Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors.

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.

Autoerythrocyte sensitization syndrome (Gardner-Diamond syndrome) associated with cutaneous vasculitis.

Autoerythrocyte sensitization syndrome (ASS) (Gardner-Diamond syndrome) is characterized by painful ecchymotic lesions affecting mostly women with emotional stress. Although it is widely accepted as a non-inflammatory disease, ASS can be accompanied by some autoimmune diseases. In this case report, we present a case with ASS associated with cutaneous vasculitis. We also briefly discuss the possible inflammatory features of ASS.

Autoerythrocyte sensitization (Gardner-Diamond) syndrome.

We describe the clinical presentation and course of a patient with autoerythrocyte sensitization (Gardner-Diamond) syndrome, and review the literature for similar cases. A 37-yr-old female presented with recurrent episodes of painful ecchymotic bruising over the anterior aspect of both thighs. These episodes were precipitated by emotional stress. The diagnosis was confirmed by induction of similar lesions by intradermal injection of the patient's own washed red blood cells and hemoglobin. The lesions did not recur for 6 months after the cause of her emotional stress was relieved. Autoerythrocyte sensitization (Gardner-Diamond) syndrome should be considered in the differential diagnosis of purpura, especially in patients with psychiatric problems.

Autoerythrocyte sensitization syndrome with thrombocytosis.

A case of autoerythrocyte sensitization syndrome in a 59-year-old female is reported. She had several episodes of circular ecchymoses on her left thigh. Intradermal injection of autoerythrocytes reproduced a similar ecchymosis. Thrombocytosis was detected and treated with busulfan which induced a delayed improvement of the ecchymosis outbreaks over 2 years of follow-up.

[Spontaneous ecchymosis disclosing acquired factor VIII inhibitor]. / Ecchymoses spontanées révélatrices d'un inhibiteur acquis du facteur VIII.

An 81-year old woman suddenly developed extensive ecchymosis. A factor VIII:c inhibitor was detected. She received porcine factor VIII, corticosteroids, intravenous immunoglobulins and cyclophosphamide. Normalization of factor VIII level was achieved in 1 month. The patient died, 3 months later, of congestive heart failure. Spontaneous development of factor VIII inhibitors is an extremely rare event which usually occurs in dramatic bleeding. Many associated diseases have been reported. Patients with serious bleeding should be given porcine factor VIII. Immunosuppressive therapy consists of corticosteroids, cyclophosphamide and intravenous immunoglobulins.

[The blue spots syndrome]. / Syndrom der blauen Flecken.

Chronic relapsing painful ecchymoses occurring in female patients are described as the painful bruising syndrome. Several authors postulate, that the cause of this disease may be due to sensitization to autologous erythrocytes, whereas others suggest an artificial origin. A 24 year-old woman with this disease was tested intracutaneously with autologous and homologous erythrocytes, erythrocyte stroma and phosphatidyl-L-serine. Her reactions were inconsistent. Control persons could produce similar painful ecchymotic reactions to autologous erythrocytes by manipulation of the tested areas. These results provide evidence that the painful bruising syndrome is not due to autosensitization, but is an artificial phenomenon.

Autosensitization to DNA.

The spontaneous occurrence of widespread ecchymoses in a patient not exhibiting coagulopathy leads to a spectrum of differential diagnoses including amyloidosis, anaphylactoid purpura, pseudoxanthoma elasticum, Ehlers-Danlos syndrome, autoerythrocyte sensitization and autosensitization to DNA (11). This paper reports on a patient exhibiting the characteristic clinical findings and skin reactivity indicative of DNA autosensitization. The syndrome will be discussed briefly with particular reference to the differential diagnosis to autoerythrocyte sensitization.

Autosensitization to DNA: evidence for an immunologic basis.

A 59-year-old female with spontaneous painful ecchymoses developed ecchymoses after intracutaneous injection of washed autologous whole blood cells and calf thymus DNA. Immunofluorescent studies of the spontaneous lesions revealed granular deposits of IgM, C3, factor B and properdin at the dermal-epidermal junction but no deposits in her normal skin. T cells were decreased in number but responded normally to polyclonal mitogens and did not transform in response to DNA containing antigens. Repair of UV-damaged DNA by her lymphocytes appeared to be depressed. The findings presented here are the first immunologic abnormalities uncovered in this disorder and may help in understanding the pathogenesis of the inflammatory lesions seen in autosensitization to DNA.

Decreased serum complement in the Gardner-Diamond syndrome: immunofluorescent findings and association with angioimmunoblastic lymphadenopathy.

Immunologic and immunofluorescent profiles of two patients with the Gardner-Diamond syndrome are described. During the time ecchymoses were present, both patients had decreased serum complement levels; when the lesions healed, the serum complement level returned to normal. One patient had associated angioimmunoblastic lymphadenopathy and subepidermal deposits of immunoglobulin IgM at the basement membrane of ecchymotic skin. The other patient had a normal immunofluorescent pattern. Both patients had increased B-cell counts. The association of immunologic and immunofluorescent findings in patients with the Gardner-Diamond syndrome is suggestive and deserves further study.