Kayo Kunimoto

A New Infant Case of Nakajo-Nishimura Syndrome with a Genetic Mutation in the Immunoproteasome Subunit: An Overlapping Entity with JMP and CANDLE Syndrome Related to PSMB8 Mutations

Nakajo-Nishimura syndrome (NNS) is a very rare hereditary autoinflammatory disorder that generally has its onset in infancy with pernio-like rashes and gradually develops into partial lipodystrophy. A distinct homozygous PSMB8 mutation encoding an immunoproteasome subunit has recently been identified as its genetic cause. Here, we report a new case of a patient with NNS who developed exudative erythemas on his face and extremities at 2 months of age, along with high fever, elevated serum hepatic aminotransferase levels and hepatosplenomegaly. Massive infiltration of inflammatory cells was observed histologically in the dermis and subcutis without apparent leukocytoclastic vasculitis. These symptoms improved with oral corticosteroids but recurred periodically, and a thin angular face with long clubbed fingers gradually developed. Identification of the PSMB8 mutation finalized the diagnosis of NNS at 5 years of age. Understanding a variety of clinicopathological features at the developmental stages is necessary to make an early diagnosis of NNS.

Progressive nodular histiocytosis.

Figure 1. (a) Clinical appearance at 7 years of age. Facial plaques were noted as well as multiple red-brown nodules with a diameter of 0.5–2 cm. (b) Clinical appearance at 4 years of age. A few red-brown nodules were seen at that time. Dear Editor, Histiocytic syndromes are classified into three types: class 1 (Langerhans cell histiocytosis), class 2 (nonLangerhans cell histiocytosis) and class 3 (malignant histiocytosis). Class 2 includes various disorders that differ in their clinical and histological findings; however, it is difficult to strictly separate these disorders because of the overlap in their histological features. Zelger et al. proposed a classification of nonLangerhans cell histiocytoses according to the predominant mononuclear and ⁄or multinuclear histiocytic cell type and the clinical presentation. Based on this classification, progressive nodular histiocytosis was newly defined and categorized as a non-Langerhans cell histiocytosis. As few reports of progressive nodular histiocytosis exist; we present a case based on clinical and histopathological findings. A 7-year-old Japanese boy presented with a 6-year history of yellow maculopapular facial lesions. There was a history of onset at the age of 1 year, when yellow macules and papules had appeared on the cheeks 1 day after falling into a dirty gutter. There was associated thickening of the cheek skin with gradual enlargement of macular lesions bilaterally. After medical consultation and a skin biopsy, he was diagnosed with benign cephalic histiocytosis and was kept under regular observation. However, the yellow macules progressed to involve his entire cheek on both sides. At the age of 7 years, he consulted our clinic because there were no signs of spontaneous resolution. On examination, there were facial plaques with bilateral involvement of the lower eyelids, cheeks and chin. Moreover, numerous red-brown nodules with a diameter of 0.5–2 cm were associated with these plaques and were asymptomatic. When the clinical appearance of the condition was compared with the appearance at 4 years of age, it was found that the yellow plaques had not resolved and the redbrown nodules had enlarged and were increased in

The continued use of sunscreen prevents the development of actinic keratosis in aged Japanese subjects.

It is well known that the trigger for actinic keratosis (AK) mainly depends on UV exposure. We evaluated the effects of long‐term use of sunscreen on the histopathological and dermoscopic changes of AK in aged patients. Eighteen months use of sunscreen produced no change in the number of actinic keratoses or the advancement of histological grade. Although a significant decrease was not observed in the number of positive cells of p53, Ki‐67 and COX‐2 of the subjects who used sunscreen for 18 months, the downward tendencies of these proteins were observed. The continued use of sunscreen decreased the number of CD31‐positive vessels significantly using the Chalkley method, and a significant improvement in scaling and vessel dots was found by dermoscopic study. Moreover, a relationship was found in the amount of sunscreen use and the number of actinic keratoses. Considering these results, it was thought that application of sunscreen reduces the risk of advancement of AK to higher grade AK and squamous cell carcinoma.

Is CANDLE the best nomenclature

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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.

