Search

Background: Patients with psoriasis report impaired health-related quality of life (HRQoL; Dermatology Life Quality Index score ≥ 2) even after achieving clear or almost-clear skin with biologic treatment. Objective: To assess the effectiveness of brodalumab in HRQoL improvement and the factors associated with incomplete HRQoL improvement in Japanese patients with psoriasis. Methods: As a part of the single-arm, open-label, multicenter, prospective ProLOGUE study (Japan Registry of Clinical Trials identifier: jRCTs031180037), patients were treated with 210 mg of subcutaneous brodalumab in daily clinical practice until week 48. The absolute Psoriasis Area and Severity Index scores and patient-reported outcomes were assessed at baseline and weeks 12 and 48. Results: Seventy-three patients (male, 82.2%; median age, 54.0 years) were enrolled. The Dermatology Life Quality Index and European Quality of Life 5-Dimension 5-Level Utility Index scores significantly improved from baseline to weeks 12 and 48. At week 48, all 13 patients with a Dermatology Life Quality Index score of ≥2 and an absolute Psoriasis Area and Severity Index score of 0 to ≤2 reported itching. Limitations: Unclear generalizability of the results to other biologics. Conclusion: Treatment with brodalumab improved HRQoL in patients with psoriasis. Itching may contribute to incomplete HRQoL improvement in patients who have achieved clear or almost-clear skin.

Aim: Chronic inflammation is closely associated with tryptophan (TRP)-kynurenine (KYN) metabolic pathway. However, TRP-KYN pathway has not been fully elucidated in psoriasis, a systemic inflammatory disease with skin lesions and extracutaneous manifestations. Herein, we studied comprehensively serum profiles of TRP-KYN pathway metabolites in psoriatic patients (PSOs) to clarify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate serum biomarkers reflecting systemic inflammation in PSOs. Methods: The concentrations of main TRP metabolites, TRP, KYN, 3-hydroxykynurenine (3HK), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), and anthranilic acid (AA), were determined by high-performance liquid chromatography in the sera from 65 PSOs and 35 healthy controls (HCs). The levels of these metabolites and the ratios of metabolites were compared between these subjects. The correlations between these values and the psoriasis area severity index (PASI) scores were analyzed. Skin samples from PSOs and HCs were subjected to immunohistochemical staining for kynureninase, catabolic enzyme from KYN or 3HK to downstream. Cytokine concentrations were comprehensively measured in the same samples and the correlations between the cytokine levels and TRP-KYN pathway metabolite levels were examined. Results: Serum TRP, KYN, and KYNA concentrations were lower and the 3HAA concentrations were higher in PSOs than in HCs. The ratios of 3HK/KYN, 3HAA/3HK, and 3HK/AA were higher in PSOs than in HCs. The AA levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the PASI scores. The AA, KYN, and KYNA levels were positively correlated with the interferon gamma-induced protein 10 (IP-10) concentrations. Kynureninase expression was enhanced in the epidermis, both involved and uninvolved skin. Conclusions: Serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs. TRP-KYN pathway-associated processes, including kynureninase activation, may be involved in the pathogenesis of psoriasis, and thus serve as targets for psoriasis therapy.

Abstract Objectives Dermatomyositis (DM) is an autoimmune disease that presents with a wide variety of clinical manifestations. Patients with DM or clinically amyopathic dermatomyositis (CADM) with antimelanoma differentiation‐associated protein 5 (anti‐MDA5) antibodies are frequently associated with interstitial pneumonia, especially rapidly progressive interstitial lung disease. Progranulin (PGRN) is an autocrine growth factor involved in inflammation. Elevated serum PGRN levels have been reported in the patients with systemic lupus erythematosus and rheumatoid arthritis. However, they have not been precisely studied in DM/CADM. We assessed PGRN levels as a potential biomarker for DM/CADM with anti‐MDA5 antibodies. Methods Twenty‐four DM/CADM patients with anti‐MDA5 antibodies, 12 patients without anti‐MDA5 antibodies, and eight healthy volunteers were enrolled. We measured serum PGRN levels and compared them between the anti‐MDA5 antibody‐positive and antibody‐negative groups. They were also measured before and after the start of treatment in anti‐MDA5 antibody‐positive patients. We examined the correlations between serum PGRN levels and laboratory data such as serum KL‐6 and ferritin levels. Results Patients with DM/CADM, especially those with anti‐MDA5 antibodies, had significantly higher serum PGRN levels than healthy individuals. They decreased after the start of treatment. Serum PGRN levels were positively correlated with serum KL‐6 and ferritin levels, and anti‐MDA5 antibody titers. Conclusions This is the first study to show that PGRN levels were significantly elevated in the sera of DM/CADM patients, particularly in those with anti‐MDA5 antibodies. PGRN may be a useful biomarker of disease activity. However, further studies are required to reveal the mechanisms of PGRN in DM/CADM more precisely.

