Generalized syringotropic mycosis fungoides responsive to extracorporeal photopheresis DOI: 10.1111/bjd.12547 DEAR EDITOR, Syringotropic mycosis fungoides (STMF), a rare variant of mycosis fungoides (MF) and a subtype of follicular MF based on current classification,1 classically presents with punctate erythematous papules or plaques on the trunk or limbs, often with alopecia or anhidrosis, and typically follows an indolent clinical course. Because of the perieccrine localization of the dermal infiltrates, STMF is often less responsive to skin-targeted therapies than classic MF, and given the rarity of the disease there is no accepted treatment approach, especially for those with generalized disease. A 72-year-old white man presented with a 10-year history of generalized severe pruritus, scored as 10/10 on the numerical rating scale (NRS),2 with erythematous papules and plaques on his trunk and extremities, associated with generalized patchy hair loss. He reported no improvement with topical corticosteroids or emollients. Clinical examination revealed erythematous plaques, folliculotropic papules with perifollicular erythema (Fig. 1a) and large, open comedones on his upper mid-back, flanks and thighs, amounting to a body surface area involvement of 15%. There was focal alopecia of the frontal and temporal scalp, without loss of follicular orifices, and diffuse thinning of the eyebrows and body hair. There was no evidence of organomegaly or lymphadenopathy on clinical examination. Routine
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laboratory testing, lactic dehydrogenase and flow-cytometric analysis of circulating T-cell subsets were normal. Several skin biopsies were performed, sampling the most prominent erythematous plaques on his back, a large comedone on his forearm and an area of alopecia on the temporal scalp. The unifying features in all biopsies were the presence of a moderate to dense perieccrine atypical lymphocytic infiltrate with exocytosis into the eccrine structures (Fig. 2a,b). In addition, a biopsy taken from an area with follicular prominence and perifollicular erythema revealed superficial perifollicular lymphocytic infiltrates. There was no evidence of scarring. Immunohistochemical stains revealed a CD3+ infiltrate, the majority of which was CD4+ admixed with few CD8+ cells. T-cell receptor (TCR) rearrangement studies revealed a clonal population of T lymphocytes. Based on clinical presentation, the histopathological findings and TCR studies, a diagnosis of STMF stage 1b (T2N0M0) was made. The treatment options for generalized STMF were discussed with the patient. Phototherapy [narrowband ultraviolet (UV) B] and photochemotherapy [psoralen plus UVA (PUVA)] were considered, but deemed unlikely to be effective given the location of the deep dermal syringotropic infiltrates. The patient was also unable to commit to the frequency of phototherapy treatment sessions. Given its systemic treatment approach, excellent tolerability and very low rate of adverse events, extracorporeal photopheresis (ECP) was started for two consecutive days every 4 weeks,3 while continuing application of topical steroids. After cycle three, the patient demonstrated
Fig 1. Response to treatment. (a) Before treatment showing the largest and thickest plaque on the mid-upper back with erythematous punctate papules. Large, open comedones with punctate perifollicular erythema are also seen at the medial border of the plaque. Similar lesions were present on the flanks, thighs and arms. (b) After treatment showing resolution of the plaque after six cycles of extracorporeal photopheresis, associated with almost complete resolution of the previously severe pruritus. Scars within the patch are secondary to skin biopsies. In other affected areas, all papules and plaques also resolved. Regrowth of hair was noted in areas of prior hair loss, including the scalp, eyebrows, nose, chest, arms and legs. 200
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Fig 2. (a, b) A total of six biopsies were taken from different areas, all showing moderate to dense perieccrine atypical lymphocytic infiltrates with exocytosis into the eccrine structures; original magnification: (a) 920; (b) 9100. Occasional multinucleated giant cells and papillary dermal fibrosis were also observed. A band-like lymphocytic infiltrate with epidermotropism and focal intraepidermal aggregates of lymphocytes was seen in only one biopsy (from the thick plaque on the mid-back) and perifollicular involvement in another biopsy (from the lower back). The latter supported the clinical suspicion of follicular involvement, as suggested by generalized alopecia, perifollicular erythema and comedone formation. Gene rearrangement studies revealed a clonal population of T-lymphocytes with rearranged T-cell receptor-c.
