Shin Iinuma

IL36RN mutations underlie impetigo herpetiformis.

TO THE EDITOR Impetigo herpetiformis (IH) is a rare pustular dermatosis that typically occurs in pregnant women sporadically with unknown etiology (Sauer and Geha, 1961). Early diagnosis is essential, as IH is life-threatening and is associated with placental insufficiency and electrolyte abnormalities. IH appears to have the same clinical and histologic appearance as generalized pustular psoriasis (GPP), which is also a rare severe episodic pustular dermatosis that occurs repeatedly in both sexes at any age. However, some researchers have regarded IH as an entity distinct from GPP, because some patients are affected by IH only in the gestational period (Lotem et al., 1989). Recently, we reported that the majority of GPP that is not accompanied by psoriasis vulgaris (PV; GPP alone) is caused by homozygous or compound heterozygous mutations of IL36RN, which encodes IL-36 receptor antagonist (IL36RN), although only a small number of cases with GPP preceding or accompanied by PV (GPP with PV) were found to have IL36RN mutations (Sugiura et al., 2013). Very recently, we reported that CARD14 c.526G4C is a significant risk factor for GPP with PV, but not for GPP alone in the Japanese cohort, which further supports the idea that GPP with PV differs genetically from GPP alone (Sugiura et al., 2014a). However, to our knowledge, there have been no reports of IH with IL36RN mutations. Here we report two cases of IH with homozygous and heterozygous IL36RN mutations. Cases 1 and 2 were a 23-year-old woman and a 28-year-old Japanese woman who were admitted to our hospitals for pustular lesions in the 29 week and the 20 week of their first pregnancies, respectively (Figure 1a and b). There was no family history of GPP, no IH, and no consanguinity in their families. Case 1 had no previous history of GPP. Her pustular lesions had begun to develop at the 21 week of pregnancy, and she had been hospitalized in a maternity hospital. Oral prednisolone at a dose of 15 mg per day had been administered, but the eruptions had persisted. A skin biopsy from a pustular eruption on the trunk revealed a spongiform pustule of Kogoj in the epidermis consistent with IH (Figure 1c). Case 2 had suffered from GPP from the age of 8 to 18 years. Skin biopsies from pustular eruptions on the trunk revealed spongiform pustules of Kogoj in the epidermis at the age of 8 and 28 years (Figure 1d). She had been admitted to hospitals four times for GPP flare-ups. She had been treated with cyclosporine or etretinate. In the ten years leading up to her pregnancy, her GPP had been in remission without any treatment. Both cases had erythema with pustules over the whole body and fever of over 38 1C. Blood examinations from Cases 1 and 2, respectively, revealed white blood cell counts of 12,000ml 1 and 21,170ml , and C-reactive protein concentrations of 6.5 and 14.9 mg dl 1 (normal range: o0.3 mg dl ). Bacterial cultures of the pustules were negative. Thus, Cases 1 and 2 were, respectively, diagnosed as having IH and IH with a previous history of GPP. Following ethical approval, written informed consent was obtained in compliance with the Declaration of Helsinki Principles. The entire coding regions of IL36RN including the exon/intron boundaries were sequenced using genomic DNA samples from the patients. Case 1 had the homozygous mutation c.115þ6T4C, which was proven to result in p.Arg10ArgfsX1 in IL36RN by us previously, and Case 2 had the heterozygous mutation c.28C4T (p.Arg10X) in IL36RN. Both of these are GPP-causing founder mutations in the Japanese cohort (Sugiura et al., 2013, 2014b; Figure 1e and f, and Figure 2). A search for a second IL36RN mutation in all intron and putative promoter regions in Case 2 revealed no other IL36RN mutations (Supplementary Figure S1 online and Supplementary Table S1 online). However, there is still the possibility of a second unidentified IL36RN mutation in Case 2. More than 10 cases of GPP with heterozygous IL36RN mutations have been reported (Capon, 2013; Korber et al., 2013; Li et al., 2013; SettaKaffetzi et al., 2013; Sugiura et al., 2013). Moreover, in some patients, heterozygous IL36RN mutations are associated with palmoplantar pustulosis, a type of pustular psoriasis, and acute generalized exanthematous pustulosis, a severe cutaneous drug reaction (Navarini et al., 2013; SettaKaffetzi et al., 2013). IL-36 is absent in normal skin but is induced by inflammatory cytokines such as tumor necrosis factor-a, IL-17A, and IL-22 (Carrier et al., 2011). When functional IL-36RN is absent or underproduced, overexpressed IL-36 can induce neutrophilrich infiltration. Tumor necrosis factor-a is often elevated in the blood of pregnant women, whereby it induces various serious diseases (Mallmann et al., 1991). As for skin diseases, tumor necrosis factor-a sometimes causes exacerbation of PV lesions in pregnant women (Puig et al., 2010). Hence, it is very likely that a pregnant woman who has the IL36RN mutation occasionally cannot produce enough IL-36RN to adequately antagonize IL-36 excessively induced by inflammatory cytokines, and this imbalance results in IH. After longstanding controversy over whether IH is an independent disease Accepted article preview online 9 April 2014; published online 1 May 2014 Abbreviations: GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; IL-36RN, IL-36 receptor antagonist; PV, psoriasis vulgaris K Sugiura et al. IL36RN Mutations and IH

