Clinical and laboratory findings characterizing the need for systemic corticosteroids and nonsteroidal systemic therapies, and the predicted outcomes in cutaneous polyarteritis nodosa: A single-centre retrospective analysis.

BACKGROUND: Cutaneous polyarteritis nodosa (cPN) is a necrotizing arteritis of medium-sized vessels limited to the skin. Because of its rarity and the diversity of its clinical manifestations, there is no consensus treatment. Moreover, there are no established indicators that predict disease severity or its outcome. OBJECTIVES: To investigate clinico-laboratory features that predict patients requiring systemic therapy, including corticosteroids, to control the disease activity. METHODS: Thirty-six cPN patients who had not received systemic corticosteroids at the initial visit were retrospectively analysed by correlating the treatment and its response with clinico-laboratory findings. RESULTS: The major medications administered were antiplatelet agents (63.9%), vasodilators (38.9%), and prednisolone (PSL) (36.1%). In all, 23 cases achieved remission without PSL; 5 were managed with compression therapy alone or even observation; 18 received antiplatelet monotherapy or combined with vasodilator/dapsone; 13 required PSL; 10 achieved remission with PSL monotherapy or PSL and single/multiple medications and 3 with PSL and multiple drugs failed to achieve remission and underwent limb amputation. There were more skin ulcers and an elevated peripheral white blood cell (WBC) count and erythrocyte sedimentation rate (ESR) before corticosteroid induction in patients requiring PSL. Three cases with treatment failure had a markedly elevated ESR (>50). CONCLUSIONS: More than half of cPN can achieve remission without corticosteroids; an elevated WBC and the presence of skin ulcers predict the need for PSL; a high ESR before corticosteroid induction predicts treatment resistance, even with PSL.

Diagnostic utility of the basophil activation test in natto-induced hypersensitivity.

BACKGROUND: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. METHODS: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. RESULTS: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. CONCLUSIONS: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation.

Using exome analysis, we identified a novel overgrowth syndrome arising from a mutation in PDGFRB, which plays a critical role in growth and differentiation. This entity is characterized by somatic overgrowth, distinctive facial features, hyperelastic and fragile skin, white matter lesions, and neurologic deterioration.

Visualization of intradermal blood vessel structures by dual-wavelength photoacoustic microscopy and characterization of three-dimensional construction of livedo-racemosa in cutaneous polyarteritis nodosa.

BACKGROUND: Photoacoustic microscopy is expected to have clinical applications as a noninvasive and three-dimensional (3D) method of observing intradermal structures. OBJECTIVE: Investigate the applicability of a photoacoustic microscope equipped with two types of pulsed lasers that can simultaneously recognize hemoglobin and melanin. METHODS: 16 skin lesions including erythema, pigmented lesions, vitiligo and purpura, were analyzed to visualize 3D structure of melanin granule distribution and dermal blood vessels. 13 cases of livedo racemosa in cutaneous polyarteritis nodosa (cPN) were further analyzed to visualize the 3D structure of dermal blood vessels in detail. Vascular structure was also analyzed in the biopsy specimens obtained from tender indurated erythema of cPN by CD34 immunostaining. RESULTS: Hemoglobin-recognition signal clearly visualized the 3D structure of dermal blood vessels and melanin-recognition signal was consistently reduced in vitiligo. In livedo racemosa, the hemoglobin-recognition signal revealed a relatively thick and large reticular structure in the deeper layers that became denser and finer toward the upper layers. The numerical analysis revealed that the number of dermal blood vessels was 1.29-fold higher (p<0.05) in the deeper region of the lesion than that of normal skin. The CD34 immunohistochemical analysis in tender indurated erythema revealed an increased number of dermal vessels compared with normal skin in 88.9% (8/9) of the cases, suggesting that vascular network remodeling had occurred in cPN. CONCLUSION: The photoacoustic system has an advantage in noninvasively detecting dermal blood vessel structures that are difficult to recognize by two-dimensional histopathology specimen examination and is worth evaluating in various skin diseases.

The prevalence of abnormal pulse wave velocity, pulse contour analysis and ankle-brachial index in patients with livedo reticularis: a controlled study.

