202 Correspondence

prior to starting ECP. Although it is difficult to make therapeutic recommendations based on a single report, we believe that ECP offers another possible therapeutic approach to STMF, especially in disease that is multifocal or generalized or in disease where typical first-line agents (e.g. phototherapy) may not be effective.

Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations DOI: 10.1111/bjd.12548


Department of Dermatology, Dermatopathology Section, Department of Dermatology, and 3Department of Hematology and Medical Oncology, Boston University Medical Center, Boston, MA 02118, U.S.A. Correspondence: Thomas M. R€unger. E-mail: [email protected] 2



References 1 Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768–85. 2 Phan NQ, Blome C, Fritz F et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol 2012; 92:502–7. 3 Talpur R, Demierre MF, Geskin L et al. Multicenter photopheresis intervention trial in early-stage mycosis fungoides. Clin Lymphoma Myeloma Leuk 2011; 11:219–27. 4 Pileri A, Facchetti F, Rutten A et al. Syringotropic mycosis fungoides: a rare variant of the disease with peculiar clinicopathologic features. Am J Surg Pathol 2011; 35:100–9. 5 Yost JM, Do TT, Kovalszki K et al. Two cases of syringotropic cutaneous T-cell lymphoma and review of the literature. J Am Acad Dermatol 2009; 61:133–8. 6 Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004; 18:397–415. 7 Gerami P, Rosen S, Kuzel T et al. Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008; 144:738–46. 8 Thein M, Ravat F, Orchard G et al. Syringotropic cutaneous T-cell lymphoma: an immunophenotypic and genotypic study of five cases. Br J Dermatol 2004; 151:216–26. 9 Tannous Z, Baldassano MF, Li VW et al. Syringolymphoid hyperplasia and follicular mucinosis in a patient with cutaneous T-cell lymphoma. J Am Acad Dermatol 1999; 41:303–8. 10 Venturini A, Zane C, Rodella R et al. Syringotropic cutaneous T cell lymphoma treated with PUVA therapy. Eur J Dermatol 2005; 15:262–4. 11 Edelson R, Berger C, Gasparro F et al. Treatment of cutaneous Tcell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 1987; 316:297–303. 12 Knobler R, Duvic M, Querfeld C et al. Long-term follow-up and survival of cutaneous T-cell lymphoma patients treated with extracorporeal photopheresis. Photodermatol Photoimmunol Photomed 2012; 28:250–7. Funding sources: none. Conflicts of interest: none declared.

British Journal of Dermatology (2014) 170, pp200–227

DEAR EDITOR, Generalized pustular psoriasis (GPP) may be caused by homozygous or compound heterozygous mutations in the gene IL36RN, which codes for interleukin-36 receptor antagonist (IL-36Ra).1,2 Such mutations are present in approximately 40% of patients with GPP in Germany.3 Anakinra, an interleukin (IL)-1 receptor antagonist, has been described as an effective treatment against GPP in several cases.4 However, there are no published data on whether anakinra is also effective in the subgroup of patients with GPP carrying IL36RN mutations. Here, we report the first case of a patient with GPP carrying IL36RN mutations who responded well to therapy with anakinra. Three years ago, a 47-year-old woman presented with a history of plaque-type psoriasis and GPP for 7 years. Skin lesions had started with scaly erythema on the elbows. Later, more widespread erythema with multiple pustules developed, particularly on her hands and feet. Over the years, the involved body surface area and the frequency of flares increased. Prior therapies included methotrexate for 3 years and ciclosporin. On her first presentation, we diagnosed liver cirrhosis, presumably due to ethanol consumption and methotrexate, and oral therapy with vitamin K was started. Molecular genetics analyses revealed compound heterozygosity for two mutations in IL36RN: c.142C>T/p.Arg48Trp and c.338C>T/p.Ser113Leu (patient P06 in K€ orber et al.),3 with one mutation transmitted from each healthy parent. We treated the patient with etanercept (50 mg subcutaneously twice weekly) for 4 months, without sufficient control of symptoms. Therefore, we switched the tumour necrosis factor blocker to adalimumab (40 mg subcutaneously every other week), and the patient reported a considerable improvement of her symptoms, with a flare 5 months after initiation. After 15 months of therapy with adalimumab, she presented again with a severe flare of GPP that had been preceded by a gastrointestinal tract infection. Skin lesions improved only moderately under additional topical therapy. One month later, the patient presented with erythroderma with disseminated massive exudative crusts (Fig. 1a). Her body temperature was 380 °C. The patient was in a poor general condition and reported chills and a burning feeling in the bladder during urination. Her C-reactive protein (CRP) level was 652 mg L l (n ≤ 5) and her leucocyte count was 301 9 109 cells L 1 (n = 4–11); parathyroid hormone was normal. A serum concentration of adalimumab below the threshold of detection and highly increased IgG antibodies

