Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview

Abstract

Paradoxical adverse events (PAEs) have been reported during biological treatment for chronic immune-mediated diseases. PAEs are defined as the occurrence during biological agent therapy of a pathological condition that usually responds to this class of drug. A wide range of PAEs have been reported including dermatological, intestinal and ophthalmic conditions, mainly with antitumour necrosis factor α (TNF-α) agents. True PAEs include psoriasis, Crohn's disease and hidradenitis suppurativa. Other PAEs may be qualified as borderline and include uveitis, scleritis, sarcoidosis and other granulomatous diseases (granuloma annulare, interstitial granulomatous dermatitis), vasculitis, vitiligo and alopecia areata. Proposed hypotheses to explain these PAEs include an imbalance in cytokine production, the differential immunological properties between the monoclonal antibodies and TNF-α soluble receptor, an unopposed type I interferon production and a shift towards a Th1/Th2 profile. Data from registries suggest that the risk for paradoxical psoriasis is low and non-significant. We discuss management of these PAEs, which depends on the type and severity of the adverse events, pre-existing treated conditions and the possibility of alternative therapeutic options for the underlying disease. Paradoxical adverse events are not restricted to anti-TNF-α agents and close surveillance of new available biological drugs (anti-interleukin-17/23, anti-integrin) is warranted in order to detect the occurrence of new or as yet undescribed events.

Keywords: Anti-TNF; DMARDs (biologic); Sarcoidosis; Treatment.

Figure 1

Palmoplantar pustular psoriasis in a patient with spondyloarthritis under golimumab.

Figure 2

Hidradenitis suppurativa in a 29-year-old woman with Crohn's disease treated with adalimumab.

Figure 3

Sarcoidosis with bilateral hilar lymph node enlargement in a patient with rheumatoid arthritis treated by adalimumab.

Figure 4

Alopecia areata in a patient with psoriasis treated with adalimumab.

Figure 5

Pathogenic mechanisms involved in psoriasiform skin lesions during anti-TNF-α therapy. TNF-α, IL-17 and IFN-α are the main cytokines that contribute to the development of psoriatic lesions. TNF-α inhibits the activity of plasmacytoid dendritic cells (pDC), which are key producers of IFN-α. During anti-TNF-α treatment, there is an unopposed IFN-α production by pDC. In parallel, IFN-α leads to the expression of chemokines such as CXCR3 on T cells, favouring T cell homing to the skin. IFN-α also stimulates and activates T cells to produce TNF-α and IL-17, sustaining inflammatory mechanisms for psoriasis lesions. IFN-α, interferon α; IL-17, interleukin 17; TNF-α, tumour necrosis factor α.

Figure 6

Mechanisms involved in aseptic granulomatous diseases occurring with anti–TNF-α therapy. Anti–TNF-α monoclonal antibodies and the p75 soluble TNF-α receptor have differential immunological properties that may be associated with granuloma formation and thus with the development of granulomatous diseases. Indeed, anti TNF-α monoclonal antibodies induce profound TNF-α inhibition, whereas etanercept partially respects the production of this cytokine. Etanercept is associated with IFN-α production, which contributes to granuloma formation, while anti–TNF-α monoclonal antibodies inhibit IFN-γ release. IFN-α, interferon α; TNF-α, tumour necrosis factor α.