Successful treatment of pustulotic arthro-osteitis with amoxicillin: A case report and review of the literature.

Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease characterized by sterile pustules on the palms and soles. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP, frequently affecting the anterior chest wall. PPP and PAO are thought to be closely associated with focal infection. We report a female in her 40s who developed pustules on her palms and soles with tenderness of both sternoclavicular and left sacroiliac joints, which were not improved with non-steroidal anti-inflammatory drugs. Of note, she showed a great response to amoxicillin, resulting in the almost complete resolution of her skin lesions and arthralgia. We also reviewed previous reports to learn more about the potential therapeutic options of antibiotics for PAO.

Possible Efficacy of Vedolizumab, an Anti-α4ß7 Integrin Antibody, in Palmoplantar Pustulosis.

Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease in which blisters and pustules repeatedly develop on palms and soles. PPP is often refractory to topical therapy, oral therapy, phototherapy, and biologics that are usually applied for PPP. We report a patient with PPP improved by vedolizumab (anti-α4ß7 integrin antibody) treatment for ulcerative colitis, suggesting the possibility of a new molecular target for PPP therapy.

The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors.

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.

An international validation study of the interleukin-2 luciferase leukocyte toxicity test (IL-2 Luc LTT) to evaluate potential immunosuppressive chemicals and its performance after use with the interleukin-2 luciferase assay (IL-2 Luc assay).

We previously reported that the IL-2 Luc LTT can detect immunosuppressive effects of drugs that are attributed to their antimitotic activity. Here, we report an official validation study of the IL-2 Luc LTT. In the Phase I study that evaluated five coded chemicals, the within-laboratory reproducibility of three independent laboratories was 100.0%. In the combined results of the Phase I and II studies that evaluated 20 coded chemicals, the between-laboratory reproducibility was 92.0%. When compared with the reference data based on the previously-reported immunotoxicological information, the predictivity of the combined Phase I and II studies was 76.0% for Lab A and 72.0% for Labs B and C. In contrast, in the study in which the lead laboratory examined 37 non-pharmaceutical chemicals, the predictivity of the IL-2 Luc LTT and the IL-2 Luc assay was 48.6% and 64.9%, respectively, whereas that of the combined assays was 74.3%. It is clear that an integrated approach combining multiple assays is necessary for the development of in vitro immunosuppression testing. These data suggest that the IL-2 Luc LTT alone is not sufficient as a component of the integrated approach, but the combination of the IL-2 Luc assay and IL-2 Luc LTT is promising.

Staphylococcus aureus skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs such as skin, kidneys, bones, and brain and the presence of autoantibodies. Although the cause of SLE is not completely understood, environmental factors, genetic susceptibility, hormone factors, and environmental factors are thought to play essential roles in the pathogenesis of SLE. Among environmental factors, the microbiota are linked to the development of different autoimmune diseases. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell-specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus on the skin. When S. aureus was epicutaneously applied on NfkbizΔK5 mice, NfkbizΔK5 mice developed SLE-associated autoantibodies, anti-dsDNA antibodies, anti-Sm antibodies, and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the interleukin-23 (IL-23)/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti-IL-23p19 and anti-IL-17A antibodies alleviated the systemic autoimmune response. Together, these findings underscore epithelial-immune cross-talk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases.

Cohort study of subclinical sensitization against galactose-α-1,3-galactose in Japan: Prevalence and regional variations.

Sensitization to galactose-α-1,3-galactose (α-Gal) leads to the development of α-Gal syndrome, which includes red meat allergy and cetuximab-induced anaphylaxis. Since tick bites represent the main cause of α-Gal sensitization, it was speculated that sensitization to α-Gal occurs throughout Japan. However, few cohort studies have investigated α-Gal sensitization in Japan. Therefore, we aimed to elucidate the subclinical sensitization rate to α-Gal in Japan. Sera were obtained from 300 participants without food or cetuximab allergy at Shimane University Hospital (Shimane prefecture), Tokyo Medical and Dental University Hospital (Tokyo metropolis), and Tohoku University Hospital (Miyagi prefecture). ImmunoCAP-bovine thyroglobulin (BTG), ImmunoCAP-beef, and IgE immunoblotting with cetuximab were performed to detect α-Gal-specific IgE. Clinical information was collected from participants using a questionnaire. The overall positivity rate of ImmunoCAP-BTG was 4.0% without significant inter-institute differences, whereas that for ImmunoCAP-beef was 9.7% with a significant inter-institute difference. Tokyo Medical and Dental University Hospital (19.0%) had the highest positivity rate. The positivity rate based on cetuximab IgE immunoblotting was 2.7%, without any significant inter-institute differences. The overall positivity rate for both ImmunoCAP-BTG and cetuximab immunoblotting was 2.0%, with a significant inter-institute difference; 5.0% of Shimane University Hospital was the highest. Two cases showed sensitization against the non-α-Gal epitope of cetuximab. The overall positivity rate for both ImmunoCAP-beef and cetuximab immunoblotting was 1.3%, without significant inter-institute differences. Male sex was associated with positive beef-specific IgE. The prevalence of subclinical sensitization to α-Gal is estimated at 2.0%-4.0% in Japan and may be higher in rural areas, supporting an association between tick bites and α-Gal sensitization. In contrast, the prevalence of subclinical sensitization to beef is 9.7% in Japan and is highest in Tokyo Metropolis, suggesting the presence of another IgE-binding epitope apart from α-Gal and another sensitization route in the sensitization to beef IgE.

