Bruton's tyrosine kinase (BTK) is a cytoplasmic nonreceptor tyrosine kinase that is expressed in B cells, myeloid cells, and platelets. In B cells, BTK activation is associated with B-cell survival, proliferation, and differentiation. Inhibitors of BTK (BTKi, such as ibrutinib, remibrutinib, acalabrutinib, pirtobrutinib, zanubrutinib, and rilabrutinib) play an important role in the treatment of B-cell lymphomas. Beyond lymphoma, ibrutinib is approved for treatment of chronic graft-versus-host disease after failure of one or more lines of systemic therapy, and remibrutinib has been approved for the treatment of chronic spontaneous urticaria. Additionally, rilzabrutinib has been approved for chronic immune thrombocytopenia.

The cutaneous adverse effects of BTKi are mainly due to off-target, non-BTK-mediated effects. For example, ibrutinib can inhibit epidermal growth factor receptor (EGFR), tyrosine-protein kinase Tec, and Rous sarcoma virus Src kinase. As such, less selective first-generation BTKis (eg, ibrutinib) theoretically have more side effects compared to their more selective second- and third-generation counterparts (eg, zanubrutinib, acalabrutinib, pirtobrutinib). In practice and in trials, however, many of these later-generation BTKis are associated with dermatologic adverse effects, although these may be less severe than adverse effects seen with ibrutinib. The most recent BTKis, rilzabrutinib and remibrutinib, may be exceptions. In their clinical trials, both of these medications featured more favorable cutaneous safety profiles.

Cutaneous toxicities are usually noted in the first year of BTKi treatment, with gradually decreasing incidence over time. The most common cutaneous toxicity is bleeding into the skin and consists of bruising, ecchymoses, hematomas, petechiae, and target-like lesions. Moreover, any inflammatory eruption may appear purpuric due to secondary hemorrhage into the skin. Bleeding complications in the setting of BTKis are thought to be secondary to platelet dysfunction related to inhibition of platelet glycoprotein signaling and TEC inhibition involved in platelet activation and aggregation.

Other common dermatologic events related to BTKis include rashes, localized peripheral edema, and nail and hair changes. Rarer events include radiation recall phenomenon, panniculitis, neutrophilic dermatoses (including acute febrile neutrophilic dermatosis, pyoderma gangrenosum, and neutrophilic panniculitis), and mucositis.

Rashes include an asymptomatic petechiae, a papular purpuric eruption typically occurring within the first 15 days of therapy, a pityriasis rosea-like eruption, morbilliform eruptions, rare severe cutaneous adverse eruptions (drug-induced hypersensitivity syndrome [DIHS], Stevens-Johnson syndrome / toxic epidermal necrosis [SJS/TEN]), as well as rashes resembling those seen in the setting of EGFR inhibition such as eczema, xerosis, and papulopustular eruptions. For more information on eczema, xerosis, and papulopustular eruptions seen with EGFR inhibitors, see cutaneous adverse effects of EGFR inhibitors.

Nail and hair changes in the setting of BTKis are common and occur several months after treatment initiation. Reported nail changes include nail brittleness, onychorrhexis, onychoschizia, trachyonychia, splinter hemorrhages, and paronychia that can be associated with periungual pyogenic granulomas similar to those seen with EGFRi therapy. Hair texture and density changes have been reported in some patients, again thought to be related to off-target EGFR effects.

Skin infections are increased in patients treated with BTKis due to both the immunosuppressive effects of the medication as well as the skin barrier defects that can occur due to eczema, xerosis, and other skin eruptions. The most common cause of skin infections in patients treated with BTKis is Staphylococcus aureus, which can present as folliculitis, impetigo, cellulitis, abscess, and potentially staphylococcal scalded skin syndrome. Other reported infections include primary infection with or reactivation of varicella zoster virus (VZV) or herpes simplex virus (HSV) as well as infections with opportunistic organisms, including fungi and nontuberculous mycobacteria.