Paradoxical Skin Reactions to Biologics in Patients With Rheumatologic Disorders

Abstract

Targeted immune-modulating treatment with biological agents has revolutionized the management of immune-mediated inflammatory diseases, including rheumatologic conditions. The efficacy and tolerability of biological agents, from the initial tumour necrosis factor (TNF)-α inhibitors to the new anti-cytokine monoclonal antibodies, have dramatically changed the natural history of debilitating conditions such as rheumatoid arthritis and seronegative spondyloarthropathies. The widening use of biologics across several rheumatologic diseases has been associated with a new class of adverse events, the so-called paradoxical reactions. These events are inflammatory immune-mediated tissue reactions, developing paradoxically during treatment of rheumatologic conditions with targeted biologics that are commonly used for treating the idiopathic counterparts of these drug-induced reactions. The skin is frequently involved, and, even if considered rare to uncommon, these cutaneous manifestations are an important cause of biologic agent discontinuation. TNF-α antagonist-induced psoriasis, which can manifest de novo or as exacerbation of a pre-existing form, is the prototypic and most frequent paradoxical skin reaction to biologics while other reactions, such as eczematous and lichenoid eruptions, hidradenitis suppurativa, pyoderma gangrenosum, Sweet's syndrome and granulomatous skin diseases, occur much more rarely. Management of these reactions consists of topical or systemic skin-directed therapies, depending on the severity and extension of the cutaneous picture, and it is generally associated with switching over to other disease-modifying regimens for treating the underlying rheumatologic condition. Here, we review in detail the current concepts and controversies on classification, pathogenesis and clinical management of this new class of cutaneous adverse events induced by biologics in rheumatologic patients.

Keywords: TNFα-inhibitors; biologics; paradoxical skin reactions; psoriasis; rheumatological disorders.

FIGURE 1

Classification and pathogenesis of cutaneous paradoxical reactions to biologic agents (^∗) and their related key immune-response/cytokine patterns. (1) TNF-α/type-1 IFN cytokine imbalance: pharmacological blockade of TNF-α by TNF-inhibitors (TNFi) determines uncontrolled activation of plasmacytoid dendritic cells (pDCs), with sustained production of IFN-α. IFN-α drives paradoxical skin inflammation via downstream effectors cytokines, thus eliciting key cutaneous immune response patterns → clinical correlation: paradoxical psoriasis and psoriasiform eruptions. (2) IFN-α induced spatial shift of activated innate immune cells and chemokine (C-X-C motif) receptor 3 (CXCR3) positive T-cells from extra-cutaneous tissue compartments to the skin → clinical correlation: de novo induction of psoriasiform eruptions and hidradenitis suppurativa. (3) TNF-α/IL-10 cytokine imbalance and Tregs and TNFR2 imbalance → clinical correlation: paradoxical cutaneous sarcoidosis and granulomatous disease. (4) Shift in cutaneous immune response pattern → clinical correlation: de novo induction of lichenoid, eczematous PR or change in psoriatic morphology (plaque to pustular). (^∗) Based on expert opinion and on current available clinical and experimental evidence; cutaneous immune response patterns adapted from Eyerich and Eyerich (2018).