Characterization of rosacea patients in Tohoku area of Japan: Retrospective study of 340 rosacea cases.

Rosacea is a chronic inflammatory skin disease with facial redness and acne-like papules and pustules. The characteristics and background of rosacea patients in Japan have not been well documented. In this study, we retrospectively collected the medical information of rosacea patients, and investigated the background, complications, exacerbating factors, and status of allergy. Between January 2010 and December 2020, 431 cases were diagnosed as rosacea or rosacea-like dermatitis. We selected 340 patients, in which we could confirm telangiectasia on facial skin. Females and males numbered 266 and 74, respectively. The average age of the first visit was 51.5 years, and the youngest and oldest were 11 and 88 years old. Among 340 cases, 323 had erythematotelangiectatic rosacea, 97 papulopustular rosacea, 20 phymatous rosacea presenting as rhinophyma, and four had symptoms of ocular rosacea. The most common complication was hay fever (93 individuals, 27.4%), and 66 (19.4%) had a medical history of contact dermatitis. Temperature differences (141 individuals, 41.5%) were the most common exacerbating factor followed by sunlight exposure (60 individuals, 17.6%). Seventy-eight individuals received allergen-specific immunoglobulin (Ig)E tests, and IgE for cedar was the most frequently observed (46 individuals, 59.0%). High frequencies of IgE for Dermatophagoides pteronyssinus or D. farinae (33 individuals, 42.3%) and house dust I (31 individuals, 39.7%) suggested that environmental conditions at home would affect rosacea symptoms. Since the facial skin is exposed to environmental stimuli every moment, this retrospective observation suggested the importance of the daily lifestyle guidance as well as medical treatments.

Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis.

BACKGROUND: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear. AIMS: To investigate the role of IκB-ζ in gut homeostasis. METHODS: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS. RESULTS: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4+ T cells in LP), and antibiotic treatment canceled this inflammatory phenotype. CONCLUSION: IκB-ζ plays a crucial role in maintaining homeostasis in the gut.

Biologics modulate antinuclear antibodies, immunoglobulin E, and eosinophil counts in psoriasis patients.

Psoriasis is a chronic disease centered on tumor necrosis factor (TNF), interleukin (IL)-23, and IL-17 axis. While psoriasis patients benefit from biologics targeting TNF, IL-17s, and IL-23 nowadays, suppression of these molecules could modulate the balances of immune systems. However, the incidence of autoimmune disease and T-helper 2 reaction during biologic treatments for psoriasis patients is not well documented. We retrospectively examined antinuclear antibody (ANA), eosinophil counts, and immunoglobulin E (IgE) levels for psoriasis patients who underwent biologic treatments in our dermatology clinic from June 10, 2010 to January 29, 2020. A cumulative total of 199 biologic treatments were performed for a total of 128 psoriasis patients. Compared to the non-biologic group of 109 psoriasis patients who received non-biologic treatment, patients treated with infliximab showed more incidents of high ANA (14%, p = 0.039) and high eosinophils (14%, p = 0.021). The use of brodalumab increased incidents of high eosinophils (21%, p = 0.005) but did not affect increase in ANA and IgE. The increase in high IgE level was observed significantly more during the use of risankizumab (15%, p = 0.011). Methotrexate was the most frequently used concomitant systemic treatment, but methotrexate did not affect ANA, eosinophil counts, and IgE levels. Since the biologics for psoriasis treatment modulate the balance of T-helper cells, careful observation is required to detect unexpected changes of systemic immune conditions under biologic treatments.

Ehlers-Danlos syndrome type IV with a novel COL3A1 exon 14 skipping variation confirmed by Tohoku Medical Megabank Organization genomic database.

