Eosinophilic fasciitis is a disease originally proposed as “diffuse fasciitis with eosinophilia” by Shulman in 1974. The patients with this disease often have history of strenuous exercise or labor a ...few days to 1–2 weeks before the onset.
The chief symptoms are symmetrical, full-circumference swelling and plate-like hardness of the distal limbs. This is accompanied by redness and pain in the early stages, with many cases exhibiting systemic symptoms such as fever or generalized fatigue. The lesions have been observed extending to the proximal limbs, though never on the face or fingers.
En bloc biopsies from the skin to the fascia show marked fascial thickening and inflammatory cell infiltration by the lymphocytes and plasma cells. Eosinophilic infiltration is useful for the diagnosis but is only seen in the early stages of the disease.
Recently, “Diagnostic criteria, severity classification, and clinical guidelines for eosinophilic fasciitis” were published.
This review article discusses about eosinophilic faciitis in detail, from its pathophysiology to the treatment.
Summary Excessive extracellular matrix deposition in the skin, lung, and other organs is a hallmark of systemic sclerosis (SSc). Fibroblasts isolated from sclerotic lesions in patients with SSc and ...cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix components, consistent with the disease phenotype. Thus, cultured scleroderma fibroblasts serve as a principal experimental model for studying the mechanisms involved in extracellular matrix overproduction in SSc. The pathogenesis of SSc is still poorly understood, but increasing evidence suggests that transforming growth factor-β (TGF-β) is a key mediator of tissue fibrosis as a consequence of extracellular matrix accumulation in the pathology of SSc. TGF-β regulates diverse biological activities including cell growth, cell death or apoptosis, cell differentiation, and extracellular matrix synthesis. TGF-β is known to induce the expression of extracellular matrix proteins in mesenchymal cells and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the extracellular matrix. This review focuses on the possible role of autocrine TGF-β signaling in the pathogenesis of SSc.
An 80‐year‐old man, who developed multiple lymph node and skin metastasis of malignant melanoma, received nivolumab monotherapy. Two weeks after the first dose, he experienced anorexia and fatigue, ...and suffered from progressive, severe dyspnea and muscle weakness. We diagnosed him with myocarditis, myositis, and myasthenic crisis induced by nivolumab. We commenced steroid therapy, immune absorption therapy, plasma exchange therapy, and i.v. immunoglobulin therapy, and succeeded in saving his life. Because his serum level of anti‐acetylcholine receptor antibodies in a sample collected before nivolumab treatment were positive and were elevated significantly after nivolumab, we suspected that nivolumab triggered a severe autoimmune response, which progressed subclinical myasthenia gravis to myasthenic crisis. We carried out T cell receptor repertoire analysis using next‐generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle after nivolumab treatment, implying a very strong T cell immune response against muscular cells. To avoid severe immune‐related adverse events, the exclusion of patients with subclinical autoimmune disease is very important for treatment with immune checkpoint inhibitors.
Myasthenic crisis and polymyositis were induced by one dose of nivolumab. We performed T cell receptor repertoire analysis using the next‐generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle tissue after the nivolumab treatment, implying the very strong T cell immune response against muscular cells
Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death‐1 protein, were suggested in previous phase 1 studies. The present phase 2, ...single‐arm study (JAPIC‐CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3‐week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression‐free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1‐ and 2‐year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug‐related adverse events were observed in 31.4% of patients. Pretreatment serum interferon‐γ, and interleukin‐6 and ‐10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.
Repeated intravenous administration of nivolumab had potent and durable anti‐tumor effects and a manageable safety profile in advanced melanoma patients in Japan. Pre‐treatment serum cytokine profiles were suggested as correlates for predicting treatment efficacy.
Cutaneous cryptococcosis is classified either as primary or secondary based on the route of infection. The disease can also be classified either as localized cutaneous cryptococcosis or cutaneous ...manifestations of disseminated cryptococcosis. However, from a physician's point of view, whether lesions are localized to the skin or are disseminated/systemic is more important than the route of infection. The Clinical Practice Guidelines for Diagnosis and Treatment of Cryptococcosis, which was established in 2019 by the Japanese Society for Medical Mycology, adopted the latter classification. Localized cutaneous cryptococcosis is defined as a condition in which lesions are confined within a limited part of the skin, not systemically disseminated at the same time, and are associated with neither cryptococcal fungemia nor antigenemia. This type of cutaneous cryptococcosis is uncommon in Japan. Only 65 cases were reported during the 50-year study period from 1968 to August 2018, with the patients divided into two groups: immunocompromised patients (n=44, 68%) and immunocompetent patients (n=21, 32%). None of the patients were infected with the human immunodeficiency virus (HIV). Localized cutaneous cryptococcosis can also occur in non-HIV-infected patients and well-appearing individuals, therefore, it is considered an important infection in routine dermatology practice. Here, we outline the classification, diagnosis, and treatment of cutaneous cryptococcosis and present a summary of cutaneous cryptococcosis cases reported in Japan.
Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death ...1 (PD‐1) ligands. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single‐arm, open‐label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee‐assessed overall response rate was 34.8% (90% confidence interval, 20.8–51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment‐related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI‐142533.)
We conducted the present single‐arm, open‐label, multicenter, phase 2 study to evaluate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Nivolumab administered at a dose of 3 mg/kg once every 2 weeks was tolerable and demonstrated favorable anti‐cancer activity. In addition, patients with BRAF wild‐type and those with BRAF mutant melanoma both experienced response.
Highlights • Exosome levels in SSc skin were up-regulated. • Increased exosomes in cultured media of SSc fibroblasts stimulated type I collagen expression levels in NS fibroblasts. • Treatment with ...serum-derived exosomes accelerated skin ulcer healing in mice.
We established diagnostic criteria and severity classification of localized scleroderma because there is no established diagnostic criteria or widely accepted severity classification of the disease. ...Also, there has been no clinical guideline for localized scleroderma, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence‐based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of localized scleroderma.
Abstract Background MicroRNA-221 (miR-221) is known to be abnormally expressed in malignant melanoma (MM) cells, and it favors the induction of the malignant phenotype through down-modulation of ...p27Kip1/CDKN1B and the c-KIT receptor. This suggests that the serum level of miR-221 might increase in patients with MM and thus could be used as a new tumor marker. Objective To evaluate the possibility that the serum miR-221 level can be a marker of MM. Methods Serum samples were obtained from 94 MM patients and 20 healthy controls. MicroRNAs were purified from serum, and miR-221 levels were measured by quantitative real-time polymerase chain reaction. Results Circulating miR-221 was detectable and could be quantified in serum samples. MM patients had significantly higher miR-221 levels than healthy controls. Among the MM patients, the miR-221 levels were significantly increased in patients with stage I–IV MM compared to those with MM in situ , and the levels were correlated with tumor thickness. Moreover, a longitudinal study revealed a tendency for the miR-221 levels to decrease after surgical removal of the primary tumor, and to increase again at recurrence. Conclusions Serum levels of miR-221 were significantly increased in MM patients and may be useful not only for the diagnosis of MM, but also for the differentiating MM in situ from stage I–IV MM, and for evaluating tumor progression and monitoring patients during the follow-up period. In addition, considering that the serum levels of miR-221 were correlated with tumor thickness, miR-221 might also be useful as a prognostic marker for patients with MM.
We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. ...Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence‐based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis.
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