© 2013 British Association of Dermatologists

Correspondence 203



Fig 1. Clinical pictures of the patient (a) upon admission and (b) 22 weeks after the start of therapy with anakinra.

against adalimumab (14 000 AU mL 1; n < 12) strongly suggested a loss of therapeutic efficacy due to formation of antidrug antibodies, and therapy with adalimumab was discontinued. We treated the patient with intravenous cefuroxime, and with oral pulse therapy with prednisolone, starting at 60 mg daily and tapered over the following 6 weeks. In addition, ascites and hypoalbuminaemia were noted and treated symptomatically. As clinical improvement was not sufficient 9 days after admission, therapy with subcutaneous anakinra 100 mg daily was started. Upon discharge 9 days later, no new pustules had appeared for several days, the leucocyte count had decreased to 148 9 109 cells L 1 and CRP was normal. When the patient presented 16 weeks after initiation of therapy with anakinra, her skin had been almost clear for 6 weeks, except for erythema, nail dystrophy, hyperkeratosis and multiple vesicles of about 1 mm in diameter on her hands and feet. The patient reported to feel very well, and CRP and leucocytes were normal. Another 6 weeks later, some erythrosquamous plaques on the trunk and legs had appeared, and palmoplantar hyperkeratosis and pustules had worsened, while no pustules had reappeared on the rest of the integument (Fig. 1b). The cytokines IL-36a, b and c are members of the IL-1 family. They are abundantly expressed in the skin and activate nuclear factor-jB signalling. They use the same receptor, IL-36R, which is coupled with the IL-1 accessory protein – a common subunit shared with IL-1R and IL-33R.5 IL-36Ra antagonizes proinflammatory signals of IL-36a, b and c at IL36R, analogous to the effect of IL-1Ra inhibition of IL-1 responses.6 GPP in our patient was caused by IL36RN mutations and was triggered or aggravated by infections and possibly liver insufficiency7 and hypoalbuminaemia. The patient responded well to anakinra. However, it remains to be clarified how anakinra can abrogate detrimental effects of IL-36Ra insufficiency. It is conceivable that the favourable effect of anakinra is due to its activity on IL-1R as a downstream target of IL-36 cytokines. Stimulation of peripheral blood mononuclear cells with IL-36a in a patient with homozygous mutations in IL36RN © 2013 British Association of Dermatologists

compared with a healthy control patient led to a higher expression of cytokines including IL-1a.1 Thus, possibly, targeting of IL-1R by anakinra might be sufficient to interrupt the inflammatory cascade in some patients with GPP. A direct inhibitory effect of IL-1Ra on IL-36R appeared less likely.8 It will be interesting to correlate causal mutations with the therapeutic responses of patients with GPP to drugs affecting the IL-1 and IL-36 pathways. 1

Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany 2 Department of Dermatology, Venereology and Allergology, University Medical Center G€ottingen, Robert-Koch-Strasse 40, D-37075 G€ottingen, Germany Correspondence: Rotraut M€ossner. E-mail: [email protected]

U . H U€ F F M E I E R 1 M . W A€T Z O L D 2 J. MOHR2 M . P . S C H O€ N 2 R . M O€ S S N E R 2

U.H. and M.W. contributed equally to this work.

References 1 Onoufriadis A, Simpson MA, Pink AE et al. Mutations in IL36RN/ IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89:432–7. 2 Marrakchi S, Guigue P, Renshaw BR et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365:620–8. 3 K€orber A, M€ ossner R, Renner R et al. Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol 2013; 133:2634–7. 4 Viguier M, Guigue P, Pages C et al. Successful treatment of generalized pustular psoriasis with the interleukin-1-receptor antagonist Anakinra: lack of correlation with IL1RN mutations. Ann Intern Med 2010; 153:66–7. 5 Towne JE, Sims JE. IL-36 in psoriasis. Curr Opin Pharmacol 2012; 12:486–90. 6 Cowen EW, Goldbach-Mansky R. DIRA, DITRA, and new insights into pathways of skin inflammation: what’s in a name? Arch Dermatol 2012; 148:381–4. British Journal of Dermatology (2014) 170, pp200–227

