Akihiro Fujisawa

Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.

OBJECTIVE Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. METHODS Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. RESULTS All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. CONCLUSION NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

BACKGROUND Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Direct Development of Functionally Mature Tryptase/Chymase Double‐Positive Connective Tissue‐Type Mast Cells from Primate Embryonic Stem Cells

Conditions that influence the selective development or recruitment of connective tissue‐type and mucosal‐type mast cells (MCs) are not well understood. Here, we report that cynomolgus monkey embryonic stem (ES) cells cocultured with the murine aorta‐gonad‐mesonephros‐derived stromal cell line AGM‐S1 differentiated into cobblestone (CS)‐like cells by day 10–15. When replated onto fresh AGM‐S1 with the addition of stem cell factor, interleukin‐6, and Flt3 ligand, these CS‐like cells displayed robust growth and generated almost 100% tryptase/chymase double‐positive MCs within 3 weeks. At all time points, the percentage of tryptase‐positive cells did not exceed that of chymase‐positive cells. These ES‐derived MCs were CD45+/Kit+/CD31+/CD203c+/HLA‐DR− and coexpressed a high‐affinity IgE receptor on their surface, which was upregulated after IgE exposure. Electron microscopy showed that they contained many electron dense granules. Moreover, ES‐derived MCs responded to stimulation by via IgE and substance P by releasing histamine. These results indicate that ES‐derived MCs have the phenotype of functionally mature connective tissue‐type MCs. The rapid maturation of ES‐derived MCs suggests a unique embryonic pathway in primates for early development of connective tissue‐type MCs, which may be independent from the developmental pathway of mucosal‐type MCs.

Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells

ABSTRACT Nivolumab has shown promising early results in patients with advanced malignancies, including melanoma and lung cancer, with generally manageable side effects. On the other hand, recent studies showed that the immune activation caused by PD-1 blockade might promote severe autoimmune toxicity. Herein, we report a case of idiopathic thrombocytopenic purpura during nivolumab therapy.

CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis.

Some familial cases of pityriasis rubra pilaris (PRP) have the CARD14 gene mutations that are also detected in familial psoriasis vulgaris. However, genotype–phenotype correlation in these two entities is poorly understood. Here, we report a case of PRP with a new mutation in CARD14. Genomic analysis of a 40‐year‐old female patient with sporadic PRP type V identified a heterozygous dominant c.412G>A mutation (p.Glu138Lys) in CARD14. Two types of CARD14 mutations causing Glu138 substitutions have been reported in cases of familial PRP and pustular psoriasis. All three types, including the present case, are predicted to cause similar loss of the negative charges at this site. This suggests that the difference in molecular charge and the resulting change in molecular interaction around the N‐terminal end of the coiled‐coil region of CARD14 molecule do not determine the phenotypic differences between psoriasis and PRP.

Spontaneous regression of Merkel cell carcinoma after biopsy

Dear Editor, Merkel cell carcinoma (MCC) is a highly aggressive skin tumor. Despite its high degree of malignancy, cases of spontaneous regression have been reported. Regression of the tumor is defined as the complete/partial disappearance of the neoplastic lesion without treatment. Major criteria for definition of histological regression include dense lymphocytic inflammatory infiltrate in close apposition to the neoplastic cells, and degeneration of cell death of neoplastic cells often with apoptosis. Similarly, spontaneous regression of MCC is possibly mediated by cellular immune response of the host, where apoptosis is frequently observed. The estimated prevalence of spontaneous regression when considering all neoplastic disease has been reported as less than one case of regression in 60 000–100 000 neoplasm. However, in MCC, the estimated rate of regression is as high as 1.7–3.0% (12/400–700 cases) by reviewing past published work and considering the reported prevalence of MCC. Here, we report a case of spontaneous regression of MCC after biopsy. A 73-year-old woman presented with a subcutaneous nodule on the right forearm from a month prior. The nodule was approximately 1 cm, slightly raised, hard and slightly pigmented (Fig. 1). Biopsy (3-mm punch biopsy) from the central portion of the nodule was performed. Histopathologically, the specimen showed atypical tumor cells with infiltration of mononuclear cells throughout the dermis (Fig. 2a). The tumor cells had scanty cytoplasm, and were larger in size than inflammatory mononuclear cells, but smaller than keratinocytes (Fig. 2b). Immunohistochemical staining showed that the tumor cells were positive for cytokeratin 20 (Fig. 2c) and chromogranin (Fig. 2d). Computed tomography showed no sign of malignancy of internal organs or metastasis in lymph nodes. From these findings, MCC was diagnosed. In a few weeks after biopsy, the subcutaneous tumor was not palpable. However, to remove residual tumor cells completely, surgical resection of the primary site with a 1-cm margin was performed. Histopathological examination of the specimen obtained by surgery showed focal infiltrates of cells in the dermis (Fig. 2e). At higher magnification, infiltrate of inflammatory mononuclear cells, but no tumor cells were found (Fig. 2f), which meant spontaneous regression of MCC after biopsy. At present, we are carefully checking the primary site and regional lymph node every 6 months. As spontaneous regression of MCC is elucidated by apoptosis in the published work, disappearance of MCC in our case is probably due to apoptosis induced by mononuclear cell infiltrate. Not including the present case, features of MCC with spontaneous regression in 12 Japanese cases reported by 2005 are: (i) the patient was female in 11 of 12 cases; (ii) the primary site was the face in 12 of 12 cases; (iii) spontaneous regression occurred after biopsy in eight of 12 cases; and (iv) recurrence after regression was reported in zero of 12 cases. So far, the molecular mechanism to induce apoptosis and spontaneous regression in MCC is unclear. Recently, clonal

