Predictive factors and scoring system for intravascular large B-cell lymphoma among suspected cases: a single-center retrospective analysis.

BACKGROUND: Although the utility of random skin biopsies in the diagnosis of intravascular large B-cell lymphoma (IVLBCL) has been confirmed, the patients who should undergo random skin biopsies remain unclear. OBJECTIVES: To assess predictive factors for IVLBCL and establish a scoring system for the applicability of random skin biopsies. METHODS: We conducted a retrospective case-control study of IVLBCL-suspected patients who underwent random skin biopsies between April 2010 and March 2022. We compared the general symptoms, imaging findings, and laboratory findings between IVLBCL and non-IVLBCL cases. RESULTS: Fifty-three patients were enrolled in this study. Eight patients were diagnosed with IVLBCL, and 35 patients were diagnosed with other diseases. The final diagnosis was unclear in 10 patients. There were no significant differences in the frequency of general symptoms and imaging findings between IVLBCL and non-IVLBCL cases. Among laboratory findings, IVLBCL cases showed significantly higher serum lactate dehydrogenase (LDH) and soluble IL-2 receptor (sIL-2R) levels and lower platelet counts than non-IVLBCL cases. We established a scoring system to predict IVLBCL by using these three parameters. The cut-off values were as follows: serum LDH level, 256 IU/l; serum sIL-2R level, 2011 U/ml; and platelet count, 107 × 109 /l. IVLBCL was not included in patients with scores of <2. The probabilities of IVLBCL in patients with scores 2 and 3 were 18% and 86%, respectively. CONCLUSIONS: Our simple scoring system can help clinicians determine the applicability of random skin biopsies in IVLBCL-suspected cases.

Increased Interleukin-36ß Expression Promotes Angiogenesis in Japanese Atopic Dermatitis.

While atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, an increase in other types of inflammatory cytokines is also noted in AD and they may also contribute to the development of the disease. Recently, the efficacy of an anti-IL-36 receptor antibody in AD was demonstrated in a clinical trial. Although there have been several reports on IL-36α and IL-36γ expression and function in AD, IL-36ß has been barely studied. In this report, we examined IL-36ß expression and function using clinical samples of AD and the epidermal keratinocyte cell line, HaCaT cells. We demonstrated that IL-36ß expression in epidermal keratinocytes was increased in AD lesional skin compared to healthy skin. IL-36ß promoted vascular endothelial growth factor A production in HaCaT keratinocytes through phosphorylation of extracellular signal-regulated kinases 1 and 2. In addition, IL-36ß up-regulated placental growth factor mRNA expression in HaCaT keratinocytes. IL-36ß expression levels in epidermal keratinocytes were correlated with the number of dermal vessels in AD skin. These results suggest that IL-36ß may play an important role for angiogenesis in lesional skin of AD and that IL-36ß can be a therapeutic target in AD.

Elevated Myeloperoxidase-DNA Complex Levels in Sera of Patients with IgA Vasculitis.

INTRODUCTION: IgA vasculitis is a systemic disease that results from the entrapment of circulating IgA-containing immune complexes in small-vessel walls in the skin, kidneys, and gastrointestinal tract. An excessive formation of neutrophil extracellular traps (NETs) is involved in the pathogenesis of vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This study aimed to clarify whether NETs are implicated in IgA vasculitis. METHODS: Twenty-two patients with IgA vasculitis and 4 healthy volunteers were enrolled in this study. Serum levels of myeloperoxidase (MPO)-DNA complex, a fragment derived from NETs, were determined by enzyme-linked immunosorbent assay (ELISA), and the association between MPO-DNA complex levels and clinical parameters was examined. The presence of the ANCA was also assessed by ELISA specific for MPO and proteinase 3 (PR3) and indirect immunofluorescence (IIF), followed by assessing the differences in clinical parameters with and without the ANCA. RESULTS: Serum MPO-DNA complex levels were significantly higher in patients with IgA vasculitis than those in healthy controls. A significant positive correlation between the serum MPO-DNA complex and IgA levels was noted. Interestingly, 63.6% of IgA vasculitis patients were ANCA-positive in IIF with an atypical pattern, whereas neither MPO-ANCA nor PR3-ANCA was detected by ELISA. These findings indicated that some IgA vasculitis patients possessed the so called minor ANCA. Serum IgA and MPO-DNA complex levels and the frequency of hematuria in the minor ANCA-positive group were significantly higher than in the minor ANCA-negative group. CONCLUSION: The collective findings suggested that NETs are certainly involved in the pathogenesis of IgA vasculitis.

Exploration of biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab: A study protocol.

BACKGROUND: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. METHODS: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment." DISCUSSION: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells.

Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders.

Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa.

We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, γ-interferon, tumor necrosis factor-α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti-moesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN.

Treatment for cutaneous arteritis patients with mononeuritis multiplex and elevated C-reactive protein.

Cutaneous arteritis (cutaneous polyarteritis nodosa, CA) is a necrotizing vasculitis of arteries within the skin. CA is a new classification under single-organ vasculitis, as adopted by the 2012 Chapel Hill consensus conference (CHCC 2012). Some patients originally diagnosed as having CA could develop additional disease manifestations that warrant reclassifying as systemic polyarteritis nodosa (PAN) according to the CHCC 2012. We retrospectively investigated 101 patients with CA seen at our department between 2003 and 2012. There was a significantly higher frequency of inflammatory plaques and leg edema in CA patients with elevated C-reactive protein (CRP) compared to CA patients with normal CRP. Similarly, there were significant differences in the incidence of arthralgia and mononeuritis multiplex between the two patient groups. We found significantly positive correlations between CRP and creatinine titers in serum in all 101 CA patients. Prednisolone was administrated in a significantly greater percentage of patients with elevated CRP compared to patients with normal CRP. Repeated i.v. cyclophosphamide pulse therapy (IV-CY) with prednisolone therapy at an early stage resulted in complete resolution without adverse effects or severe complications. We regard inflammatory plaques and leg edema with elevated serum CRP as an indication of a more severe condition, and treated them effectively with prednisolone. Assuming mononeuritis multiplex and/or arthritis exist with elevated CRP, we propose that earlier treatment by IV-CY with prednisolone should be indicated for CA patients who demonstrate these more severe manifestations to prevent progression to PAN.