Abstract Objectives Cutaneous IgM/IgG vasculitis (IgM/IgG V) is characterized by leukocytoclastic vasculitis histologically and by IgM‐ or IgG‐ perivascular deposition. However, clinical differences between IgM/IgG V and skin‐limited IgA vasculitis (IgA V) have not been fully clarified. In the present study, we assessed the clinical and histopathological differences between IgM/IgG V and IgA V. Methods We examined 14 patients with IgM/IgG V and 24 patients with skin‐limited IgA V. The cases associated with systemic diseases were excluded. Clinical findings, laboratory data, and histological findings were compared between IgM/IgG V and IgA V groups. Results Livedo lesions appeared more often, and palpable purpura less often in IgM/IgG V. Localization of the lesions was more limited to the lower legs in IgM/IgG V. In laboratory data, there were no statistical differences in peripheral blood cell counts, IgG, IgA, and IgM levels between the two groups. Histopathological findings showed less infiltration of neutrophils, CD8+ T cells, and CD3+ T cells, and nuclear dusts in IgM/IgG V. Systemic steroids were administered significantly less frequently in IgM/IgG V cases, but the recurrence rate did not differ. Conclusions Based on these results, IgM/IgG V may be a clinically and histologically different entity from IgA V. However, further studies are necessary to define the differences between them more clearly.

Abstract Introduction Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2‐antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses. Methods We investigated the roles of α2AP in the pathogenesis of LN using a pristane‐induced lupus mouse model. Results The levels of plasmin‐α2AP complex and α2AP were elevated in the lupus model mice. In addition, α2AP deficiency attenuated the pristane‐induced glomerular cell proliferation, mesangial matrix expansion, collagen production, fibrin deposition, immunoglobulin G deposition, and proinflammatory cytokine production in the model mice. We also showed that interferon‐γ (IFN‐γ), which is an essential inducer of LN, induced α2AP production through the c‐Jun N‐terminal kinase (JNK) pathway in fibroblasts. In addition, plasmin attenuated the IFN‐γ‐induced proinflammatory cytokine production through the AMPK pathway in macrophages, and α2AP eliminated these effects. Furthermore, we showed that α2AP induced proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages. Conclusion α2AP regulates the inflammatory responses through plasmin inhibition and proinflammatory cytokine production and is associated with the development of LN. Our findings may be used to develop a novel therapeutic approach for SLE.

Myositis-specific autoantibodies (MSAs) including anti-Mi-2 and anti-nuclear matrix protein 2 (NXP-2) antibodies have been detected in the patients with dermatomyositis (DM), and are useful tools for identifying clinical subsets of DM. MSAs are exclusively found in DM patients. Anti-Mi-2 antibody-positive DM patients show the typical skin lesions and myositis and are rarely associated with internal malignancy and interstitial lung disease (ILD). On the other hand, adult DM patients with anti-NXP-2 antibody often show calcinosis and internal malignancy, but rarely ILD. In addition, anti-NXP-2 antibody-positive DM patients have severe phenotype with myalgia, peripheral edema, and significant dysphagia, but with mild skin lesions. Herein, we report a rare case of classic DM coexisting with both anti-Mi-2 and anti-NXP-2 antibodies, clinically, without ILD or internal malignancy. Our patient had typical skin manifestations, muscle weakness, muscle pain, and general fatigue without calcinosis, peripheral edema, or dysphagia. Thus, the clinical phenotype was similar to anti-Mi-2 antibody-positive DM.