A novel COL3A1 variant was identified in a Japanese case of Ehlers-Danlos syndrome type IV (EDS-IV) with a characteristic "Madonna" face, fragile uterus, and easy bruising in addition to a history of cavernous sinus fistula. We confirmed variable diameters of collagen fibrils in the dermis and decrease in type 3 collagen production from cultured fibroblasts. Genomic DNA sequencing of the COL3A1 region and COL3A1 cDNA sequence expressing in cultured fibroblasts identified that a nucleotide variation at c.951+2T>G on intron 14 leads to skipping of exon 14 in COL3A1 cDNA. The novel variation in the splice site of COL3A1 region g.IVS14+2T>G was not listed in the EDS-IV pathogenic genetic databases including Human Gene Mutation Database, ClinVar, and Leiden Open Variation Database. Using the whole genome sequence database of 8380 Japanese individuals reported by the Tohoku Medical Megabank Organization (ToMMo) cohort study, we also confirmed that COL3A1 g.IVS14+2T>G was not a common single nucleotide variation in the Japanese population, although 13 EDS-related COL3A1 variants were identified in the ToMMo database of 8380 Japanese individuals. These results demonstrated that our case of EDS-IV was a result of the novel variation of COL3A1 g.IVS14+2T>G. These statistical genetics approaches with the combination of the ToMMo database of 8380 Japanese individuals and pathogenic genetic databases are a useful method to confirm the uniqueness of novel variation in Japanese.

Body mass index, HbA1c and serum C-reactive protein are predictors of secondary failure in infliximab continuance for Japanese psoriasis patients: A hospital-based retrospective case-control study.

Biologics has had a great impact on psoriasis treatment as well as the life of psoriasis patients. Infliximab (IFX), one of the biologics targeting tumor necrosis factor (TNF), is the first of the biologics introduced to Japanese psoriasis patients. Many patients had benefits of IFX from initial applications and sustained remission of skin lesions and arthritis. Some, however, fall into so-called secondary failure, in which patients become less responsive to IFX when the treatment is repeated. The mechanism of secondary failure and the background of patients with secondary failure have not been completely elucidated. To address this issue, we retrospectively evaluated psoriasis patients treated with IFX in our department. In this retrospective, single-center, case-control study based on the clinical record, a total of 34 patients were enrolled. We excluded 7 patients who discontinued IFX because of adverse events of IFX. We divided other 27 patients into two groups; 16 patients who kept using IFX (Continuance group); and 11 patients who switched to other treatments (Discontinuance group). Among various clinical features, body mass index (BMI), HbA1c, and serum CRP level were significantly higher in the Discontinuance group than the Continuance group. The results indicated that these three clinical features of BMI, HbA1c and serum CRP level before treatment are the predictors of successful IFX treatment and suggest that improvement of metabolic conditions contributes to avoiding secondary failure and discontinuance of IFX.

2020 guidelines for the diagnosis and treatment of prurigo.

Prurigo is a treatment-resistant skin disease characterized by multiple isolated papules/nodules that cause severe itch. Prurigo papules/nodules occur either as primary lesions or as secondary lesions due to persistent scratching. The fundamental concepts and classifications of prurigo have not been sufficiently established, and considerable confusion remains regarding this topic. Clinical guidelines for chronic prurigo in Japan were published in 2012 in an attempt to reduce confusion regarding the concepts of prurigo and to standardize laboratory tests and treatments. However, the diagnostic terms for prurigo and associated concepts have changed over time, and new forms of treatment are under development. We have, thus, updated and revised the guidelines to classify prurigo based on clinical forms and causes, and disease name classifications based on the clinical form have been further simplified, such as prurigo nodularis, prurigo chronica multiformis, and prurigo (not otherwise specified). Expressions for acute, subacute, and chronic forms are not used. These guidelines outline the current concepts and specify treatments for prurigo.

2020 guidelines for the diagnosis and treatment of cutaneous pruritus.

The mechanisms underlying itch are not fully understood. Physicians usually encounter difficulty controlling itch in generalized pruritus. Since only a small percentage of patients with generalized pruritus respond to antihistamines (H1 receptor antagonists), a variety of itch mediators and mechanisms other than histaminergic signals are considered to be involved in itch for these non-responsive patients. In 2012, we created guidelines for generalized pruritus. Those guidelines have been updated and revised to make some of the definitions, diagnostic terms, and classifications more applicable to daily clinical practice. Cutaneous pruritus as designated in these guidelines is a disease characterized by itch without an observable rash. Generalized pruritus (without skin inflammation) is defined as the presence of itch over a wide area, and not localized to a specific part of the body. This entity includes idiopathic pruritus, pruritus in the elderly, symptomatic pruritus, pregnancy-associated pruritus, drug-induced pruritus, and psychogenic pruritus. Localized pruritus (without skin inflammation) represents fixed itch localized to a specific part of the body, and includes anogenital pruritus, scalp pruritus, notalgia paresthetica, and brachioradial pruritus. These guidelines outline the current concepts and specify the diagnostic methods/treatments for cutaneous pruritus.

