Tomoko Miyake

Hydroa Vacciniforme Is Associated with Increased Numbers of Epstein–Barr Virus–Infected γδT Cells

Hydroa vacciniforme (HV) is a rare photosensitivity disorder of childhood associated with Epstein-Barr virus (EBV)(+) T-cell infiltration. We have summarized clinical manifestations of HV, and analyzed EBV(+) T-cell subsets as well as EBV DNA load in lymphocyte fractions, in comparison with hypersensitivity to mosquito bites (HMB), an EBV-associated T/natural killer (NK) lymphoproliferative disorder. We found that 31 of 33 (93.9%) HV lesions were composed of EBV(+) T cells and reactive EBV(-) cytotoxic T cells, without significant CD56(+) cell infiltration, whereas many CD56(+) cells were present in 8 of 9 (88.9%) HMB lesions. Of 13 (20.6%) HMB patients with or without HV, 12 (92.3%) showed increased percentages (>32%) of NK cells in the peripheral blood, whereas in the 16 patients with HV alone, 14 (87.5%) showed no increase. Of the 11 HV patients, 10 (90.9%) had increased percentages (>5%) of circulating γδT cells, with a mean value of 15.7 ± 2.9%, and the γδT-cell fractions contained larger amounts of EBV DNA than non-γδT-cell fractions. A triple-labeling method revealed that all three HV patients examined had increased percentages of EBER(+), T-cell receptor (TCR)γδ(+), and TCRαβ(-) cells. Our observations indicate that HV is associated with increased numbers of EBV(+) γδT cells, whereas HMB is associated with EBV(+) NK cells.

Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites.

Epstein‐Barr virus (EBV)‐associated T/natural‐killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors.

Annular pustular psoriasis with a heterozygous IL36RN mutation

Annular pustular psoriasis (APP) is a rare form of pustular psoriasis, characterized by erythematous, annular or polycyclic lesions, eruptions of small sterile pustules and fine desquamation without systemic inflammation [1]. APP is a chronic and recurrent disease but has a benign course, contrasting with generalized pustular psoriasis (GPP), which is another severe form of pustular psoriasis with systemic inflammatory response syndrome [2]. Recent studies in Japan have shown that the majority of [...]

Primary signet‐ring cell/histiocytoid carcinoma of the axilla expressing human epidermal growth factor receptor 2

residues and sugar chain structures. Besides “natural’’ IFN-b, local injections of “recombinant’’ IFN-b (rIFN-b) are currently used to treat multiple sclerosis (MS). rIFN-b has structural variants, 1a and 1b. The differences in these IFN variants are shown in Table 1. rIFN-b sometimes induces local reactions including redness, pain, and occasionally, skin ulcers. Further, it has been reported that s.c. injections of IFN-a used to treat MM can also cause skin ulcers at the injection sites. The pathogenic mechanisms underlying skin ulcers induced by IFN injections remain unclear. Previous published work has indicated that some forms of IFN, including rIFN-b, produced direct vasospastic effects on acral skin. This, in combination with the susceptibility of the amputation wound of the toe to skin necrosis, further aided by the site of the injections, could have contributed to skin ulcer development. We could not find any prior reports either in Japanese or English of skin ulcers following nIFN-b injections. According to Daiichi Sankyo (Tokyo, Japan), 300–400 MM patients begin treatment with nIFN-b yearly. In contrast, official patient data from the past 16 years indicate that some 20 000 MS patients annually began treatment with rIFN-B-1a worldwide. The relative scarcity of nIFN-b use in comparison with rIFN-b use may account for the absence of reports concerning nIFN-b-induced skin ulcers. The present paper may be the first report of skin ulcers following local injections of nIFN-b. However, such cases may in fact have hitherto simply been unreported.

