Naoya Mikita

Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis

Generalized pustular psoriasis is a distinct type of psoriasis characterized by recurrent febrile attacks with disseminated subcorneal pustules on generalized skin rashes. Recently, homozygous and compound heterozygous mutations of the IL36RN gene, which encodes the anti‐inflammatory cytokine interleukin (IL)‐36 receptor antagonist, were identified in familial and sporadic cases of various ethnicities with generalized pustular psoriasis. Here we report a 39‐year‐old Japanese male patient who had suffered from repeated attacks of generalized pustular psoriasis since infancy with intervals of several years. At presentation, erythematous lesions with a few pustules were found only on some parts of the body and controlled with topical corticosteroids. An analysis of the IL36RN gene revealed compound heterozygous mutations of c.28C>T and c.368C>T. While the former mutation causing the premature termination p.Arg10X is recurrent in Japanese cases, the latter missense mutation causing p.Thr123Met substitution is novel, but another mutation in the same position has been reported in one Japanese case. Our report further supports the presence of the Japanese‐specific hot spots in the IL36RN gene, 28C and 368C, and suggests the functional significance of Thr123. This special type of generalized pustular psoriasis caused by IL36RN mutations has been designated as deficiency for IL‐36 receptor antagonist, a new hereditary autoinflammatory disease, and its phenotypes have emerged to include other related pustular disorders, palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis. The genetic analysis of the cases with these diseases would be important for establishment and application of the specific treatments targeting the IL‐36 signaling.

Recent advances in cytokines in cutaneous and systemic lupus erythematosus.

Lupus erythematosus (LE) includes a broad spectrum of diseases from a cutaneous‐limited type to a systemic type. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which affects multiple organs. Cutaneous lupus erythematosus (CLE) includes skin symptoms seen in SLE and cutaneous‐limited LE. Although immune abnormalities, as well as heritable, hormonal and environmental factors, are involved in the pathology of LE, the actual pathogenesis is still unclear. Recently, the involvement of various cytokines has been shown in the pathogenesis of LE. Moreover, some trials with biological agents targeted specific cytokines are also ongoing for SLE. In this article, we review the contributions of major cytokines such as interferon, tumor necrosis factor‐α and interleukin‐18 to LE, especially SLE and CLE.

The protective effects of ultraviolet A1 irradiation on spontaneous lupus erythematosus-like skin lesions in MRL/lpr mice.

We investigated the effects of ultraviolet A1 (UVA1) irradiation on spontaneous lupus erythematosus- (LE-) like skin lesions of MRL/lpr mice, using a disease prevention model. UVA1 irradiation significantly inhibited the development of LE-like skin lesions, without obvious changes of the disease including renal disease and serum antinuclear antibody levels. Besides the massive infiltration of mast cells in the LE-like skin lesions, in the nonlesional skins, more mast cells infiltrated in the UVA1-irradiated group compared with the nonirradiated group. Although apoptotic cells were remarkably seen in the dermis of UVA1-irradiated mice, those cells were hardly detectable in the dermis of the nonirradiated mice without skin lesions. Further analysis showed that some of those apoptotic cells were mast cells. Thus, UVA1 might exert its effects, at least in part, through the induction of the apoptosis of pathogenic mast cells. Our results supported the clinical efficacy of UVA1 irradiation for skin lesions of lupus patients.

The Expression of Histamine Receptors in Skin Lesions of MRL/MPlpr/ lpr Mice

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease accompanied with systemic organs dis- order including skin changes. The MRL/MP-lpr/lpr (MRL/l) mouse is a model of human LE. MRL/l mice skin lesions ex- hibit a decreased activity in histamine-N-methyltransferase (HMT) and impaired histamine metabolism. In order to clarify the role of histamine receptors (HRs) including H1R, H2R and H3R in MRL/l skin lesions, the relationship between HRs and skin lesions was assessed by immunohistochemical staining and RT-PCR methods. The expression of H2R was seen in the non-lesional skin of 2-month-old (mo) MRL/l mice; H2R expression continued for a couple of months, and then de- creased in the skin lesions of 5-mo MRL/l mice. In MRL/l skin lesions, a dense mast cell infiltration expressed H2R was seen. In conclusion, an increased expression of H2R in mast cells may be associated with histamine metabolism in skin le- sions from MRL/l mice.

