Enikő Kuroli

Gábor Hegede

Judit Csomor

Judit Hársing

Márta Marschalkó

Márta Medvecz

Norbert Kiss

Sarolta Kárpáti

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202 ACTA DERMATOVENEROLOGICA CROATICAActa Dermatovenerol Croat                     2019;27(3):202-204                            LETTER TO THE EDITORLymphomatoid Papulosis Type B in a Patient with Crohn’s Disease Treated with TNF-Alpha Inhibitors  Infliximab and AdalimumabDear Editor,Lymphomatoid papulosis (LP) is a chronic, recur-rent, usually self-limited papulonecrotic or papulo-nodular skin disease, which belongs to the group of primary cutaneous CD30+ lymphoproliferative disor-ders (1). Three main histological subtypes of LP have been recognized: type A (histiocytic), type B (myco-sis fungoides-like), and type C (anaplastic large cell lymphoma-like). Recently, new histologic LP variants classified as type D (CD8-positive, cytotoxic form) and type E (angioinvasive form) have also been described. The etiology of LP has not been determined to date (2-4). Herein we report a case of LP type B evolving in a patient with Crohn’s disease after treatment with infliximab and adalimumab. A 38-year-old man suffering from terminal ileitis form of luminar Crohn’s disease for 10 years present-ed at our department. During the last 10 years, the patient had been treated with a number of conven-tional disease-modifying anti-inflammatory drugs including non-steroid anti-inflammatory drugs, me-salazine, and immunomodulatory agents such as cor-ticosteroids and azathioprine. As the disease was not sufficiently controlled, TNF-α inhibitor therapy was initiated. Infliximab was administered in standard dosage (5 mg/kg body weight every 8 weeks after the induction period) for one year. Concomitant ther-apy with azathioprine was established to reduce the risk of adverse immunological reactions. Since the patient showed only partial clinical response, inflix-imab was switched to adalimumab (40 mg biweekly), resulting in notable improvement. 18 months after the initiation of adalimumab treatment, asymptom-atic, small, red to brown papules developed on the extremities. Multiple lesions were observed, initially on the legs, but the symptoms rapidly progressed to the arms and trunk (Figure 1). An acquired ichthyosis further complicated the disease course by extended, extremely xerotic, scaling skin lesions. Neither sys-temic symptoms nor significant lymphadenopathy was observed. Figure 1. Clinical manifestation. (a) Multiple papules on the legs. (b) Scaling papules with a crusted necrotic center.203ACTA DERMATOVENEROLOGICA CROATICALetter to the editor Acta Dermatovenerol Croat    2019;27(3):202-204The clinical picture suggested either ichthyosi-form mycosis fungoides or a coincidence of LP and acquired ichthyosis. The histology of a typical papule showed perivascular and periadnexal lymphoid infil-tration with massive hemorrhage in the dermis. The infiltration was dense, composed of small-to-medium-sized lymphoid cells showing focal significant epider-motropism (Figure 2). Most observed epidermal lym-phocytes were CD3+, CD4+, and CD30+, while the dermal infiltration had higher CD4 and lower CD30 expression (10-15%). Polymerase chain reaction (PCR) analysis of skin and peripheral blood samples did not show clonal rearrangement of T-cell receptor gamma (TcRgamma) genes. Normal phenotypes of lympho-cyte subsets were detected by flow cytometry of pe-ripheral blood. Ichthyosiform mycosis fungoides was excluded since histology of ichthyosiform skin lesions showed only hyperkeratosis with a reduced granular layer. While the cutaneous CD4+ epidermotropic in-filtrate was suspicious of either mycosis fungoides or LP type B, the complexity of clinicopathological data confirmed the diagnosis of LP type B. The peripheral blood counts, serum biochemical tests, and urinalysis were within normal range, while the elevated serum anti-Saccharomyces cerevisiae antibodies (ASCA) of IgG and IgA subclasses indicated the activity of Crohn’s disease. Adalimumab and azathioprine were discontinued, and oral budesonide therapy was start-ed in combination with topical corticosteroids and PUVA phototherapy. The skin lesions resolved with hyperpigmentation, and there was no relapse during the twelve-month follow-up.Recent data suggest that LP occurs more com-monly in immunocompromised patients, especially in those with solid organ or bone marrow trans-plants (3). Though