mild improvement, with flattening of the papules and plaques, but erythema and pruritus (NRS 7/10) persisted. After cycle six he had almost complete resolution of his pruritus (NRS 1/ 10), with clearance of all papules and plaques, combined with a reduction in the number of comedones and perifollicular inflammation (Fig. 1b). In addition, there was slow return of hair growth, especially on the chest, legs and temporal scalp. For the next 15 months the patient remained stable on a monthly ECP regimen; however, he subsequently developed slow but progressive recurrence of pruritus. Oral bexarotene was commenced in addition to ECP,3 which promptly controlled his disease. He is now stable on monthly ECP and oral bexarotene 225 mg daily, 24 months after diagnosis. This report of STMF demonstrates classic clinical features of this rare entity: punctate erythematous papules and plaques, pruritus, alopecia and an indolent clinical course. It is classically thought to present with solitary lesions,4 but on review of the 38 reported cases, approximately half of these were described as having multifocal or generalized disease. Our patient also presented with generalized disease, with scattered papules, plaques and significant hair loss at multiple sites. Large, open comedones, a striking feature on clinical examination in our patient, have been described in only one other report.4 Syringotropic mycosis fungoides often exhibits concomitant involvement of the hair follicles. It was therefore not surprising that our patient demonstrated patchy alopecia, perifollicular punctate erythema, with histological evidence of follicular involvement. It is a source of debate as to whether STMF and folliculotropic MF are two distinct diseases or whether they are part of the same spectrum. Yost et al.5 suggested that the former seemed more likely, because of a more favourable prognosis of STMF. Folliculotropic MF is known to have poor prognosis, with 5- and 10-year survival rates of 68% and 26%,6 and early-stage disease overall survival of 41%, much lower than the reported 91% with early-stage classic MF.7 © 2013 British Association of Dermatologists
Although overall survival for STMF is not known, the clinical course of reported cases appears to follow a more benign, chronic path, similar to classic MF. Syringotropic mycosis fungoides is often less responsive to skin-targeted therapies than classic MF, owing to the perieccrine and perifollicular location of the infiltrates in the deep dermis. Combined with this, and the rarity of the disease, a consensus on treatment of STMF has yet to be established and is largely based on single case reports of treatment responses. Topical corticosteroids and topical retinoids are generally of limited value because of poor penetration to the level of eccrine and follicular structures. Most success has been reported with local radiotherapy for focal disease.5,8,9 For treatment of multifocal or generalized STMF, a variety of treatments have been reported, with variable outcomes. Remission with PUVA10 or UVB5 has been described but associated with, at best, a partial response.5,8 Systemic agents such as vorinostat have been reserved for more aggressive disease with lymph node involvement.5,8 ECP has not previously been reported for use in STMF. Extracorporeal photopheresis has been an effective treatment for cutaneous T-cell lymphoma since its development by Edelson et al.11 in 1987. It is a safe and well-tolerated therapy with minimal side-effects and a median response time of 7 months, which has been shown to be durable.12 It is, however, a time-consuming and expensive treatment and not as abundantly accessible as phototherapy. It is typically reserved for Sezary syndrome or advanced-stage MF but has also been shown to be effective as second-line therapy for earlier stage disease.3 In our patient, ECP was started as a systemic monotherapy due to the generalized nature of his disease with intense pruritus and the deep dermal location of the infiltrates. After six cycles of therapy, the patient demonstrated marked improvement in pruritus and resolution of plaques. This response cannot be solely attributed to the concomitant use of topical steroids, as these were not effective when used British Journal of Dermatology (2014) 170, pp200–227
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]
L. JENNINGS S.M. CAMPBELL1 R. YAAR2 M. MAHALINGAM2 D. SAHNI1 A. LERNER3 T . M . R U€ N G E R 1
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.
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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
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