Epstein-Barr virus reactivation is induced, but abortive, in cutaneous lesions of systemic hydroa vacciniforme and hypersensitivity to mosquito bites

BACKGROUND Epstein-Barr virus (EBV)-associated T/natural killer (NK)-lymphoproliferative disorders (LPDs) include hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). The pathomechanisms of these diseases are still unclear. OBJECTIVE To understand the inflammatory process, we examined EBV reactivation markers, BZLF1 and BDRF1 mRNA in the tissue and blood from patients with EBV-associated T/NK-LPDs. METHODS Sixty-four patients with EBV-associated LPDs and epithelial neoplasms, and EBV+ cell line cells were studied. DNase-treated and resistant EBV DNA load in blood and cell culture supernatants were calculated. An EBV reactivation signal was analyzed in the tissue, blood and cell line cells. RESULTS In the tissue, BZLF1 mRNA was detected in 5 of 6 (83%) samples of EBV+ epithelial neoplasms, 16 of 21 (76%) of EBV+ lymphomas, and 5 of 15 (33%) of systemic HV and/or HMB, but negative in all 15 patients with classical HV. In the blood, BZLF1 mRNA was detected in only one of 19 (5.3%) samples of EBV-associated T/NK-LPDs. A down-stream reactivation signal, BDRF1 mRNA was expressed in all 6 samples of EBV+ epithelial neoplasms, but it was positive in only one of 15 (6.7%) samples from systemic HV and HMB in the tissue. EBV+ T/NK-cell line cells treated with phorbol 12-myristate 13-acetate produced BZLF1 and BDRF1 mRNA, and encapsidated EBV DNA was detected in the culture supernatants of cell line cells. CONCLUSION Stimulation-induced EBV reactivation occurred both in vivo and in vitro, but it was almost abortive in vivo. Reactivation-related EBV antigens might be responsible for induction of systemic HV and HMB.

Oculomucosal and gastrointestinal involvement in Epstein-Barr virus-associated hydroa vacciniforme

In a series of patients with Epstein-Barr virus (EBV)-associated hydroa vacciniforme (HV) and related disorders, we reviewed the incidence of oculomucosal and gastrointestinal involvement. Of 63 patients with EBV-related HV and/or hypersensitivity to mosquito bites (HMB), 11 patients (17.5%) presented with mucosal lesions such as aphthous stomatitis and ulcerative gingivitis, 3 patients (4.8%) had ocular symptoms including iritis, conjunctival hyperemia and corneal erosions, and 2 patients (3.2%) presented with severe HV complicated gastrointestinal involvement. Oculomucosal lesions are sometimes complicated in patients with EBV-related HV and HMB, and gastrointestinal involvement may occur in the severe form.

Epstein–Barr virus‐positive mucocutaneous ulcer in a patient with polycythemia vera treated with oral hydroxyurea

Dear Editor, Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EMU), a proposed entity, is one of the EBV-positive lymphoproliferative disorders that arise in individuals with various immunosuppressive conditions. EMU is characterized by clinically localized disease with an indolent course and Hodgkin-like histopathological features. We present a case of EMU caused by oral hydroxyurea. In June 2013, a 79-year-old Japanese man was referred to us because of a 9-month history of a gradually developing perioral tumor (Fig. 1a). In 1994, he had been diagnosed as having polycythemia vera, and he was treated with oral hydroxyurea, which resulted in a favorable clinical course. Our physical examination of him revealed a 15-mm indurated erythemic nodule on his lower lip. No mucosal ulcer was observed in his oral cavity. No swollen node was detected in his neck. The laboratory findings were as follows: lactate dehydrogenase, 381 U/L (normal, 120–240); and soluble interleukin-2 receptor, 493 U/mL (normal, 122–496). Blood EBV DNA load was not determined. No significant accumulation was detected by F-fluorodeoxyglucose positron emission tomography. A biopsy specimen from the tumor showed dense infiltration of lymphoid, plasmacytoid and large abnormal lymphoid cells, suggestive of malignant lymphoma (Fig. 1b). The infiltrating large cells mimicked Hodgkin cells, with expressions of CD20, CD30 and EBV-encoded RNA (Fig. 1c,d). CD3 was not expressed on these large tumor cells. A diagnosis of EMU was made. However, clonal B-cell populations were not detected by polymerase chain reaction amplification of immunoglobulin genes, using DNA extracted from the biopsy specimen. We stopped the patient’s oral hydroxyurea regimen, resulting in spontaneous tumor regression within 2 weeks. However, the oral hydroxyurea was restarted 3 weeks later, when marked leukocytosis and thrombocytosis were observed. Again, a perioral tumor gradually recurred on the same lesion as before (Fig. 1e). Histopathological findings of a biopsy specimen from the recurrent tumor were similar to the previous findings. He was successfully treated with four rounds of polychemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine and prednisone, followed by radiation therapy (30 Gy) for the involved site. However, in April 2014 during the follow up after the radio-chemotherapy, the patient died of an unknown cause independent of the EMU. Usually, EMU presents as a solitary nodule with or without ulcer, preferentially at the transition site of mucosa and skin.