The effect of hydroxychloroquine on lupus erythematosus-like skin lesions in MRL/lpr mice

Abstract Objectives: To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE). Methods: We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis. Results: Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively. Conclusions: HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.

A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression.

We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine.

Involvement of FcεR1α immunopositive cells in alopecia areata with atopic dermatitis and a high titer of serum immunoglobulin E

Alopecia areata (AA) is often observed in patients with atopic dermatitis (AD) although the etiology is unclear. Previous studies have provided evidence that a history of atopy and/or autoimmune diseases is a risk factor for AA [1, 2]. Furthermore, the serum levels of total immunoglobulin E (IgE) were also significantly higher in AA patients than in controls [3, 4]. However, the immunopathology of AA associated with AD and/or a high serum IgE titer is still unclear. We hypothesized that the pathomechanism [...]

CO2 narcosis as a notable cause of premature death in Nakajo-Nishimura syndrome

Abstract Nakajo-Nishimura syndrome (NNS) is an inherited inflammatory and wasting disease caused by a distinct homozygous mutation of the PSMB8 gene, which encodes the β5i subunit of the immunoproteasome. Although NNS was originally reported in Japan more than 70 years ago, related diseases with an overlapping entity, namely joint contractures, muscular atrophy, microcytic anemia and panniculitis-associated lipodystrophy (JMP) syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, have recently been reported and these three diseases are now collectively referred to as proteasome-associated autoinflammatory syndromes (PRAAS). Although some distinct characteristics can be pointed out in each disease, most patients with these diseases commonly start to show inflammatory attacks in infancy and, after growing-up, clinically resemble progeria with marked emaciation especially in the upper body. Notably, some NNS cases with premature or sudden death have been reported and cardiac failure was considered to be a major cause of death. Here we report a Japanese male case with NNS, who had received no continuous medication and died of CO2 narcosis (respiratory acidosis) triggered by an acute septic infection in the absence of cardiac failure at 47 years of age. Due to a remarkable lipomuscular atrophy and contracture of the chest wall, CO2 narcosis should be noted as an important complication of NNS/PRAAS, which can develop into premature death.

Prognostic factors of daily blood examination for advanced melanoma patients treated with nivolumab

Biomarkers to distinguish patients with advanced melanoma responsive to nivolumab are of great interest. Therefore, we examined the possibility that laboratory data of daily blood examination become novel biomarkers. Laboratory data of 16 melanoma patients who were treated with nivolumab were retrospectively analyzed. Patients were classified as responder group or non-responder group. Examined were: white blood cell count (WBC), absolute lymphocyte counts (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute eosinophil count (AEC), and absolute basophil count (ABC), as well as levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), one hour value of erythrocyte sedimentation rate (ESR), and 5-S-cysteinydopa (5-S-CD). Responder group showed significantly higher baseline levels of ESR or CRP and significantly lower ALC level before nivolumab treatment. Additionally, nivolumab treatment decreased the levels of CRP, ESR, and ANC, while it increased ALC level in the responder group. CRP was the most effective in distinguishing responder group from non-responder group both before and during treatment, according to the receiver operating characteristic (ROC) curve. We firstly showed that ESR is also the baseline biomarker of the efficacy of nivolumab. Furthermore, we confirmed that CRP is useful to predict the efficacy both before and during the treatment, and suggested that CRP is the most effective biomarker among daily blood examination by using ROC curve analysis. There is a possibility that nivolumab treatment may be more effective for malignant melanoma with stronger inflammation.

Case of Legionella pneumophila pneumonia (legionellosis) developed in a psoriatic arthritis patient receiving adalimumab.

terms of time interval between every dose, and the dose escalation and the increased dilution are more linear, allowing a feasible application. Of note, our protocol has shown its efficacy regardless of the underlying disease. Finally, our patients were free of corticosteroids and antihistamines at the time of the procedure, showing a good tolerance of our protocol. On the basis of these considerations, we suggest that a standardized protocol may be developed and applied to all patients presenting delayed cutaneous reaction to this biological drug.