OBJECTIVE: To evaluate the prevalence of abnormal pulse wave velocity (PWV), pulse contour analysis (PCA) and abnormal ankle-brachial pressure index (ABPI) in patients with livedo reticularis (livedo) and without livedo. METHODS: We recruited 74 patients, of whom 41 had livedo: 16 APS, 9 APS with SLE and 16 with livedo (negative for aPL or lupus). The other group of 33 patients without livedo consisted of 10 APS, 8 APS with SLE and 15 with SLE only. Livedo was diagnosed and confirmed by a dermatologist. PWV was assessed in fasting patients by the Micro Medical PulseTrace analyser using a 4 MHz continuous-wave directional Doppler probe and digital PCA was analysed by Micro Medical PulseTrace by the same operator. Chi-square with Yates's correction was used for comparing results. RESULTS: The median age of the livedo patients was 46 (29-71) years and of the non-livedo patients was 45 (25-68) years. Abnormal values of PWV in 10/41 (24.40%), ABPI in 4/41 (9.8%) and PCA in 10/41 (24.40%) patients were observed in the livedo group and in the non-livedo group abnormal values of PWV in 1/33 (P ≤ 0.025), ABPI in 0/33 (P = NS) and PCA in 5/33 (P = NS) were observed. CONCLUSION: Patients with livedo reticularis are more likely to have abnormal PWV, indicating arterial stiffness.

Cutaneous plasmacytosis: report of 6 cases with or without systemic involvement.

BACKGROUND: Cutaneous plasmacytosis and systemic plasmacytosis are rare entities arising primarily in patients of Japanese descent. The origin and exact pathogenesis are poorly understood. OBJECTIVE: We sought to determine clinicopathologic features of cutaneous and systemic plasmacytosis. METHODS: We describe the clinicopathologic features of 6 patients with cutaneous plasmacytosis with or without systemic involvement (male:female = 3:1; mean age: 49.7 years; median age: 50.5 years; age range: 29-64 years). RESULTS: Patients presented clinically with multiple, red-brown infiltrated plaques and flat tumors, mainly located on the trunk. Histology revealed in all cases the presence of clusters of mature plasma cells within the dermis. Lymphoid follicles with reactive germinal centers were seen in 3 cases. Five cases showed the expected polyclonal expression of immunoglobulin light chain by the plasma cells, but monoclonality was observed in 1 case, thus showing overlapping features with cutaneous marginal zone lymphoma. One patient revealed overlapping features with multicentric Castleman disease. LIMITATIONS: This was a retrospective study on a relatively small number of patients. CONCLUSIONS: Despite typical clinical presentation, some of our patients presented with histopathologic and immunohistochemical features that deviated from the conventional appearance. Our observation confirms and expands previous observations of this elusive entity, suggesting that the spectrum of clinicopathologic presentations may be wider than previously recognized.

Response to hydroxychloroquine in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI).

BACKGROUND: Hydroxychloroquine (HCQ) is not available in Japan. To design a clinical trial of HCQ, we evaluated the response to HCQ in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI). METHODS: Twenty-seven patients with lupus-related skin disease who started HCQ at four hospitals were included. Patients were categorized into responders by the CLASI response criteria. The points and the rate of improvement in the CLASI activity score after 16 weeks of treatment were analyzed, focusing on six parameters: systemic lupus erythematosus (SLE), skin manifestations, disease duration, prednisolone, smoking, and severity. RESULTS: Twenty-seven patients, including 17 with SLE (6 with SLE/Sjögren's syndrome), were analyzed retrospectively. Twenty-three patients (85 %) were categorized as responders. The mean CLASI activity score improved from 10.1 to 4.5 (p < 0.0001). The improvement rate did not differ in these parameters except for that of annular erythema (81.6 versus 34.3 %, p = 0.036). On multivariate analysis, the baseline CLASI activity score (CLASI ≥9) correlated with the greatest decrease in CLASI activity score (F = 69.7, p < 0.0001). CONCLUSIONS: CLASI is a reliable indicator to evaluate the efficacy of the drug, and HCQ is an effective treatment for Japanese patients with lupus-related skin disease.