Clinical and Laboratory Markers Associated With Relapse in Cutaneous Polyarteritis Nodosa

Importance In cutaneous polyarteritis nodosa (CPAN), less aggressive treatments can be selected, because CPAN is not associated with life-threatening or progressive outcomes. Although patients with a recurrent clinical course may require additional immunosuppressive therapies, no pretreatment factors associated with a worse prognosis in CPAN have been reported. Objective To identify clinical or laboratory markers associated with relapse of CPAN. Design, Setting, and Participants This retrospective case series was performed at a dermatology clinic of a tertiary referral center in Okayama, Japan, from October 1, 2001, through April 30, 2017. Of 30 patients identified with CPAN, the 21 with histopathologic evidence of disease were eligible and enrolled in the study. Main Outcomes and Measures The medical database was examined for sex, age at diagnosis, affected anatomical sites, type and extent of skin lesion, laboratory data, initial therapies, duration of follow-up, and current status. Relapse was defined as the first reoccurrence or new onset of cutaneous disease that required further escalation of treatment with prednisolone at a dosage of greater than 20 mg/d and/or add-on use of immunosuppressant therapy, more than 6 months after initial treatment. The pretreatment factors were statistically evaluated between the groups without and with relapse. Results The 21 patients included 5 males and 16 females with a median age of 49 years (range, 11-74 years) at diagnosis. The median follow-up was 42 months (range, 8-374 months). Pretreatment cutaneous ulcer was significantly associated with relapse between the 2 groups (0 of 11 in the nonrelapse group vs 4 of 10 in the relapse group; &khgr;21 = 4.67; P < .05). In the laboratory test results, significantly higher mean (SD) values were observed in the relapse group for C-reactive protein level (0.23 [2.00] vs 6.03 [3.10] mg/dL; standard error of the mean [SEM], 3.40 mg/dL; 95% CI, 0.01-10.8 mg/dL; P = .01), absolute neutrophil count (ANC) (3.4 × 103/&mgr;L [1.1 × 103/&mgr;L] vs 6.0 × 103/&mgr;L [3.2 × 103/&mgr;L]; SEM, 2.9 × 103/&mgr;L; 95% CI, 1.9 × 103/&mgr;L to 14.6 × 103/&mgr;L; P = .001), neutrophil-to-lymphocyte ratio (1.4 [0.8] vs 2.8 [0.9]; SEM, 1.2; 95% CI, 1.1-4.9; P = .002), and systemic immune-inflammation index (5.1 × 105 [3.9 × 105] vs 11.7 × 105 [7.7 × 105]; SEM, 7.3 × 105; 95% CI, 3.3 × 105 to 31.1 × 105; P = .007). The estimated 2-year cumulative relapse rate was significantly high in the patients with blood ANC of greater than 4.9 × 103/&mgr;L compared with 4.9 × 103/&mgr;L or less (9 of 10 [90%] vs 2 of 11 [18%]; 95% CI, 6%-72%). Conclusions and Relevance Pretreatment status of cutaneous ulcer, the serum C-reactive protein level, the blood ANC, the neutrophil-to-lymphocyte ratio, and the systemic immune-inflammation index are associated with a worse prognosis in CPAN.

