Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail. METHODS: This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs. RESULTS: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4). CONCLUSION: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Regulates Epidermal Keratinization under Psoriatic Skin Inflammation.

Psoriasis is an autoinflammatory/autoimmune skin disease and the epitome of an exaggerated primary inflammatory response in the surface barrier tissue. Despite the efficacy of dimethyl fumarate, an electrophilic drug for psoriasis management, there is a paucity of mechanistic evidence in vivo. In response to electrophiles, the Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) system mediates a myriad of cytoprotective mechanisms, including the regulation of excessive inflammatory response and epidermal differentiation. Because the psoriasiform tissue reaction comprises neutrophil infiltration and parakeratotic scaling, it is hypothesized that Nrf2 not only regulates inflammatory responses but also maintains epidermal differentiation, a hallmark of epidermal homeostasis. By using the imiquimod-induced cutaneous inflammation model, an exaggerated inflammatory response and impaired epidermal differentiation in Nrf2-/- mice was detected. Dimethyl fumarate treatment in Nrf2+/+ mice attenuated a psoriasiform tissue reaction and rescued epidermal differentiation, which was not observed in Nrf2-/- mice. In accordance with the fact that psoriasis plaques form well-demarcated parakeratotic lesions in association with the psoriasiform tissue reaction, the lesional skin showed reduced expression levels of NRF2 and its downstream target genes compared with nonlesional skin. In conclusion, Nrf2 attenuates the psoriasiform tissue reaction and underscores the mechanistic legitimacy of the electrophile-based approach for the management of psoriasis.

Unusual Bone Lesions with Osteonecrosis Mimicking Bone Metastasis of Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa.

Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone lesions were osteonecrosis without tumor cells. We suggest that cancer-induced osteonecrosis should be included in the differential diagnosis of bone lesions suspected of being metastases on magnetic resonance imaging.

Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barré syndrome: a case report.

Nivolumab, an anti-programmed death-1-specific monoclonal antibody, has demonstrated a durable response and effect on overall survival and has become one of the standard treatments for patients with advanced melanoma. Reported herein is a case of nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy, in which an 85-year-old woman with stage IV melanoma developed grade 1 paresthesia 2 weeks after the initial dose of nivolumab was administered. With continued treatment, the neurological deficiency deteriorated rapidly, mimicking Guillain-Barré syndrome, causing such a dramatic decrease in her activities of daily living that she could no longer function in daily life. Thus, nivolumab treatment was discontinued. A course of intravenous immunoglobulin infusion yielded a dramatic clinical improvement; in particular, improved motor control was observed within a few days. Her initial presentation was suggestive of acute inflammatory demyelinating polyradiculoneuropathy, a subtype of Guillain-Barré syndrome; however, the good response to steroids and exacerbation 8 weeks after the onset were suggestive of chronic inflammatory demyelinating polyradiculoneuropathy induced by nivolumab. This is the first case of Guillain-Barré syndrome-like autoimmune polyradiculoneuropathy induced by programmed death-1/programmed death-ligand 1 inhibitors. Although neurological adverse events related to nivolumab are rare, they can become severe, requiring early diagnosis and intervention. Intravenous immunoglobulin may be considered as an effective initial treatment for patients who develop acute autoimmune nervous system disorders due to nivolumab.

Evaluation of apremilast, an oral phosphodiesterase 4 inhibitor, for refractory cutaneous dermatomyositis: A phase 1b clinical trial.