Increased serum C-reactive protein level in Japanese patients of psoriasis with cardio- and cerebrovascular disease

Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio‐ and cerebrovascular diseases. We investigated the relation between serum C‐reactive protein (CRP) and cardio‐ and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety‐seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio‐ and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio‐ and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio‐ and cerebrovascular disease.

Correlation of disease activity and serum level of carcinoembryonic antigen in acquired idiopathic generalized anhidrosis: A case report

Hypohidrosis and anhidrosis are congenital or acquired conditions which are characterized by inadequate sweating. Acquired idiopathic generalized hypohidrosis/anhidrosis (AIGA) includes idiopathic pure sudomotor failure (IPSF), which has the following distinct features: sudden onset in youth, increased serum immunoglobulin E and responds favorably to systemic corticosteroid. No clinical markers reflecting the disease severity or activity have been established. Here, we report a case of AIGA in a Japanese patient successfully treated with repeated methylprednisolone pulse therapy. In this case, serum carcinoembryonic antigen (CEA) levels increased up to 19.8 ng/mL along with aberrant CEA immunoreactivity of eccrine sweat glands. Interestingly, the serum CEA level normalized as sweating improved with repeated methylprednisolone pulse therapy. Therefore, serum CEA level may serve as a useful clinical marker of hypohidrosis or anhidrosis.

Serum carcinoembryonic antigen (CEA) as a clinical marker in acquired idiopathic generalized anhidrosis: a close correlation between serum CEA level and disease activity

Hypohidrosis/anhidrosis are congenital or acquired sweating impairments. Among them, acquired idiopathic generalized anhidrosis/hypohidrosis (AIGA) is the most common, and characterized by favourable response to systemic corticosteroid, however, no clinical markers for disease severity or activity have been developed.

Toxic epidermal necrolysis with prominent facial pustules: a case with reactivation of human herpesvirus 7.

A 37-year-old Japanese man presented with confluent erythemas and progressive erosive lesions on the almost entire body including the oral mucosa and genitalia. This was accompanied with prominent facial pustules. Although a lymphocyte stimulation test was positive only for acetaminophen, he took other agents including carbamazepine for his depression. He was diagnosed as having toxic epidermal necrolysis with prominent facial pustules and treated by methylprednisolone pulse therapy, which resulted in a good response. During the course, human herpesvirus 7 (HHV-7) DNA was detected in his peripheral blood. The HHV-7 reactivation might be related to facial pustulosis, which is occasionally observed in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

Prevalence of coronary artery calcification in Japanese patients with psoriasis: A close correlation with bilateral diagonal earlobe creases

Psoriasis is a multifactorial inflammatory disorder, in which the inflammation affects not only the skin but also the other internal organs, and can induce cardiovascular and cerebrovascular involvements. However, few predictive factors of cardiovascular diseases have been clarified in patients with psoriasis. This study was performed to verify whether diagonal earlobe creases (ELC) can reflect the hidden comorbidities in Japanese psoriatic patients. Prevalence and subtypes of ELC were analyzed in patients with psoriatic and with non‐psoriatic skin diseases, and the correlation with coronary artery calcification (CAC) or fatty liver (FL) detected by computed tomography. Prevalence of CAC was approximately twice higher than data of a Japanese resident‐based study previously reported. Generally, prevalence of ELC in a psoriatic group and mean age of psoriatic groups accompanied by ELC were higher and younger than those of a non‐psoriatic skin disease group, respectively. Statistically significant differences were detected in the mean age of total or male subjects accompanied by bilateral ELC with complete and incomplete length. Bilateralism of ELC was closely correlated with prevalence of CAC and CAC on multiple branches in psoriatic patients (P = 6.6e‐6 and odds ratio [OR] = 14.1, P = 0.00884 and OR = 10.7, respectively), but not with that of FL. On the contrary, body mass index of more than 25 was closely correlated with prevalence of FL, but not that of CAC. Comorbidities of psoriatic patients are frequently unnoticed. ELC, an apparatus‐related feature, can be a useful predictive factor for hidden coronary artery involvements in psoriatic patients.