Abstract Background Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanisms underlying these disorders remain unclear. It was recently reported that α2-antiplasmin (α2AP) is elevated in fibrotic tissue and that it is associated with the development of fibrosis. In the present study, we examined the mechanism underlying the production of α2AP on the development of fibrosis. Methods To clarify the mechanism underlying the production of α2AP on the development of fibrosis, we focused on high-mobility group box 1 (HMGB1), which is associated with the development of fibrosis. The mouse model of bleomycin-induced fibrosis was used to evaluate the production of α2AP on the development of fibrosis. Results We found that HMGB1 induced the production of α2AP through receptor for advanced glycation end products (RAGE) in fibroblasts. Next, we showed that macrophage reduction by a macrophage-depleting agent, clodronate, attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycin-induced mice. We also showed that IL-4-stimulated alternatively activated macrophages induced the production of HMGB1, that IL-4-stimulated alternatively activated macrophage conditioned media (CM) induced pro-fibrotic changes and α2AP production, and that the inhibition of HMGB1 and RAGE attenuated these effects in fibroblasts. Furthermore, the blockade of IL-4 signaling by IL-4Rα neutralizing antibodies attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycin-induced mice. Conclusion These findings suggest that alternatively activated macrophage-derived HMGB1 induced the production of α2AP through RAGE and that these effects are associated with the development of fibrosis. Our findings may provide a clinical strategy for managing fibrotic disorders.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) shows various clinical features and is histologically characterized by palisaded granulomas surrounding degenerated collagen. PNGD is known to be associated with a variety of systemic conditions such as rheumatoid arthritis and systemic lupus erythematosus. Furthermore, PNGD has been reported to be associated with antineutrophilic cytoplasmic antibody-associated vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis. Here, we report a case of PNGD associated with GPA, which showed the infiltration of CD163-positive M2 macrophages in the skin lesion with elevated serum level of soluble CD163 (sCD163). The serum sCD163 level was reduced to normal range after systemic steroid therapy. Thus, M2 macrophages may play a role in the pathomechanisms of PNGD associated with GPA.

Royal jelly (RJ), a creamy substance secreted by honeybees, is the exclusive diet for queen bee differentiation and life maintenance. RJ has been used in cosmetics, beverages, medicines, and supplements worldwide. However, allergy is a concerning issue for RJ, especially in atopic dermatitis (AD) and asthma patients. In some cases, allergic reactions are seen after the first intake of RJ, suggesting the existence of allergens cross-reactive with RJ. Information about the cross-reactive allergens is very important for the safe application of RJ; however, study of this cross-reactivity is quite limited. In this study, we attempted to identify allergens cross-reactive with RJ by using serum samples from 30 AD patients who had never been exposed to RJ. In an enzyme-linked immunosorbent assay (ELISA) experiment, RJ-binding IgE antibodies were detected in the serum of 10 out of 30 patients, and their antibody titers ranged from 4- to 2,048-fold dilution ratios. Additionally, 3 AD patients were determined to be positive in a skin-prick test (SPT) with an RJ solution. Significant correlations were observed between the anti-RJ antibody titer and nonspecific IgE and between the anti-RJ antibody titer and the Eczema Area and Severity Index score. We further examined the cross-reactivity between RJ and 14 typical allergens by using an ELISA-inhibition assay and demonstrated that the following 6 allergens showed cross-reactivity with RJ: the European house dust mite (HDM) (Dermatophagoides pteronyssinus), American HDM (Dermatophagoides farinae), snow crab (Chionocetes spp.), edible crab (Cancer pagurus), German cockroach (Blatella germanica), and honeybee venom (Apis mellifera). In conclusion, people with a history of allergic diseases, including AD, asthma, and allergic rhinitis, should be cautioned against consuming RJ products because of the potential for cross-reactive responses to ensure the safe and successful use of RJ supplements.

Panniculitis is an uncommon skin eruption observed in patients with dermatomyositis (DM)/clinically amyopathic dermatomyositis (CADM), especially in anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM. We present here a 51-year-old Japanese woman with an anti-MDA5 antibody-positive DM who initially had cellulitis-like erythema on her right mandible. Histopathological findings showed a subcutaneous lobular infiltration of lymphocytes. The patient developed typical skin eruptions of DM/CADM, rapidly progressive interstitial lung disease, and severe muscle weakness 2 weeks after the first visit. After the diagnosis of anti-MDA5 antibody-positive DM, she was treated with intravenous steroid pulse therapy (methylprednisolone, 1,000 mg/day for 3 days), oral prednisolone at 1.0 mg/kg/day, and tacrolimus at 4.0 mg/day. The lesions of panniculitis associated with DM/CADM typically present on the buttocks, thighs, arms, and abdomen. This is the first DM/CADM case with localized panniculitis on the face. Panniculitis and myositis usually show simultaneous improvement during treatment. Although panniculitis disappeared with steroid and tacrolimus treatment and did not recur, muscle weakness was intractable and recurred in this case. This indicates that the clinical courses of panniculitis and myositis of DM/CADM do not always change in parallel.

Epidermal nevus syndrome (ENS) is a congenital disorder characterized by widespread linear epidermal lesions consisting of epidermal nevus and extracutaneous involvements, especially of the central nervous system and skeletal system. Garcia–Hafner–Happle syndrome, also known as fibroblast growth factor receptor 3 (FGFR3)-ENS, is characterized by a systematized keratinocytic EN of soft and velvety type with neurological abnormalities such as seizures, intellectual impairment, and cortical atrophy. We present a case of a 9-year-old Japanese boy afflicted with Garcia–Hafner–Happle syndrome associated with dwarfism and atopic dermatitis. We show the results of physical examination, DNA analysis, and imaging studies and discuss the mutation underlying the child’s disorder.