Dermatomyositis, an idiopathic inflammatory myopathy, is characterized by cutaneous itchy manifestations, which are frequently refractory and recurrent even after intensive immunosuppressive treatments. To evaluate the effectiveness and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in treating skin-dominant dermatomyositis in which myositis and interstitial lung disease are absent or in remission, we performed this prospective, single-arm, interventional study. A total of five Japanese patients (one male and four females, median [range] age, 64 [37-71] years) with refractory dermatomyositis-associated cutaneous manifestations were recruited and treated with a 12-week course of oral apremilast. Among five enrolled patients, three experienced diarrhea with full-dose apremilast (30 mg twice daily), two of whom withdrew from the study and recovered quickly afterwards. A total of three evaluable female patients (median [range] age, 65 [64-71] years) received apremilast treatment for 12 weeks. A 39.4% reduction from baseline Cutaneous Dermatomyositis Disease Area and Severity Index total activity score, but not the damage score, at week 12 was observed in all three patients. Visual analog scale of itching, and quality of life by Dermatology Life Quality Index were slightly improved in one and two apremilast-treated patients, respectively. As apremilast was effective, with expected and recoverable digestive adverse events (diarrhea), in patients with refractory and recurrent dermatomyositis-associated cutaneous manifestations in this first phase Ib study, it can be suggested as a possible treatment when aggressive immunosuppressive therapies with high-dose systemic corticosteroid and/or immunosuppressive agents for other manifestations, myositis, and interstitial lung disease, are not required.

Intravenous immunoglobulin-induced thrombocytopenia: a case report and review of the literature

Background: Intravenous immunoglobulin (IVIG), a pooled blood product acquired from multiple healthy donors, is an effective treatment for various types of autoimmune diseases, haematological disorders, and infectious diseases. Adverse haematological events such as throm-bocytopenia are rarely caused by IVIG. Objectives: To investigate the phenomenon of IVIG-induced thrombocytopenia. Materials & Methods: A case study and a review of the previous literature based on a search using MEDLINE (PubMed) and ICHUSHI (for Japanese literature) electronic databases. Results: The present case of dermatomyositis exhibited two episodes of IVIG-induced thrombocytopenia, which occurred a few days after initiating IVIG and was significant within two weeks without haemorrhagic symptoms. Spontaneous remission of thrombocytopenia was repeatedly observed. Based on a review of five cases, the underlying disorders were autoimmune bullous diseases in three of the five cases. Polyethylene glycol-treated human immunoglobulin products were used in three of the five cases. The clinical course of IVIG-induced thrombocytopenia was similar to that in our present case. Conclusion: Because of the rarity of severe haemorrhagic symptoms and spontaneous remission of IVIG-induced thrombocytopenia, discontinuation of IVIG due to thrombocytopenia is not straightforward.

Reliability of antinuclear matrix protein 2 antibody assays in idiopathic inflammatory myopathies is dependent on target protein properties.

A line blotting assay (LB) is currently used to detect myositis-specific autoantibodies (MSAs) in patients with idiopathic inflammatory myopathies (IIMs), because of its simplicity; however, the sensitivity and specificity of this assay is low. The aim of this study is to evaluate the accuracy of the commercial LB in detection of antinuclear matrix protein 2 (NXP2) antibody. Seventy-seven serum samples from patients with IIMs, in which anti-NXP2 antibodies were detected through immunoprecipitation and western blotting (IP-WB) using K562 cell lysate, were enrolled. All samples were assessed by LB and IP-WB using recombinant human NXP2 whole protein (rNXP2) produced by insect cells, and the positive rates of each assay were compared. Thirty-two samples (41.6%) showed false-negativity by LB, which includes 11 samples with negative results by IP-WB using rNXP2. Relative intensities of IP-WB using cell lysate were significantly higher in the samples with positive results by both LB and IP-WB using rNXP2, compared to samples with positive by IP-WB using rNXP2 but negative by LB. Three of 11 samples with negative results by both LB and IP-WB using rNXP2 revealed high antibody titers. Further, differences in post-transcriptional SUMOylation were observed between recombinant and natural NXP2 proteins. In conclusion, the LB showed low sensitivity for detection of anti-NXP2 antibody, an effect exacerbated at low titers of anti-NXP2 antibodies. Moreover, there appears to be differences in the reactivities of antibodies to recombinant and natural NXP2 proteins with different post-transcriptional modifications.

Invasive and in situ lesions of squamous cell carcinoma are independent factors for postoperative surgical-site infection after outpatient skin tumors surgery: A retrospective study of 512 patients.