Podoplanin expression is inversely correlated with granular layer/filaggrin formation in psoriatic epidermis

1 Imai Y, Tsuda T, Aochi S et al. YKL-40 (chitinase 3-like-1) as a biomarker for psoriasis vulgaris and pustular psoriasis. J Dermatol Sci 2011; 64: 75–77. 2 Johansen JS, Jensen HS, Price PA. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol 1993; 32: 949–955. 3 Bojesen SE, Johansen JS, Nordestgaard BG. Plasma YKL-40 levels in healthy subjects from the general population. Clin Chim Acta 2011; 412: 709–712. 4 Mastroianni A, Minutilli E, Mussi A et al. Cytokine profiles during infliximab monotherapy in psoriatic arthritis. Br J Dermatol 2005; 153: 531–536. 5 Jensen P, Wiell C, Milting K et al. Plasma YKL-40: a potential biomarker for psoriatic arthritis? J Eur Acad Dermatol Venereol. Published online: 23 May 2012; doi: 10.1111/j.1468-3083.2012.04570.x.

Close correlation of bone mineral density and body mass index in Japanese psoriasis patients

Dear Editor, Psoriasis is currently considered as a systemic inflammatory disorder that involves not only the body surface but also joints, cardiovascular and endocrine–metabolic systems. Bone mineral loss (BML) can also be correlated with the severity or duration of psoriasis in non-Asian populations. We analyzed femoral bone mineral density (BMD) of Japanese psoriasis patients, focusing on subtypes and duration of psoriasis, and body mass index (BMI). Femoral BMD reflecting systemic BMD was measured by dual-energy X-ray absorptiometric scanning in a total of 57 cases of psoriasis at the Department of Dermatology, Asahikawa Medical University Hospital. Topical treatment only, systemic therapy except biologics (oral prednisolone, cyclosporin, methotrexate or salazosulfapyridine) or biologics were applied for 14, 14 and 29 cases, respectively. Systemic corticosteroid was administrated only for three cases of psoriatic arthritis (PsA), and the BMD (% young adult mean [%YAM]) of the cases was 85, 109 and 129, respectively. We include both osteopenia (%YAM, <80) and osteoporosis (%YAM, <70) as BML in this study. The data of healthy controls was quoted from a recent study in a Japanese population. The study protocol was approved by the Asahikawa Medical University ethics committee.

Disseminated superficial actinic porokeratosis in a psoriasis patient with a long-term sun-bathing habit

Dear Editor, Porokeratosis is characterized by annular or linear circumscribed skin lesions with slightly raised thread-like borders. Cornoid lamellae are typically observed at the elevated border in histopathology. Porokeratosis is assumed to develop from abnormal clone of keratinocytes, which is induced by ultraviolet (UV) irradiation, immunosuppression and other factors. Chronic sun exposure could initiate disseminated lesions disseminated superficial actinic porokeratosis (DSAP). DSAP following UV treatment has been described in psoriasis patients. We report a case of psoriasis with porokeratosis, which may be associated with UV irradiation by sun-bathing. A 58-year-old man (skin type IV) had had plaque type psoriasis for 15 years. He was treated with topical corticosteroid and active vitamin D3 ointments. Besides the topical treatment, the patient had been regularly sun-bathing for almost 30 years. No family history of porokeratosis or psoriasis was detected. At the time of initial inspection, the psoriatic skin lesion was relatively well-controlled, however, a considerable number of small plaque lesions developed (Fig. 1a). During the course, several asymptomatic annular erythematous plaques with thread-like borders also developed on his trunk and thighs (Fig. 1b). Histopathological analysis of a small plaque on the trunk with hematoxylin–eosin staining showed the typical feature of psoriasis (Fig. 1c). Histopathology of the non-psoriatic type annular lesion with thread-like border obtained from the dorsal left thigh showed a typical thin column of parakeratotic zone along with hypogranulosis immediately beneath the localized compact hyperkeratosis, a characteristic finding of DSAP (Fig. 1d). Psoriatic lesions except DSAP disappeared following topical application of active vitamin D3 ointment. Porokeratosis is assumed to be a clonal disorder of keratinization. Two disseminated forms are described, DSAP and its non-actinic variant disseminated superficial porokeratosis (DSP). DSP may be induced by immunosuppression, such as medication, transplantation and immunosuppressive infection. Previously, there have been reports of psoriasis with DSAP following ultraviolet UV-B or psoralen plus ultraviolet A therapy. On the other hand, psoriasis associated with porokeratosis without any past history of UV irradiation therapy or systemic immunosuppressive medication has been described. Although our case had not been treated by UV irradiation therapy, the patient had been sun-bathing regularly for almost 30 years, and this may explain the location of the porokeratotic lesions on buttocks and thighs, which are usually non-sun-exposed sites. Topical application of the strongest potent glucocorticoid ointment for 4–5 year might also have resulted in the cutaneous immunosuppressive condition. Recently, various biologics have become available for the treatment of psoriasis. DSP during the treatment of etanercept for psoriasis has been described, suggesting a role of immunosuppression. UV irradiation could also induce local immunosuppression on the irradiated site. Psoriasis patients treated with UV irradiation, cyclosporin, methotrexate and biologics may result in development of DSP. Thus, careful examination should be performed for the possible induction of porokeratosis for these patients.

