A patient with ankylosing spondylitis is treated with adalimumab. Paradoxically, she develops a new-onset pustular psoriasis. This exemplifies a reaction known as a 'paradoxical adverse effect of anti-TNF therapy.' Which cytokine pathway, upregulated when TNF is blocked, best explains TNF-blocker-induced psoriasis?

• A IL-17/IL-23 Th17 pathway — amplified by type I interferon induction when TNF is blocked, driving neutrophil-rich psoriasiform inflammation ✓
• B IL-4/IL-13 Th2 pathway — unopposed after TNF blockade, causing atopic dermatitis-like psoriasiform reaction
• C IL-2 Treg depletion — TNF blockade impairs regulatory T cells, unleashing CD8 cytotoxic psoriasis
• D B-cell hyperactivation — anti-TNF produces drug-induced lupus-like immune complex psoriasiform dermatitis

Explanation

Paradoxical psoriasis during anti-TNF therapy is a well-recognized phenomenon. The mechanistic basis involves: anti-TNF therapy enhancing plasmacytoid dendritic cell (pDC) production of type I interferons (IFN-alpha/beta), which in turn promote Th17 polarization. Elevated IL-17A and IL-23 then drive psoriasiform skin changes. Since TNF normally suppresses pDC IFN-alpha production, its blockade disinhibits IFN-alpha, amplifying the IL-17/IL-23 axis. This paradox also explains why switching from anti-TNF to anti-IL-17 agents (secukinumab, ixekizumab) resolves the paradoxical psoriasis.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.