Surgical-site infection (SSI) is one of the major postoperative complications in surgery, which can cause significant morbidity. However, factors associated with SSI in dermatological surgery are not well understood. Here, we retrospectively investigated 512 patients who underwent outpatient surgery for skin tumors at the University of Tsukuba Hospital to analyze factors associated with postoperative SSI. The overall incidence of SSI was 28 (5.5%). Univariate logistic regression analysis revealed that SSI was significantly associated with invasive squamous cell carcinoma (iSCC), Bowen's disease (BD), actinic keratosis (AK), longer diameter of defects, presence of ulcer, reconstruction with full-thickness skin graft and local skin flaps, medical history of diabetes mellitus, and use of immunosuppressive agents. However, in the multivariate analysis only iSCC, BD, and AK retained significance. The frequencies of SSI in iSCC, BD, and AK were 22% (13/58 patients), 15.6% (5/32), and 25% (2/8), respectively; however, the frequency of other non-SCC tumors was only 1.9% (8/414). χ2 -Tests revealed that the frequency of SSI in iSCC, BD, and AK were all significantly higher than in non-SCC tumors, with the frequencies being more than eight times higher. These results suggest that invasive and in situ lesions of SCC are independent risk factors of SSI development after outpatient skin surgery.

Serum lactate dehydrogenase level as a possible predictor of treatment preference in psoriasis.

BACKGROUND: The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. OBJECTIVE: This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. METHODS: The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. RESULTS: There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. CONCLUSION: Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.

Anti-PM/Scl Antibody-positive Systemic Sclerosis Complicated by Multiple Organ Involvement.

A 40-year-old Japanese woman developed malignant-phase hypertension complicated by thrombotic microangiopathy, progressing to end-stage renal disease. Five years later, she was diagnosed with pulmonary arterial hypertension and interstitial pneumonia. Despite a lack of overt skin sclerosis, nucleolar staining in our indirect immunofluorescence analysis and nailfold capillaroscopy facilitated the diagnosis of anti-PM/Scl antibody-positive systemic sclerosis. We observed the persistent presence of anti-PM/Scl antibodies throughout the clinical course, suggesting that her kidney disease was scleroderma renal crisis. Anti-PM/Scl antibodies can be associated with multiple organ diseases. Careful attention to a patient's antinuclear antibody pattern and dermatological findings may help clarify the etiology of undiagnosed diseases.

The Possibility of Deep Learning-Based, Computer-Aided Skin Tumor Classifiers.

The incidence of skin tumors has steadily increased. Although most are benign and do not affect survival, some of the more malignant skin tumors present a lethal threat if a delay in diagnosis permits them to become advanced. Ideally, an inspection by an expert dermatologist would accurately detect malignant skin tumors in the early stage; however, it is not practical for every single patient to receive intensive screening by dermatologists. To overcome this issue, many studies are ongoing to develop dermatologist-level, computer-aided diagnostics. Whereas, many systems that can classify dermoscopic images at this dermatologist-equivalent level have been reported, a much fewer number of systems that can classify conventional clinical images have been reported thus far. Recently, the introduction of deep-learning technology, a method that automatically extracts a set of representative features for further classification has dramatically improved classification efficacy. This new technology has the potential to improve the computer classification accuracy of conventional clinical images to the level of skilled dermatologists. In this review, this new technology and present development of computer-aided skin tumor classifiers will be summarized.

Juvenile case of multiple morphea profunda resulting in joint contracture that was successfully treated with cyclosporin A: A case report and review of the published works.

Morphea profunda refers to inflammatory and sclerotic lesions that start primarily from the deep dermis, subcutaneous fat and fascia. Its pediatric case published work is limited. Here, we report the case of an 8-year-old girl with a 5-year history of multiple subcutaneous nodules on her extremities and a right wrist joint contracture who had been previously diagnosed with juvenile idiopathic arthritis and treated with salazosulfapyridine, low-dose prednisolone (PSL) and methotrexate. We performed biopsies of two subcutaneous nodules, which revealed the typical morphology of morphea profunda. She was administrated a tapered course of oral PSL then cyclosporin A (CyA) for 20 weeks which completely resolved her joint contracture and subcutaneous nodules. We reviewed 11 previously reported cases of morphea profunda and found that some include circumscribed/linear morphea that develop into subcutaneous tissues, indicating that "classical" morphea profunda arising within the deep tissues has rarely been reported. Our report is the first to demonstrate the efficacy of CyA for treatment of morphea profunda, and the possibility of CyA as a treatment option to reduce oral steroid doses in juvenile cases.

