A first case of successful using of ibrutinib in treating paraneoplastic pemphigus related bronchiolitis obliterans concurrent with CLL

Abstract

Paraneoplastic pemphigus (PNP) is a rare life-threatening disease which always associated with an underlying neoplasm. Tumor-related PNP most commonly precedes the detection of a hematological malignancy, with some cases seen during disease remission following cytotoxic drug therapy or radiotherapy. The lung is the most frequently-involved site in PNP, second only to the eyes, and involvement is seen in 59.2% to 92.8% of PNP cases. Bronchiolitis obliterans (BO) is the end stage of respiratory involvement and is regarded as life-threatening. The key point in treatment of PNP is to control the associated underlying hematologic neoplasia. High-dose systemic corticosteroids combined with other immunosuppressants are considered the first line of treatment. Other therapies that have shown beneficial effects include plasmapheresis, intravenous immunogloblin (IVIG), and more recently, daclizumab, alemtuzumab, and rituximab. There is no effective treatment for BO with PNP, and suppression of the cellular immune response may be necessary. Patients with PNP-BO associated with lymphoma mostly die within approximately 1 year. Herein, we reported a patient who diagnosed with PNP-BO concurrent with chronic lymphocytic leukemia. He was successful treated with ibrutinib and had achieved the longest survival which suggested that ibrutinib may be the best treatment choice for such patient.

Keywords: bronchiolitis obliterans; chronic lymphocytic leukemia; ibrutinib; mechanism; paraneoplastic pemphigus.

Figure 1

The patient’s clinical evaluation and treatments. (A) Pemphigus lesions on the skin and lip were extremely severe before treatment. A lymph node biopsy revealed (B) small B-cell lymphoma (magnification, ×400). Positive immunohistochemical results were observed for (C) CD5 (magnification, ×400), (D) CD20 (magnification, ×400), and (E) CD23 (magnification, ×400). Skin biopsy specimens demonstrating intraepidermal vesicle [(F) (magnification, ×200)]. During the treatment of the relapse period, the patient developed shortness of breath and wheezing. (G) At the onset of bronchiolitis obliterans, high-resolution computed tomography revealed hyperinflation and bronchial wall thickening in bilateral lungs. (H) After treatment, the bronchial wall thickening was alleviated. (I) Currently, the skin lesions are healing and the patient is in relatively good health (J).

Figure 2

Potential mechanism of ibrutinib in the treatment of bronchiolitis obliterans (BO). Autoantibodies against plakin and desmoglein proteins could recognize the antigens expressed in stratified squamous epithelia and transitional columnar epithelia. Ibrutinib reduced the production of antibodies by inhibiting special B cell clones or reactive B cells. Chronic lymphocytic leukemia (CLL) cells may impair T-cell effector function, leading to a proliferation of infiltrating CD8+ T lymphocytes invading the bronchiolar walls. Ibrutinib targets CLL, and after treatment, CD8+ T cells decreased significantly. The nitric oxide (NO) pathway plays a significant role in BO, and ibrutinib treatment decreased NO production by downregulating Nos2 expression. Ibrutinib may also inhibit inflammatory changes, including the inflammatory cytokines (IL-6, TNF-a) and vascular endothelial growth factor (VEGF). Green line, promote. Red line, inhibit.