Optimization of the IL-2 Luc assay for immunosuppressive drugs: a novel in vitro immunotoxicity test with high sensitivity and predictivity.

We have reported that the IL-2 Luc assay can detect the effects of chemicals on IL-2 promoter activity by using a dual reporter cell line, 2H4 cells that measure IL-2 promoter-driven luciferase activity (IL2LA) and GAPDH promoter-driven luciferase activity (GAPLA). Since the IL-2 Luc assay cannot detect immunosuppressive drugs that are antimitotic towards rapidly proliferating cells, we attempted to establish a new assay to detect these chemicals by taking advantage of the dual reporter cell properties of 2H4 cells. We first determined the optimal incubation time with drugs and the seeding cell density, and confirmed that the change in GAPLA and IL2LA levels reflects the change in cell count and IL-2 production of 2H4 cells after drug treatment. We designed the IL-2 luciferase lymphotoxicity test (IL-2 Luc LTT) to detect the antimitotic effects of chemicals by modifying the protocol and criteria of the IL-2 Luc assay. To determine the performance of the IL-2 Luc LTT and that of the combination of the IL-2 Luc LTT and the IL-2 Luc assay, we examined 46 drugs: 19 immunosuppressive drugs with different mechanisms of action, 12 anti-cancer drugs, and 15 non-immunosuppressive drugs. The performances of the IL-2 Luc LTT, the IL-2 Luc assay and their combination were 43.3%, 61.3%, and 93.3%, respectively, for sensitivity, 84.6%, 53.3%, and 50.0%, respectively, for specificity, and 55.8%, 58.7%, and 79.5%, respectively, for accuracy. These results demonstrated that the combination of these two assays is promising for the detection of immunosuppressive drugs with different mechanisms of action.

Pediatric psoriasis induced by HLA-B46-Cw1 haplotype: A retrospective study of psoriasis onset after hematopoietic stem cell transplantation.

Genome-wide association studies have identified more than 60 susceptibility loci for psoriasis, highlighting the role of genetics in psoriasis development. Although the HLA region is suggested as the most prominent susceptibility locus, the role of the HLA haplotype in the development of psoriasis is unclear. The aim of this study is to investigate how HLA haplotype changes affect the onset of psoriasis and which HLA haplotypes are associated with the development of psoriasis. A longitudinal, retrospective case series study of children was conducted at Tohoku University Hospital in Japan, between November 1981 and October 2020. We evaluated a total of 378 pediatric patients who underwent hematopoietic stem cell transplantation in the Department of Pediatrics. The background of these patients and their HLA haplotypes before and after transplantation was assessed. Among the 378 cases, aged 0-22 years old (median age 6) identified, 117 cases received autologous transplantation, 260 cases received allogeneic transplantation, and one case received syngeneic transplantation. Only two cases developed de novo psoriasis, and these cases had acquired HLA-B46-Cw1 after allogeneic transplantation. Others who had HLA-B46-Cw1 before and after allogeneic transplantation did not develop psoriasis. Our findings suggest that the HLA-B46 and HLA-Cw1 combination contributes to the development of psoriasis in this Asian population.

Successful treatment of BRAF/MEK inhibitor-resistant advanced cutaneous melanoma with nivolumab plus ipilimumab combination therapy followed by intensity-modulated radiotherapy.

BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapeutic regimens for the treatment of advanced BRAF-mutant melanoma. Although the NCCN guideline for cutaneous melanoma recommended BRAF/MEK inhibitors as first-line therapies for unresectable BRAF-mutated melanoma, resistance to these drugs should be taken into account in real-world practice. Therefore, development of a protocol for BRAF/MEK inhibitor-resistant advanced melanoma is needed. In this report, a case of BRAF/MEK inhibitor-resistant advanced cutaneous melanoma that was successfully treated with nivolumab plus ipilimumab combination therapy followed by intensity-modulated radiotherapy (IMRT) is reported. In the present case, not only the locally irradiated lesion, but remote metastases including inguinal lymph nodes decreased after ipilimumab plus nivolumab followed by IMRT treatment leading to complete remission, suggesting that IMRT triggered an abscopal response. Moreover, immunohistochemical analysis showed increased CD3+ , CD4+ , and CD8+ T cells after radio-immunotherapy (RIT). This case suggests that RIT might break the tolerance in the tumor microenvironment and induce a systemic anti-melanoma immune response.