Sweet’s syndrome is a neutrophilic dermatosis characterized by an abrupt onset of painful erythematous lesions showing neutrophilic infiltrates in the dermis. Fever and an elevated neutrophil level are generally observed. Sweet’s syndrome may be idiopathic, malignancy-associated, or drug-induced (mainly involving granulocyte colony-stimulating factor (G-CSF) administration). Although systemic corticosteroids are usually effective, the symptoms of Sweet’s syndrome recur in some refractory cases. Herein, we report a case of a 55-year-old Japanese woman with recurrent symptoms of fever (>39°C) and painful erythematous lesions on her four extremities, trunk, and neck. Laboratory findings revealed leukocytosis and high levels of C-reactive protein (CRP) and G-CSF. She was diagnosed with a recurrence of Sweet’s syndrome, and was exclusively treated with granulocyte and monocyte adsorption apheresis (GMA) therapy once a week for 3 consecutive weeks. After the first session of GMA therapy, all symptoms including the erythematous lesions and fever were completely resolved, and serum G-CSF level was reduced. Leukocyte count, neutrophil count, serum amyloid A protein, and CRP levels were restored within normal ranges by 2 weeks. Thus, GMA therapy can successfully treat a patient with recurrent Sweet’s syndrome, potentially related to the restoration of elevated serum G-CSF levels.

IFN-γ is detected in chronic lesions of atopic dermatitis (AD); however, its specific role remains to be elucidated. An impaired stratum corneum barrier function is a hallmark of AD, and it is associated with a reduction in ceramides with long-chain fatty acids (FAs) in the stratum corneum. FA elongases, ELOVL1 and ELOVL4, are essential for the synthesis of these ceramides, together with ceramide synthase 3 (CerS3). We have previously shown that IFN-γ, but not other cytokines, induced the downregulation of these enzymes in cultured keratinocytes. Our aim was to investigate the in vivo role of IFN-γ in the lesional skin of AD by analyzing mouse dermatitis models. The local mRNA expression of IFN-γ increased in mite fecal antigen-induced AD-like dermatitis in NC/Nga mice but not in imiquimod-induced psoriasis-like dermatitis in BALB/c mice. The mRNA expression of ELOVL1 and ELOVL4 significantly decreased in AD-like dermatitis, whereas ELOVL1 increased in psoriasis-like dermatitis. The expression of CerS3 increased slightly in AD-like dermatitis, but it increased by 4.6-fold in psoriasis-like dermatitis. Consistently, the relative amount of ceramides with long-chain FAs decreased in AD-like dermatitis but not in psoriasis-like dermatitis. These results suggest that IFN-γ in the lesional skin may reduce ceramides with long-chain FAs by decreasing the expression of ELOVL. Thus, IFN-γ may contribute to the chronicity of AD by impairing barrier function.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

Drug-induced hypersensitivity syndrome (DIHS) is a severe multiorgan system adverse drug reaction with reactivation of human herpesviruses (HHVs) such as HHV-6, HHV-7, cytomegalovirus (CMV) and Epstein-Barr virus. Various complications, including autoimmune diseases, sometimes appear during the course of DIHS. We report a case of salazosulfapyridine-induced DIHS associated with HHV-6 reactivation. Two and a half months after the onset of DIHS, subacute thyroiditis occurred, possibly associated with CMV reactivation. Prednisolone (20 mg/day) was effective for subacute thyroiditis. Long-term follow-up is needed in patients with DIHS because of the possible onset of autoimmune diseases.

Eosinophilic fasciitis is clinically characterized by symmetrical scleroderma-like indurations of the skin with pain. The histological features are fascial inflammation with lymphocytes and eosinophils as well as thickened and fibrotic fascia. Lymphocytic infiltration and degeneration of the underlying muscle are rarely observed. We report a 69-year-old Japanese woman who presented with multiple areas of glossy induration and painful peau d'orange-like lesions on the chest and four extremities. T2-weighted magnetic resonance imaging showed significant hyperintense thickening of the fascia of the lower extremities. Histopathological examination of a biopsy specimen from the induration showed marked fibrinoid degeneration of the fascia and the neighboring muscle with mixed cellular infiltration of lymphocytes and eosinophils. The predominant CD8+ lymphocytic infiltrates were observed by immunohistological study. A diagnosis of eosinophilic fasciitis with myositis was made. Oral administration of prednisolone and discontinuation of exercise significantly improved the lesions and pain.

Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies.Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated.In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006).Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.

OBJECTIVE: To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). METHODS: This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. RESULTS: Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. CONCLUSION: Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the "anti-synthetase syndrome."