How does nivolumab (Opdivo) cause psoriasis flares in patients with a history of psoriasis?

Mechanism of Nivolumab-Induced Psoriasis Flares

Nivolumab causes psoriasis flares through immune dysregulation by blocking the PD-1 pathway, which removes inhibitory signals on T cells and allows uncontrolled T-cell activation against self-antigens in the skin, triggering or exacerbating psoriatic inflammation. 1

Immunologic Mechanism

The fundamental mechanism involves checkpoint inhibitor-mediated loss of immune tolerance:

• Nivolumab binds to the PD-1 receptor on T cells and blocks the inhibitory PD-1/PD-L1 pathway, which normally functions to dampen T-cell responses and maintain peripheral tolerance 2, 3
• This blockade removes the "brakes" on cytotoxic T cells, allowing them to become hyperactivated and attack not only tumor cells but also normal tissue antigens 2, 4
• The deregulation of immune tolerance specifically enables autoreactive T cells to target keratinocytes and trigger the inflammatory cascade characteristic of psoriasis 2

Cytokine dysregulation plays a central role in the pathophysiology:

• Patients who develop psoriasiform dermatitis after nivolumab demonstrate significantly increased serum IL-6 levels, a key pro-inflammatory cytokine in psoriasis pathogenesis 5
• All six patients who developed psoriasiform dermatitis in one study exhibited elevated IL-6 after nivolumab treatment, compared to decreased IL-6 in non-afflicted patients 5
• This cytokine shift creates a pro-inflammatory milieu that favors psoriatic plaque formation 5

Clinical Patterns and Risk Factors

Both exacerbation of pre-existing psoriasis and de novo psoriasis can occur:

• The American Academy of Dermatology guidelines note that unmasking or worsening of psoriasis has been reported during treatment with PD-1 inhibitors, with more frequent flare of pre-existing autoimmune disease 1
• ESMO guidelines report that exacerbation of psoriasis has been anecdotally reported with checkpoint inhibitors, as well as psoriasiform skin reactions in patients without any history of such skin disease 1
• De novo psoriasis after nivolumab is a rare entity but well-documented, particularly with palmoplantar involvement 2, 3, 6

Personal and family history of psoriasis are significant risk factors:

• Patients with a history of autoimmune disease are at risk for worsening of their autoimmune disease while on immune checkpoint blockade 1
• Not only personal but also related family history of psoriasis are significant risk factors that need to be outlined before treatment initiation 4
• One case series found that 3 out of 5 patients who developed psoriasis flares had either active psoriatic lesions, past history of psoriasis, or strong family history (3/5 siblings with psoriasis) 4

Temporal Characteristics

Psoriasis typically develops after multiple treatment cycles:

• Skin rashes appeared in all patients after the fourth cycle of immunotherapy in one case series 4
• Onset of skin immune-related adverse events with PD-1 inhibitors typically occurs later than with anti-CTLA4 antibodies 1
• Cases have been reported after as few as 2 doses or as many as 11 doses of nivolumab 5, 6

Clinical Presentation Patterns

Guttate and palmoplantar patterns are particularly common:

• Four out of 5 patients in one series experienced guttate lesions 4
• Severe palmoplantar psoriasis with nail involvement has been reported as a predominant pattern 2, 6
• Associated psoriatic arthritis can develop concurrently with cutaneous manifestations 6

Important Clinical Caveats

The severity and management approach differ from typical drug-induced psoriasis:

• Most dermatologic immune-related adverse events are low-grade and manageable, though severe cases requiring treatment modification can occur 1
• Systemic corticosteroids are required in 100% of patients with immune-mediated rash according to FDA labeling data 7
• Four out of 5 patients in one series managed to continue nivolumab treatment after close dermatologic monitoring, demonstrating that psoriasis flares don't always necessitate permanent discontinuation 4

Strict skin surveillance is essential for patients with risk factors:

• If personal or family history of psoriasis exists, strict skin surveillance can lead to early diagnosis and treatment of psoriatic exacerbations that could otherwise severely affect quality of life or compromise therapeutic protocols 4
• Baseline dermatologic assessment is warranted in patients with a known history of immune-related skin disorders such as psoriasis 1