The effects of continuous application of sunscreen on photoaged skin in Japanese elderly people – the relationship with the usage

Since photoaging of skin is caused by chronic sun exposure, it is well-recognized that regular sunscreen use can help prevent photoaging of skin in fair-skinned people. Therefore, application of sunscreen is recommended for the prevention of photoaging in many countries. However, the relationship between UV exposure and photoaging has rarely been investigated in clinical studies in Japan. In addition, there have been almost no long-term interventional studies in Japanese people. We have previously conducted a study where Japanese actinic keratosis patients were instructed to continuously apply sunscreen. The results indicated that long-term application of sunscreen is effective in suppressing actinic keratosis progression and generation. In the present study, we investigated the effects of sunscreen on photoaged skin in 14 elderly Japanese people. Skin conditions such as water content, transepidermal water loss, the number of spots, wrinkles, and skin color tone uniformity were measured and compared before and after the study. A statistically significant difference was observed only in skin surface hydration. There were large inter-individual differences in amount of sunscreen used throughout the study. The changes in the number of spots and skin color tone uniformity during the 18 months showed good correlation with amount of sunscreen being used. These results suggest an increase in the number of spots and deterioration in skin color tone uniformity in the 18-month non-sunscreen application period, and that such skin conditions improved with increasing use of sunscreen. In this study, we suggested an inhibitory effect on photoaging symptoms such as spots and skin color tone non-uniformity, by application of the appropriate amount of sunscreen over a long period of time in Japanese people, similar to Caucasians.

Beneficial effect of methotrexate on a case of Nakajo-Nishimura syndrome.

Nakajo-Nishimura syndrome (NNS) is a very rare autosomal recessively-inherited autoinflammatory disorder that onsets in infancy with pernio-like rashes and gradually develops into partial lipodystrophy, accompanied with remittent fever and nodular skin eruptions. This disease is caused by a unique mutation of the PSMB8 gene, which not only impairs an enzymatic activity of the encoding beta5i subunit, but also disturbs formation of the immunoproteasome complex. As the pathogenesis for NNS, cellular accumulation of ubiquitinated and oxidized proteins due to immunoproteasome deficiency is considered to cause MAP kinase activation with nuclear accumulation of phosphorylated p38 and following IL-6 production. The treatment for Nakajo-Nishimura syndrome has not been established. Inflammatory attacks can temporarily respond to the oral administration of high-dose corticosteroid, but they easily recur by tapering the dose of corticosteroid. Furthermore, the high-dose corticosteroid therapy has various side effects such as growth failure in infancy. In our child case of NNS (Kunimoto et al, Dermatology 2013), additional administration of methotrexate (MTX) significantly decreased a frequency of febrile attacks, in comparison to the treatment with oral corticosteroid alone. Notably, effectiveness of MTX was previously described on some infant cases of CANDLE syndrome, another PSMB8-mutated proteasome-associated autoinflammatory syndrome (PRAAS). MTX is known to execute anti-inflammatory effects through inhibition of folic acid-dependent enzymes, including dihydrofolate reductase (DHFR) and aminoimidazole carboxamide ribonucleotide transformylase (ATIC). ATIC inhibition causes accumulation of intracellular aminoimidazole carboxamide ribonucleotide and inhibits AMP deaminase, to increase the production of adenosine. Adenosine can inhibit superoxide production of neutrophils and their attachment to endothelial cells. As preliminary results, increased ROS production has been observed in primary neutrophils of NNS patients, suggesting one of the points that MTX affects.

Temporal changes of serum cytokine/chemokine levels in patients of Nakajo-Nishimra syndrome treated with tocilizumab

In Nakajo-Nishimura syndrome (NNS), proteasome disability due to a loss-of-function PSMB8 mutation induces storage of ubiquitinated proteins and overproduction of inflammatory cytokines and chemokines. However, the precise mechanisms causing complex phenotypes of the disease, including pernio-like eruptions, lipodystrophy and calcification of basal ganglia, is mostly unclear. As IL-6 overproduction in association with p38 hyperactivation was supposed to have a role in NNS (Arima et al, PNAS 2011), tocilizumab, a monoclonal antibody for IL-6 receptor, has recently been applied for two patients with NNS after informed consents were obtained. Decreased serum CRP and CPK levels in both patients and improved myalgia and arthralgia in one patient have been observed, whereas none of decrease in serum LDH level or improvement of fever and eruptions have been achieved. By analysis of serum cytokine/chemokine levels, IL-6, G-CSF and MCP-1 levels have changed in accordance to the CRP level, whereas IP-10 has shown constantly high levels independent of the CRP level. Furthermore, both the patients-derived peripheral blood monocytes and monocytes differentiated from a patient-derived iPS cells produced higher level of IP-10 than control cells after IFNgamma stimulation. These findings suggest that monocyte-derived IP-10 has a major role in pathogenesis of the sustained/progressing phenotypes in NNS.