Background/Purpose

Drug surveillance of biologics in juvenile patients using registries is of immense importance as patient numbers and duration in clinical trials are limited. There is a special interest in allergic, autoimmune, hematologic, infectious, thrombotic, vascular and malignant disorders.

Methods Patients with JIA were prospectively observed in the German JIA biologic registry BiKer. Predefined adverse events of special interest (AESI) were recorded by physicians. Total Rate per exposure year (EY) and risk ratio (RR) were calculated with 95 % confidence intervals. Differences were analyzed using the Wald test. Biologics naïve patients were recruited from JIA patients receiving methotrexate (controls). In all three biologics cohorts, methotrexate as well as other DMARDS were allowed to be given concomitantly.

Results Methotrexate (without a biologic agent) was applied to a total of 1517 patients, Etanercept (ETA) to 1925, Adalimumab (ADA) to 498 and Tocilizumab (TOC) to 104 patients for a total exposure time or 3019; 3958; 561 and 103 years, respectively. A total of 1227 adverse events (AE) were reported In the control group (406/1000 PY[389-424]) with 44 classified as serious (15/1000PY[11-20]). In the ETA cohort there were 1131 AE (286/1000PY [272-300]) and 149 SAE (38/1000PY[32-44]), in the ADA cohort 373 AE (665/1000 PY [625-703]) and 28 SAE (50/1000 PY [35-71] and in the TOC cohort there were 97 AE (941/1000 PY [878-973]) with 10 SAE (97/1000 PY [54-170]. In the control cohort, a total of 252 AE qualified as ESI, upon ETA 234, upon ADA 60 and upon TOC 13 (table).

Thus, compared to the control group the incidence of severe infections is significantly higher upon ETA and ADA, that of autoimmunity and uveitis are significantly higher upon ADA, and MAS is significantly more frequent upon TOC, while the incidence of hepatic events is lower in all the biologics cohorts than with MTX alone. A higher RR failing to reach level of significance was found for chronic inflammatory bowel disease with ETA, and anaphylaxis with TOC. Further ESI including malignancies revealed no differences.

Conclusion This progress report from the ongoing BiKeR-registry showed a higher incidence for several adverse events of interest including severe infections, autoimmunity, uveitis, anaphylaxis and MAS while the total rate is surprisingly low. In general, JIA patients tolerated biologic treatment very well. Differences between the cohorts are at least in part biased by differences in JIA category distribution and preexisting uveitis risk.

	MTX (3019 years)	ETA(3959 years)			ADA (561 years)			TOC (103 years
	Rate*	rate	RR (95% CI)	p-Wert	rate	RR (95% CI)	p-Wert	rate	RR (95% CI)	p-Wert
Anaphylaxis	1.32	0.25	0.2(0.02-1.7)	0.138	3.56	2.7(0.5-14.7)	0.253	9.71	7.3(0.8-65.6)	0.074
Autoimmunity	0.33	0			10.69	33.3(3.9-333.3)	0.001	0
Bleeding	0.66	0.76	1.1(0.2-6.9)	0.882	3.56	0,2(0.03-1.3)	0.092	0
Chronic inflammatory bowel disease	0.99	3.28	3.3(0.9-11.6)	0.061	1.78	1.8(0.2-17.3)	0.613	0
Cytopenia	3.64	5.81	1.6 (0.8-3.3)	0.202	1.78	2.1(0.36-16.7)	0.494	29.12	8.0(2.2-28.7)	0.001
Demyelination	0	0.51			0			0
Hepatic events	51.67	13.39	0.26(0.2-0.4)	<0.001	17.82	2.9(1.5-5.5)	0.001	29.12	0.6(0.2-1.8)	0.352
Severe infection	9.60	15.66	1.6(1.1-2.5)	0.029	24.95	2.6(1.4-4.9)	0.003	29.12	3.0(0.9-10.0)	0.067
Malignant disease	0.99	1.77	1.8(0.5-6.9)	0.403	0
MAS	0.33	0.25	0.8(0.1-12.5)	0.848	0			29.12	90.9(9.2-1000)	<0.001
Pregnancy	0	0.25			0			0
Thrombotic disorders	0	0			1.78			0
Uveitis	13.91	16.92	1.2(0.8-1.8)	0.318	40.99	3.0(1.8-4.9)	<0.001	0
Stroke	0	0			0			0

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/drug-safety-in-treatment-of-juvenile-idiopathic-arthritis-jia-biologic-therapy-compared-with-mtx/