Clinical and histological characteristics of livedo racemosa in essential thrombocythemia: A report of two cases and review of the published works.

Essential thrombocythemia (ET) is a rare clonal myeloproliferative disorder with a prevalence rate of approximately 1-3 cases per 100 000 individuals per year. ET is characterized by a persistent increase in the platelet count with hyperplasia of bone marrow megakaryocytes. It is difficult to make a diagnosis of ET, because most thrombocythemia are reactive to certain disease conditions including iron deficiency anemia, infection, collagen diseases and malignant tumors. Mutation in the Janus kinase (JAK)2 gene is present in approximately 50-70% of ET patients, and somatic mutations in the calreticulin (CALR) gene were recently discovered in approximately 20-25% of sporadic patients with ET or primary myelofibrosis. Various cutaneous manifestations of ET often occur by microvascular thrombosis and precede severe arterial and venous thromboembolic events in other organs. Therefore, in order to prevent such severe events, it is important to make an early diagnosis of ET based on a number of cutaneous manifestations. Here, we report two cases of ET diagnosed based on livedo racemosa on feet with gene mutations in JAK2 and CALR, respectively, and show the pathological and immunohistological findings of the livedo resulting from platelet thrombosis rather than vasculitis. We also review the cutaneous manifestations in current published reports of Japanese ET patients. Our patients were successfully treated with low-dose aspirin, a vasodepressor and hydroxyurea, following regressed livedo and reduced platelet counts.

Pyoderma gangrenosum and underlying diseases in Japanese patients: A regional long-term study.

Pyoderma gangrenosum (PG) is a chronic inflammatory disease of unknown cause that presents as an inflammatory and ulcerative disorder of the skin. PG is often associated with an underlying systemic disease. However, the frequencies of the underlying diseases are unclear in Japanese patients. In this retrospective, observational study, all patients diagnosed with PG who visited dermatology departments of nine regional hospitals in and around Ibaraki Prefecture were collected from 1982 to 2011 or 2014. The diagnoses of PG were based on the characteristic clinical and histological appearances and ruling out of infection. Sixty-two PG patients, including 29 males and 33 females, were identified. The ages of onset were 16-89 years, and the mean age was 50.2 years. Fifty (80%) of the 62 patients presented with an ulcerative PG, and the lower leg was the most common site (74%). Forty-six (74%) PG patients had underlying diseases. The most frequent was ulcerative colitis (32%), followed by myelodysplastic syndrome (11%), rheumatoid arthritis (6%) and aortitis syndrome (5%). For treatment, 54 cases (87%) received systemic corticosteroids and 10 received additional treatment with cyclosporin. There was no significant correlation between underlying diseases and response to the initial treatment. Multivariate analysis revealed that the number of affected sites negatively correlated with successful initial treatment. Fifteen (24%) of the 62 cases relapsed. In conclusion, ulcerative colitis and hematological disorders were frequently associated with PG while approximately a quarter of the cases were idiopathic.

The formation of an inclusion complex between a metabolite of ginsenoside, compound K and γ-cyclodextrin and its dissolution characteristics.

OBJECTIVES: 20S-protopanaxadiol 20-O-ß-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of ß-CyD complex. METHODS: The interactions of compound K with ß and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system. KEY FINDINGS: γ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for ß-CyD. The apparent 1:1 stability constant (1.5 × 10(5) m(-1) ) for the γ-CyD complex was 18-fold larger than that (8.2 × 10(3) m(-1) ) of the ß-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax ) of the drug and the time (Tmax ) to reach the maximum plasma level after its oral administration to rats. CONCLUSIONS: The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the ß-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.