TypeD(CD8+) lymphomatoid papulosis in a patient with classic (CD4+) mycosis fungoides

EJD, vol. 28, n◦ 2, March-April 2018 267 a daily practice cohort of AD patients treated with CsA were reported to discontinue treatment due to side effects [4]. This is also in line with a recent prospective randomised, non-inferiority trial comparing MTX with CsA in 97 patients [3] which showed that the MTX-related adverse events were significantly less frequent than with CsA: 30% vs 55%, respectively (p<0.0001) [3]. Although the initial efficacy of oral MTX at 15 mg/week was inferior to oral CsA at 2.5 mg/kg/day at Week 8, the up-dosing of MTX to 25 mg/week induced a significant improvement versus the up-dosing of CsA to 5 mg/kg/day at Week 20. Therefore, we recommended initiating MTX at 20 or 25 mg/week, depending on patient weight and disease severity; and using the subcutaneous route to increase bioavailability and efficacy. These findings, which were obtained here in a real life situation, are of interest, since 75% of our patients showed a SCORAD of 50 after one year, whereas only 49% of the patients from the study of Politiek et al. [5] exhibited a good response after a one-year treatment with MTX, evaluated by Physician’s Global Assessment score (PGA1). This discrepancy can be explained by: (1) subcutaneous administration in only 11% of patients from the study of Politiek et al. vs 75% in our cohort; and (2) a lower initial mean dose of MTX in the study of Politiek et al. (13 mg/week) compared with our study (21 mg/week). Although MTX acts more slowly than CsA, the absence of major side effects makes MTX an excellent systemic option in AD treatment. Thus, due to its good efficacy, tolerance, and low medico-economic impact, MTX should be a systemic anti-inflammatory molecule of choice, before switching to new biologics. In conclusion, MTX could be a first-line systemic treatment, in combination with local treatments, for patients with moderate-to-severe AD. For this indication, we strongly recommend initiating MTX using the subcutaneous route at 20 or 25 mg/week in AD adults, in order to obtain a good balance between tolerance and efficacy. Disclosure. Financial support: none. Conflict of interest: none.

Warfarin-induced skin necrosis accompanied by aggravation of vasculitis in a patient with cutaneous arteritis

In February 2010, a 62 year-old woman was referred to us based on a 5-month history of progressive, painful livedoid erythema on the legs (Fig. 1a). The histopathological findings of the biopsy specimen from the indurated erythema showed arteritis in the subcutaneous fat (Fig. 1b–d). The laboratory findings were as follows: white blood cell (WBC) count, 10,090/ll; serum C-reactive protein (CRP), 6.33 mg/dl. A diagnosis of cutaneous arteritis was made with a lack of apparent extracutaneous involvement of vasculitis. In March 2010, oral prednisolone 40 mg daily was started, and prompt improvement was observed. However, a relapse of the vasculitis was shown by tapering of the prednisolone dose. In August 2010, the patient was hospitalized again because of aggravation of the vasculitis on oral prednisone 20 mg daily. On hospital day 2, oral warfarin 1 mg daily was started as an additional treatment and was escalated to a maximum dose of 2.5 mg daily over 4 days. On hospital day 4, new purpuric erythema developed on the lower legs with unresolved fever (Fig. 1e). On hospital day 7, multiple bloody bullae on the lower legs had emerged rapidly with leukocytosis and elevated levels of serum CRP (Fig. 2). The prothrombin time international normalized ratio (PT/INR) was elevated from 0.92 (hospital day 3) to 3.24 (hospital day 9) in a short period, that is, 6 days (Fig. 2). Histopathological findings of the biopsy specimen from the bloody bullae showed multiple thrombi of dermal to subcutaneous veins (Fig. 1f,i,j). In addition, leukocytoclastic vasculitis (LCV) was observed in the dermal venules (Fig. 1g,h). On hospital day 10, we stopped the oral warfarin. However, the oral prednisone had to be increased to 50 mg daily in order to fully control the disease activity (Fig. 2). These symptoms and laboratory findings then soon recovered, resulting in deep skin necrosis on the lower legs and feet (Fig. 1k). On hospital