Persistent pruritus in psoriatic patients during administration of biologics

Dear Editor, In addition to the visible lesions, pruritus is another bothersome symptom in psoriatic patients, and systemic agents including biologics are effective against the symptom. However, persistent and worsened pruritus has been reported in psoriatic patients during biologic therapy. Here, we present cases of psoriasis accompanied by persistent pruritic symptom even after achievement of clear Psoriasis Area and Severity Index during biologic therapy. The itch was correlated with serum level of thymus and activation-regulated chemokine (TARC). Case 1 was a 72-year-old man with a 36-year history of psoriasis vulgaris who suffered from persistent pruritus over almost the entire body. He had been treated by monthly secukinumab (300 mg) for 3 years, and the skin lesions of psoriasis were completely cleared at the time. Because of cellulitis, the administration was stopped and the pruritus was gradually reduced. However, administration of ustekinumab against recurrence of psoriasis induced the pruritus again with increased serum TARC levels from 1016 to 4931 pg/mL. Lowdose cyclosporin (1.5 mg/kg per day) succeeded in reducing the pruritus and serum TARC (310 pg/mL), but was terminated due to renal failure. Initiation of adalimumab also induced pruritus with elevation of serum TARC (2399 pg/mL). Currently, he is being treated with apremilast and regular narrowband ultraviolet B (NBUVB) irradiation, and the pruritus and psoriasis lesions are well controlled. Case 2 was a 47-year-old man with a 30-year history of psoriasis vulgaris and a 5-year history of psoriatic arthritis who suffered from persistent pruritus with elevation of serum TARC (6950 pg/mL) and immunoglobulin (Ig)E (406 IU/mL). He had been treated by monthly s.c. injection of secukinumab (300 mg) for 6 months, and the skin lesions of psoriasis were completely cleared at the time. Termination of secukinumab and low-dose cyclosporin A (1 mg/kg per day) reduced the pruritic symptom. Currently, apremilast and regular NBUVB irradiation have succeeded in controlling the pruritic symptoms and serum TARC (1944 pg/mL) and IgE (155 IU/mL). Psoriasis is considered a T-helper (Th)17-mediated skin disorder. While Th17 is differentiated from naive CD4 T cells as with other Th populations, Th17 and Th2 reciprocally regulate. A rare concomitance of psoriasis and atopic dermatitis supports this regulatory mechanism. In the present cases, persistent pruritus accompanied by elevation of serum TARC levels was experienced in moderate to severe psoriatic patients successfully treated by biologics. The orientation of Th differentiation can be explained by three axes of representative cytokines: transforming growth factor (TGF)-b, interleukin (IL)-12 and IL-23. TGF-b, a crucial cytokine for naive T-cell differentiation into Th17 cells, inhibits development of Th2 cells. In the present cases, complete suppression of psoriatic lesions by biologics was followed by persistent pruritus and elevation of serum TARC, one of the Th2 cytokines. The most recent study on experimental asthma revealed that asthma, which has been considered a Th2dominant disease, can be divided into three subtypes: a Th2dominant type, a Th17-dominant type, and a both Th2and Th17-low type. In addition, Th2 and Th17 can inhibit each other, and inhibition of only one Th subset can enhance the other Th subset. The heterogeneity may be involved in the pruritus induced during biologic administration in psoriasis.