Biologic agents have revolutionized the management of immunologic-based diseases such as psoriasis and rheumatoid arthritis. These agents include tumor necrosis alpha or IL inhibitors, especially IL-23 and IL-17. While their use can be associated with an increased risk of serious infections, malignancy, and hematological disturbances, they may also be associated with injection site reactions (ISRs).

ISRs can be either one of two types: alpha reactions, which are caused by high levels of proinflammatory cytokines that result in flu-like symptoms, or beta reactions that can either be delayed due to T-cell activation or rapid due to IgE and manifest as local wheal, erythema, urticaria, or anaphylaxis. Although biologic-related ISRs tend to be mild, they can adversely affect adherence. Yet, comparative data between the agents for the risk of ISRs are lacking.

Investigators performed a systematic review (SR) and proportional meta-analysis (MA) with the primary goal of pooling epidemiologic data on biologic-related ISRs to provide better estimates of their point prevalence. They also sought to summarize the types of ISRs that occur and to make recommendations to improve ISR reporting. Proportional MA was used to determine point estimates of the pooled prevalence of ISRs for each biologic agent.

A literature review was conducted of Medline, Embase, and CENTRAL databases from inception through February 8, 2022. To be included in the SR/MA, studies had to be original phase III clinical trials that involved the administration of an injectable biologic agent and contained complete adverse event (AE) reports for ISRs. While clinicaltrials.gov and references of included studies were checked for additional trials, secondary analyses such as post-hoc analyses and long-term extensions were excluded, as were studies involving unlabeled indications.

The Medical Dictionary for Regulatory Activities (MedDRA), a standardized medical terminology dictionary, was used for coding AEs. Under MeDRA, studies were classified as those that reported all ISRs under “injection site reactions”; studies that reported on all high-level ISRs and the preferred terms within; and studies that reported only on the most common preferred terms; this latter group was excluded. ISRs are defined as a “high-level” grouping term with subclasses of “preferred terms” describing the type of reaction, which include erythema, reaction, pain, pruritus, edema, swelling, ecchymosis, irritation, hematoma, rash, nodule, coldness, bruising, induration, hypersensitivity, hemorrhage, urticaria, inflammation, macule, papule, and warmth.

A total of 158 studies were included in this review. Almost two-thirds (63.2%) of the studies were published since 2015, and they involved multiple countries. Among the biologics that were identified in this study were abatacept, adalimumab, amgevita, briakinumab, brodalumab, canakinumab, certolizumab pegol, dupilumab, etanercept, goliumumab, guselkumab, ixelkizumab, mepolizumab, netakinumab, imalizumab rilonacept, risankizumab, tocilizumab, ustekinumab, and vedolizumab.

Information was available for fewer than one-half (44.9%) of ISR “preferred terms,” with the most common reactions being erythema (42.8%), reaction (not defined; 23.3%), pain (12.4%), and pruritus (5.7%). Approximately 30% of studies (48 studies) reported on treatment discontinuation due to ISRs. Only one-half of studies (80 out of 158) were eligible for MA; the rest were not because they had incomplete reporting or involved non–FDA approved regimens.

The prevalence of biologic-induced ISRs in decreasing order were canakinumab (15.5%), dupilumab (11.4%), etanercept (11.4%), ixekizumab (11.2%), sarilumab (9.6%), adalimumab (9%), tocilizumab (6.9%), omalizumab (4.5%), golimumab (3.5%), certolizumab pegol (2.5%), amgevita (2%), secukinumab (1.9%), ustekinumab (2.8%), brodalumab (1.3%), guselkumab (1.3%), and risankizumab (0.8%).

Erythema was the most common ISR for adalimumab, etanercept, ixekiziumab, and ustekinumab.

Limitations of this study included difficulty in tracking ISR AEs as all AEs were lumped together; varying follow-up study durations that may have affected the accuracy of the prevalence data; significant heterogenous estimates of prevalence indicating that the pooling of prevalence data may have been done inappropriately; exclusion of studies that did not report on the presence or absence of ISRs in any capacity; and limiting reporting to ISRs preferred terms designated by MedDRA.

One possible intervention to reduce ISR is the use of a citrate-free formulations. The formulation has been associated with significant reductions in ISRs associated with ixekizumab.

This study provides pharmacists with information that they can utilize when counseling patients on the potential for experiencing ISR AEs with biologics.

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