Clinical severity scores as a guide for prediction of initial treatment responses in pemphigus and pemphigoid patients.

Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second-line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut-off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control.

Differential expression of wound fibrotic factors between facial and trunk dermal fibroblasts.

Clinically, wounds on the face tend to heal with less scarring than those on the trunk, but the causes of this difference have not been clarified. Fibroblasts obtained from different parts of the body are known to show different properties. To investigate whether the characteristic properties of facial and trunk wound healing are caused by differences in local fibroblasts, we comparatively analyzed the functional properties of superficial and deep dermal fibroblasts obtained from the facial and trunk skin of seven individuals, with an emphasis on tendency for fibrosis. Proliferation kinetics and mRNA and protein expression of 11 fibrosis-associated factors were investigated. The proliferation kinetics of facial and trunk fibroblasts were identical, but the expression and production levels of profibrotic factors, such as extracellular matrix, transforming growth factor-ß1, and connective tissue growth factor mRNA, were lower in facial fibroblasts when compared with trunk fibroblasts, while the expression of antifibrotic factors, such as collagenase, basic fibroblast growth factor, and hepatocyte growth factor, showed no clear trends. The differences in functional properties of facial and trunk dermal fibroblasts were consistent with the clinical tendencies of healing of facial and trunk wounds. Thus, the differences between facial and trunk scarring are at least partly related to the intrinsic nature of the local dermal fibroblasts.

Detection of iron deposition in dermal fibrocytes is a useful tool for histologic diagnosis of nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is a fibrotic disease that presents with a history of renal dysfunction. The differential diagnosis generally includes scleromyxedema, systemic sclerosis, and morphea. Especially, scleromyxedema can be extremely difficult to distinguish microscopically. Although the fibrocytes in NSF are often positive for CD34 and procollagen-I, this is not specific for NSF. We identified positive iron staining in the skin of a patient with NSF and investigated whether this was a specific feature among 9 patients with NSF reported in Japan. We found that 6 of 9 patients showed positive iron staining in the dermal fibrocytes. The amount of iron deposition seemed to have no correlation with the degree of fibrosis or duration of the skin lesions but correlated with apparent history of the use of gadolinium-based contrast agents. As controls, skin biopsies from patients with scleromyxedema, morphea, and systemic sclerosis were evaluated by iron staining. None of these control patients showed iron deposition, indicating that positive iron staining may be specific to NSF and can be a useful tool for NSF diagnosis.

Efficacy of hydroxychloroquine for treating annular erythema associated with Sjögren's syndrome.

Annular erythema is one of the cutaneous manifestations of Sjögren's syndrome (SS). Topical corticosteroids and tacrolimus, and oral corticosteroids, have been used as treatments for this condition. However, the safety and efficacy of these treatments remains unsatisfactory, and further development of therapies are desired. In this study, we performed a retrospective analysis of 16 annular erythema associated with SS (AESS) patients treated with hydroxychloroquine (HCQ). Disease activity was assessed using a modified version of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), which we termed the modified CLASI (m-CLASI). HCQ treatment improved AESS lesions in all 16 patients. The mean m-CLASI score was reduced by 85.6% at the 12-week follow-up relative to baseline (p < 0.01). Notably, 60% (6/10 cases) of patients with AESS lesions limited to the facial area achieved complete remission within 4 weeks. In the analysis of six patients who had taken oral prednisolone before starting HCQ, all were able to reduce the dose within 52 weeks without relapse. Particularly, 75% (3/4 cases) of patients with prednisolone dose of more than 5 mg/day could reduce their dose to less than 5 mg/day in combination with HCQ. For the safety concerns, two patients experienced grade 1 diarrhea during the 52-week observation period. However, neither serious adverse events nor adverse events requiring discontinuation of treatment occurred. The results of the present study suggest that HCQ may not only be highly effective as a single agent, but may also be useful as a steroid-sparing agent in refractory case requiring long-term steroid administration, making it a good treatment option for AESS.

Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita).

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients.

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m2 of body surface area). The primary end-points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19-positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.

Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis.

Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.