Onychomadesis developed only on the nails having cutaneous lesions of severe hand-foot-mouth disease.

This paper reported a case of onychomadesis which appeared on the nails after heal of cutaneous lesions of hand-foot-mouth disease (HFMD). There were a few reports describing onychomadesis after HFMD; however, the mechanism is still unclear. The present case was prospectively observed, and onychomadesis was found to develop only on the nails having cutaneous lesions of HFMD. We considered that nail dysfunction due to direct inflammation spreading from skin eruptions around nail is one of the causes of onychomadesis linked to HFMD.

Enhanced NF‐κB activation with an inflammasome activator correlates with activity of autoinflammatory disease associated with NLRP3 mutations outside of exon 3: Comment on the article by Jéru et al

was followed by a decrease in IgG and IgM serum levels within 72 hours, and a typical biopsy-proved cryoglobulinemic membranoproliferative glomerulonephritis. In a case described by Odum et al (2), IVIG infusion was followed within 48 hours by diffuse purpura, a rise in plasma creatinine levels, a microscopic hematuria, and high-level proteinuria strongly suggestive of glomerulonephritis. Yebra et al reported a flare of hepatitis C virus–related cryoglobulinemic vasculitis 4 hours after the first IVIG infusion, an increase of cryoglobulin precipitation, and depletion of the monoclonal IgM after in vitro addition of IVIG, and suggested that this simple method could help to predict the risk of cryoglobulin–IVIG immune complex formation and should be performed before starting IVIG in patients with mixed cryoglobulinemia (3). As with infliximab and rituximab, we have reported in our article that polyvalent exogenous human immunoglobulins were also recognized in vitro by RF-positive IgM . Taken together, these results strongly suggest that the recognition of monoclonal or polyclonal immunoglobulin by RF-positive IgM is not specific and that treating RF-positive IgM cryoglobulinemic vasculitis with either monoclonal immunoglobulins (e.g., rituximab or infliximab) or polyvalent immunoglobulins is associated with a risk of increased cryoprecipitation and vasculitis flare shortly after treatment initiation. We believe that, in the presence of RF-positive IgM type II cryoglobulinemic vasculitis, any treatment with IVIG should be used with caution. IVIG does not have the clear benefit of rituximab in cryoglobulinemic vasculitis, and there is not a rationale for the use of monoclonal anti–tumor necrosis factor antibodies. The use of rituximab, should, as well, be proposed cautiously in patients with a RF-positive IgM type II cryoglobulinemic vasculitis. We recommend that plasma exchanges should be performed to reduce high serum cryoglobulin levels, and that rituximab should be given in low doses. This precaution should also be recommended for other treatments that are based on B cell–depleting monoclonal antibodies, which have not yet been used in cryoglobulinemic vasculitis, such as veltuzumab (anti-CD20), inotuzumab ozogamicin, and epratuzumab (anti-CD22). Dr. Cacoub has received consulting fees and honoraria from Bristol-Myers Squibb, Sanofi-Aventis, Gilead, Schering-Plough (less than

Three-dimensional evaluation of subclinical extension of extramammary Paget’s disease: Visualization of histological border and its comparison to clinical border

10,000 each), Roche, and Servier (more than

A Case of an Undifferentiated Squamous Cell Carcinoma Arising from an Epidermal Cyst

10,000 each).