The Complex Clinical Picture of Side Effects to Biologicals

Adapted classification for ADR to biologicals

With certain modifications but analogous to the aforementioned “type A to E scheme” for xenobiotics, ADR to biologicals can be classified as types α to ɛ, using the Greek alphabet to distinguish them from xenobiotic-induced side effects (Fig. 1). This classification is not based on similarity of clinical symptoms but is an attempt to classify ADR to biologicals according to their pathomechanism. This might help in guiding future therapy concerning reexposure, premedication, and/or switch to an

Type α (overstimulation)

Most cytokines are produced locally and have a predominant local activity. Thus, for most cytokines, only the local concentration is relatively high.4, 5 If the cytokine is applied therapeutically the situation is reversed: comparatively high systemic concentrations are applied to achieve a sufficiently high concentration locally. Such high systemic concentrations of cytokines can sometimes cause severe side effects limiting their use, for example, flu-like symptoms during interferon (INF)-α

Type β (hypersensitivity/immunogenicity)

A substantial part of biologicals are monoclonal antibodies (mAbs) produced in cell lines of animal origin, therefore biologicals contain nonhuman parts either in their protein backbone or in their glycosylation pattern (posttranslational protein modification in the Golgi apparatus). Those nonhuman parts are immunogenic by definition, and like all foreign proteins can lead to a predominantly, but not exclusively humoral immune response.⁴ The therapeutic application of mAbs of murine origin in

Type γ (immunodeviation)

The immune system has evolved to control infections and to prevent them from becoming harmful for the infected individual. Therefore, it is constantly active without causing clinical symptoms in apparently healthy individuals. The immune system controls invading organisms, for example, intracellular herpes viruses and various intracellular bacteria, and stimulates the innate immunity, especially in border regions such as mucosal surfaces or the skin. Important players in this silent but highly

Type δ (cross-reactivity)

Especially in oncology, the target cell surface structures (over-)expressed on tumor cells are usually to some extent also present on healthy tissues such as skin or intestinal mucosa. Therefore, monoclonal antibodies directed against these shared antigens may lead to considerable “off-target” tissue damage. The well-known phenomenon of acneiform lesions during cetuximab treatment is an illustrative example for this mechanism, because the targeted epidermal growth factor receptor is not only

Type ɛ (nonimmunologic side effects)

Many molecules that are defined as therapeutic target structures on a certain disease background may well be involved in other physiologic functions that are not known until the routine use of a certain biological. Daily clinical practice may actually reveal these to date unknown functions of a targeted molecule. An intense postmarketing surveillance is therefore not only important for patient safety but also for deepening the knowledge of the role of the targeted structure in human physiology.

ADR to biologicals: clinical picture in daily practice

The presented subclassification of ADR to biologicals may be helpful for physicians using biologicals in their daily clinical practice, especially for allergologists who are trying to clarify the underlying pathomechanism for a firm diagnosis. Depending on the type of reaction, dose adjustments, change of preparation, or stoppage of therapy may be advised based on a balanced evaluation of the pros and cons of the treatment.

The clinician directly involved in the treatment of the affected patient

Summary

The clinical picture of ADR to biologicals can be misleading with regard to pathogenesis of the reaction, because different pathomechanisms may lead to similar symptoms. This is especially important for acute infusion reactions, whereby no clear clinical distinction between allergic, IgE-mediated, and the more frequent nonallergic, most probably complement-mediated reactions is possible. Emergency treatment of those reactions is identical, but they differ substantially according to their

Key messages

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  Biologicals differ from classic drugs in their mode of action and ADR

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  ADR to biologicals are a common phenomenon but not well understood

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  Acute infusion reactions and injection site reactions are the most common clinical presentation

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  Not all acute infusion reactions are allergic (on the contrary, it seems to be the exception rather than the rule)

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  Most acute infusion reactions are mild, and the culprit biological can be restarted at a slower infusion rate

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  For proven or highly suggestive IgE-mediated