outcome within specified medication class. There were 6105 patients in each model.

Lastly, we restricted our analyses to only patients on biologics (Supplementary Table 2). There was no statistically significant difference in the odds of severe COVID-19 across biologic classes. The proportion of patients who experienced death was similar across biologics. When we included a covariate for mesalamine or sulfasalazine use in models of patients treated with biologics, there was no difference in outcomes with mesalamine or sulfasalazine use compared with nonuse (hospitalization or death: aOR, 1.11; 95% CI, 0.82–1.50; severe COVID-19: aOR, 0.94; 95% CI, 0.48–1.82).

Supplementary Table 2

Associations Between Biologic Class and COVID-19 Outcomes Among Patients Receiving Biologic Therapy

Medication classes for each outcome model	Total no. in model	Experienced outcome of interest, n (%)	aOR	Lower 95% CI	Upper 95% CI	P value
Total no. of patients in the model	3817	—	—	—	—	—
Hospitalization or death	3817	392 (10.2)	—	—	—	—
TNF antagonist (Ref)	2596	256 (9.9)	Ref
IL-12/23 antagonist	565	47 (8.3)	0.73	0.61	0.89	.001
Integrin antagonist	656	89 (13.6)	1.15	0.96	1.37	.12
Severe COVID-19	3817	82 (7.6)	—	—	—	—
TNF antagonist (Ref)	2596	46 (1.8)	Ref
IL-12/23 antagonist	565	10 (1.8)	0.85	0.56	1.28	.43
Integrin antagonist	656	26 (4.0)	1.25	0.56	2.80	.59
Deatha	3826	27 (0.7)	—	—	—	—
TNF antagonist (Ref)	2596	14 (0.5)	—	—	—	—
IL-12/23 antagonist	565	5 (0.9)	—	—	—	—
Integrin antagonist	656	8 (1.2)	—	—	—	—

NOTE. Each model included country (as a random effect), days from first case reported, age, sex, race (White vs non-White), ethnicity (Hispanic vs non-Hispanic) disease type (Crohn’s disease vs ulcerative colitis/IBD-unclassified), disease activity by physician global assessment (active vs nonactive), smoking, body mass index (≥30 kg/m2 vs others), number of comorbidities and calendar month. Final model was selected using backward selection.

IL, interleukin; Ref, referent.

No adjusted models were performed for outcome of death due to low event rate.

Using a global registry of patients with IBD who developed COVID-19, we evaluated associations between IBD medications and COVID-19 outcomes. The robust number of cases now reported to SECURE-IBD enabled us to perform more granular analyses than before. Reassuringly, biologics were not associated with more severe COVID-19 outcomes and may have protective effects. Importantly, mesalamine or sulfasalazine does not appear to be associated with worse COVID-19 outcomes. Combination of TNF antagonists with thiopurines was associated with an increased risk of adverse COVID-19 events, but combination with methotrexate was not.

As in previous SECURE-IBD publications, corticosteroids were associated with increased odds of severe COVID-19 outcomes. , Although we adjusted for physician global assessment in our models, it is an imperfect disease activity measure, and separating the impact of corticosteroids from uncontrolled disease remains challenging. However, the strength and consistency of this signal across immune-mediated inflammatory diseases suggest a true harmful association.3, 4, 5

Our biologic medication analyses substantiate previous studies among patients with immune-mediated inflammatory diseases, which found that these therapies are safe to continue during the COVID-19 pandemic. , , , The current findings reinforce prior observations that biologics are not associated with an increased risk of severe COVID-19 outcomes. , We also observed that combination therapy of TNF antagonists with thiopurines was associated with higher risk of adverse COVID-19 events compared with TNF antagonist monotherapy. In contrast, a combination of TNF antagonists with methotrexate was not significantly associated with any adverse outcomes, which is consistent with previous literature on combination therapies and infection risk. ,

Prior SECURE-IBD analyses suggested that mesalamine or sulfasalazine may be associated with increased risk of worse COVID-19 outcomes. This finding appropriately surprised the international gastroenterology community, as mesalamine is considered a low-risk medication with minimal systemic effects. Our updated analysis suggests that mesalamine or sulfasalazine is not associated with worse outcomes. Earlier findings were likely due to reporting bias or reporting delays, as mild cases of COVID-19 among patients on mesalamine or sulfasalazine may have gone unreported if patients did not alert their IBD provider that they had COVID-19. In contrast, the SECURE-IBD registry may have captured a relatively higher proportion of mild cases among patients on biologics, as these medications require more frequent provider–patient contact. As the pandemic has evolved and testing for COVID-19 has become more widespread, patients with mild COVID-19 symptoms are more likely to be tested and therefore reported to SECURE-IBD. With increased reporting of mild cases among patients on mesalamine or sulfasalazine, the earlier associations may have attenuated substantially.

Strengths of this study include the global, collaborative nature of the SECURE-IBD registry, which that includes more than 6000 cases from 6 continents. However, these data are subject to reporting, confirmation, and recall biases, along with residual or unmeasured confounding. Patient self-discontinuation of medications could have introduced measurement bias, likely toward the null for higher-risk medications. Finally, although the registry now includes enough patients to adequately power many analyses, some, including those involving tofacitinib and budesonide, remain underpowered.

Overall, these results suggest that many commonly used IBD medications, including biologics and mesalamine or sulfasalazine, are not associated with severe COVID-19 outcomes, and that some medications may even exert a protective effect. In addition, TNF antagonist combination therapy with methotrexate might confer lower risk of adverse COVID-19 outcomes than combination with thiopurines. Corticosteroids appear to increase the risk of adverse COVID-19 outcomes and providers should work with patients to wean off corticosteroids when possible. These results support maintaining IBD patients on medications that optimally treat their IBD during the COVID-19 pandemic.