TNF-α inhibitors have dramati-cally advanced the treatment of various diseases, the risk of lymphoma associated with their use remains controversial (5). Several cases of cutaneous lym-phoproliferative disorders associated with TNF-α in-hibitor treatment have been reported, including two patients with LP (6). One of the two patients with LP received infliximab for Crohn’s disease (7), while the other one had juvenile rheumatoid arthritis and re-ceived adalimumab (8). Our case is the third report on LP developing under TNF-α inhibitor therapy and the first LP type B in a patient with Crohn’s disease treated with infliximab and later with adalimumab. A further interesting aspect of our case is that it also represents an example of the known association of acquired ichthyosis with inflammatory bowel disease (9). Multidisciplinary management was needed to provide optimal care and disease outcome for our patient. Since it is usually difficult to prove causality in most of such cases, it is important to collect similar clinical observations.   Acknowledgments:The authors are grateful to Dr. László Bene, Dr. József Szakonyi, and Dr. Fruzsina Kovács for addi-tional medical care of the patient and to Tamás Szaák for the clinical photos. The authors thank Prof. Miklós Sárdy for his critical review of the paper.References:1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for Figure 2. Histopathology showing perivascular and periadnexal dense, small-to-medium sized lymphoid cell infiltration with focal epidermotropism, and hemorrhage (hematoxylin and eosin staining (HE), ×100 magnification). (a) Epidermotropic infiltration by small-to-medium sized atypical lymphocytes (HE, original magnification ×100). (b-d) Immunohistochemical staining of infiltrating lymphocytes for (b) CD3, (c) CD4 and (d) CD30 (×100 magnification).204 ACTA DERMATOVENEROLOGICA CROATICAcutaneous lymphomas. Blood. 2005;105:3768-85.2. Macaulay WL. Lymphomatoid papulosis. A conti-nuing self-healing eruption, clinically benign-his-tologically malignant. Arch Dermatol. 1968;97:23-30.3. Kempf W, Pfaltz K, Vermeer MH, Cozzio A, Ortiz-Romero PL, Bagot M, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoprolife-rative disorders: lymphomatoid papulosis and pri-mary cutaneous anaplastic large-cell lymphoma. Blood. 2011;118:4024-35.4. Marschalko M, Gyongyosi N, Noll J, Karolyi Z, Wi-konkal N, Harsing J, et al. Histopathological aspec-ts and differential diagnosis of CD8 positive lymp-homatoid papulosis. J Cut Pathol. 2016;43:963-73.5. Kawalec P, Mikrut A, Wisniewska N, Pilc A. Tumor necrosis factor-alpha antibodies (infliximab, ada-limumab and certolizumab) in Crohn’s disease: systematic review and meta-analysis. Arch Med Sci. 2013;9:765-79.6. Martinez-Escala ME, Posligua AL, Wickless H, Ruth-erford A, Sable KA, Rubio-Gonzalez B, et al. Pro-gression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol. 2018;78:1068-76.7. Outlaw W, Fleischer A, Bloomfeld R. Lymphoma-toid papulosis in a patient with Crohn’s disease treated with infliximab. Inflamm Bowel Dis. 2009;15:965-6.8. Park JH, Lee J, Lee JH, Lee DY, Koh EM. Lympho-matoid papulosis in a patient treated with adali-mumab for juvenile rheumatoid arthritis. Derma-tology. 2012;225:259-63.9. Katsanos KH, Stergiopoulou C, Tzambouras N, Zioga A, Tsianos GV, Hatzis J, Tsianos EV. Acquired ichthyosis in ulcerative colitis. Annals Gastroente-rol. 2004;17:413-6.Márta Medvecz1, Norbert Kiss1, Judit Hársing1, Enikő Kuroli1, Gábor Hegede2, Judit Csomor3, Sarolta Kárpáti1, Márta Marschalkó11Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary 2Department of Gastroenterology, Péterfy Sándor Hospital, Budapest, Hungary31st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, HungaryCorresponding author:Márta Medvecz, MD, PhDDepartment of Dermatology, Venerology and DermatooncologySemmelweis UniversityMária utca 411085 BudapestHungarymedvecz.marta@med.semmelweis-univ.huReceived: January 16, 2019Accepted: August 2, 2019Letter to the editor Acta Dermatovenerol Croat    2019;27(3):202-204

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Lymphomatoid papulosis type B in a patient with Crohn\u27s disease treated with TNF-alpha inhibitors infliximab and adalimumab

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Lymphomatoid papulosis type B in a patient with Crohn\u27s disease treated with TNF-alpha inhibitors infliximab and adalimumab

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