204 Correspondence 7 Zhu KJ, Zhu CY, Fan YM. Alcohol consumption and psoriasis risk: a meta-analysis of case–control studies. J Dermatol 2012; 39:770–3. 8 Towne JE, Renshaw BR, Douangpanya J et al. Interleukin-36 (IL36) ligands require processing for full agonist (IL-36a, IL-36 b, and IL-36c) or antagonist (IL-36Ra) activity. J Biol Chem 2011; 286:42594–602. Funding sources: none. Conflicts of interest: R.M. and M.P.S. have received payments for conduction of clinical trials, as invited speaker or advisor, or for travel grants from the following companies: Abbott GmbH & Co. KG, Biogen IDEC GmbH, Essex Pharma GmbH, Janssen-Cilag, LEO Pharma GmbH, Merck Serono GmbH, Novartis Pharma GmbH, Pfizer GmbH and Wyeth Pharma GmbH. M.P.S. has received research grants from Abbott and BiogenIdec, and has received consulting fees from Abbott, BiogenIdec, Janssen-Cilag, LEO Pharma, Novartis Pharma and Pfizer.

A case of CD8+ small/medium-sized pleomorphic T-cell lymphoma: clinical and histopathological differential diagnosis DOI: 10.1111/bjd.12549 DEAR EDITOR, CD8+ lymphoid proliferation is a rare type of cutaneous T-cell lymphoma.1 Recently, CD8+ lymphoid proliferations that usually present with solitary, slow-growing nodules on the face or ear, and which resolve after treatment, have raised the possibility of a distinct entity, although the prognostic influence of the CD8 phenotype is still unclear. Irrespective of the histopathological appearance suggesting a high-grade lymphoma in some cases, clinical behaviour should be the main basis for the determination of treatment.2,3 A 60-year-old female patient was admitted with the complaint of progressively increasing red and swollen lesions on her face. Histopathological examination of the initial biopsy, performed 6 years previously, had been compatible with rosacea; a partial regression occurred with rosacea treatments. However, more prominent lesions recurred at almost the same (a)


sites after nearly 1 year. A second biopsy exhibited ‘perifollicular lymphoid infiltration’. The patient had no drug history. A partial regression has been noticed with intralesional steroid injections. Dome-shaped, discrete nodules, bright pink in colour, involved the forehead, nasolabial folds and cheeks – prominently confined to sun-exposed areas (Fig. 1). The main characteristics of the clinical picture suggested a photoinduced dermatosis. Our first skin biopsy was interpreted as ‘cutaneous lymphoproliferative lesion with CD8+ cytotoxic phenotype’. Peripheral T-cell lymphoma and actinic reticuloid were proposed in the differential diagnosis. We did not detect the characteristic photosensitivity when applying photopatch test using ultraviolet (UV) A and UVB. There was partly diffuse or patchy infiltration within the dermis and subcutaneous fatty tissue, composed of small-to-medium-sized lymphoid cells with oval or round nuclei, dark chromatin and scant cytoplasm. The epidermis was spared and a subepidermal Grenz zone was prominent in the upper dermis. All T cells were CD3+, CD2+, CD5+ and CD8+. While immunoreactivity with granzyme-B and TIA-1 was identified in most of the lymphoid cells, they were negative for CD4, CD7 and CD56. The proliferative activity with Ki67 was 5% (Fig. 2). A clonal T-cell population was not encountered using BIOMED 2 (http://cordis.europa.eu/ biomed/). The patient was investigated for systemic involvement. b2Microglobulin was 1749 mg L 1; human immunodeficiency virus was negative; other biochemical tests, and thoracal and neck tomography scans were normal. There was no association with Epstein–Barr virus. Using flow cytometry, the cell count was very low; in CD45/side scatter graphs, the percentages of lymphocyte, granulocyte, monocyte and CD45– cells were 23%, 69%, 5% and 2%, respectively; in forward scatter/side scatter graphs, the percentage of T lymphocytes was 66%. There was an increase (36–37%) of natural killer cells and the ratio of CD4+/CD8+ T lymphocytes was normal. Topical steroid and retinoid–psoralen plus UVA (PUVA) provided a remarkable resolution of lesions after 4 weeks. Because new formation of infiltrated papular lesions was


Fig 1. (a) Firm, pinky-red, shiny, hemispherical, infiltrative papules and nodules located on the forehead; (b) infiltrative papules and nodules restricted to sun-exposed areas are noteworthy; (c) almost complete response after treatment, with residual grouped papules. British Journal of Dermatology (2014) 170, pp200–227

© 2013 British Association of Dermatologists

Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations.

202 Correspondence prior to starting ECP. Although it is difficult to make therapeutic recommendations based on a single report, we believe that ECP...
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