Targeting B cells for treatment of systemic sclerosis.

PURPOSE OF REVIEW: The pathogenesis of systemic sclerosis (SSc) has been linked to dysfunctional B cells as demonstrated in previous research. This review aims to show the evidence and ongoing clinical trials of B cell-targeted therapy and overview the various aspects of B cell involvement in SSc. RECENT FINDINGS: We provide an overview of the current understanding and therapeutic strategies targeting B cells in SSc patients. Several molecular targets of B cells have been identified for treating SSc, including CD20, CD19, B-cell activating factor (BAFF), and proteasome. SUMMARY: Many clinical trials have demonstrated that B cells play a critical role in the pathogenesis of SSc and may be a potential therapeutic target to improve disease symptoms. Although large-scale clinical studies are needed, various B cell-targeted therapies have the potential to address the unmet needs of SSc patients.

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.

The IL-1 promoter-driven luciferase reporter cell line THP-G1b can efficiently predict skin-sensitising chemicals.

IL-1 functions as an essential pro-inflammatory mediator for the sensitisation of allergic contact dermatitis (ACD). However, studies conducted to date have typically used a limited number of haptens and examined their effects only on murine ACD or murine dendritic cells (DCs). It therefore remains unclear whether IL-1α and/or IL-1ß is produced in ACD induced by haptens other than those commonly used in mouse ACD models, and whether they are essential for sensitisation leading to ACD in humans. In addition, it is unclear whether human DCs also produce IL-1α or IL-1ß after stimulation by haptens in general. Here, we first demonstrated that 10 haptens (3 extreme, 1 strong, 3 moderate and 3 weak) increased both IL-1α mRNA and IL-1ß mRNA expression by the human monocyte cell line THP-1, a commonly used surrogate of DCs in in vitro skin sensitisation tests. Next, we constructed an in vitro skin sensitisation test using a stable IL-1ß reporter cell line, THP-G1b, and evaluated whether 88 haptens and 34 non-haptens increase IL-1ß reporter activity. We found that 94% of 77 haptens evaluated after considering their applicability domain and solubility in the chosen media stimulated reporter activity. These studies demonstrated that most haptens, irrespective of their potency, increased IL-1ß mRNA expression by THP-1 cells, confirming that human DCs also produce IL-1ß after stimulation by most haptens. The luciferase assay using THP-G1b cells is thus another skin sensitisation test based on the adverse outcome pathway with reasonable performance.

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.

Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay.

We established a luciferase reporter assay system, the Multi-ImmunoTox Assay (MITA), which can evaluate the effects of chemicals on the promoter activities of four cytokines: IL-2, IFN-γ, IL-1ß, and IL-8. We previously reported that MITA correctly reflected the change in mRNA of human whole-blood cells treated with dexamethasone, cyclosporine, FK506, or several other immunosuppressive drugs. In this study, we combined MITA with the IL-8 Luc assay to detect skin sensitization chemicals (OECD 442E) (modified MITA: mMITA) and established a data set of 60 chemicals examined by mMITA. Using the mMITA results, chemicals can be classified based on the lowest observed effect level (LOEL) of chemicals in suppressing or augmenting the promoter activities of the four cytokines. Moreover, we demonstrated that K-means clustering and hierarchical clustering of the 60 chemicals based on the LOEL for their effects on IL-2 and IL-8 promoter activities and the judgment by the IL-8 Luc assay resulted in the same 6-cluster solution: cluster 1 with preferential suppression of IL-8, cluster 2 with suppression of IL-2 and a positive IL-8 Luc assay result, cluster 3 with suppression of both IL-2 and IL-8, cluster 4 with no effects on IL-2 or IL-8 and a negative IL-8 Luc assay result, cluster 5 with suppression of both IL-2 and IL-8 and a negative IL-8 Luc assay result, and cluster 6 with preferential suppression of IL-8. These data suggest that mMITA is a promising novel high-throughput approach for detecting unrecognized immunological effects of chemicals and for profiling their immunotoxic effects.

Milia En Plaque as a Distinct Follicular Hamartoma With Cystic Trichoepitheliomatous Features.

Milia en plaque (MEP) is an uncommon disorder characterized by an erythematous plaque containing numerous milia. The pathogenesis of MEP is not clear. The authors report a man with an erythematous plaque on the right retroauricular area, containing numerous white-yellow cysts varying in size. Histological examination showed that multiple cystic structures at various levels of the dermis that were lined by stratified squamous epithelium and contained keratinous material-these findings were consistent with the diagnosis of multiple milia. In addition to epidermal cysts, however, the lesion consisted of a branched proliferation of pale-staining keratinocytes lined with basal keratinocytes budding from the overlying epidermis. Moreover, some cysts were formed within the branched epithelial proliferation, had thicker cyst walls than the ordinary milium, or had irregular or branched projections toward the surrounding dermis. From these findings, the authors conclude that MEP is a distinct follicular hamartoma with cystic trichoepitheliomatous features.

Serum levels of AGGF1: Potential association with cutaneous and cardiopulmonary involvements in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, aberrant immune activation, and extensive tissue fibrosis of the skin and internal organs. Because of the complicated nature of its pathogenesis, the underlying mechanisms of SSc remain incompletely understood. Angiogenic factor with a G-patch domain and a Forkhead-associated domain 1 (AGGF1) is a critical factor in angiogenesis expressed on vascular endothelial cells, associated with inflammatory and fibrotic responses. To elucidate the possible implication of AGGF1 in SSc pathogenesis, we investigated the association between serum AGGF1 levels and clinical manifestations in SSc patients. We conducted a cross-sectional analysis of AGGF1 levels in sera from 60 SSc patients and 19 healthy controls with enzyme-linked immunosorbent assay. Serum AGGF1 levels in SSc patients were significantly higher than those in healthy individuals. In particular, diffuse cutaneous SSc patients with shorter disease duration had higher levels compared to those with longer disease duration and limited cutaneous SSc patients. Patients with higher serum AGGF1 levels had a higher incidence of digital ulcers, higher modified Rodnan Skin Scores (mRSS), elevated serum Krebs von den Lungen-6 (KL-6) levels, C-reactive protein levels, and right ventricular systolic pressures (RVSP) on the echocardiogram, whereas they had reduced percentage of vital capacity (%VC) and percentage of diffusing capacity of the lungs for carbon monoxide (%DLCO) in pulmonary functional tests. In line, serum AGGF1 levels were significantly correlated with mRSS, serum KL-6 and surfactant protein D levels, RVSP, and %DLCO. These results uncovered notable correlations between serum AGGF1 levels and key cutaneous and vascular involvements in SSc, suggesting potential roles of AGGF1 in SSc pathogenesis.

Bilaterally Aligned Electroosmotic Flow Generated by Porous Microneedle Device for Dual-Mode Delivery.

Here, a novel porous microneedle (PMN) device with bilaterally aligned electroosmotic flow (EOF) enabling controllable dual-mode delivery of molecules is developed. The PMNs placed at anode and cathode compartments are modified with anionic poly-2-acrylamido-2-methyl-1-propanesulfonic acid and cationic poly-(3-acrylamidopropyl) trimethylammonium, respectively. The direction of EOF generated by PMN at the cathode compartment is, therefore, reversed from cathode to anode, countering the unwanted cathodal suctioning of interstitial fluid caused by reverse iontophoresis. With the bilateral alignment of EOF, the versatility of the proposed device is evaluated by delivering molecules with different charges and sizes using Franz cell. In addition, a 3D printed probe device is developed to ease practical handling and minimize electrical stimulation by integrating two PMNs in closed proximity. Finally, the performance of the integrated probe device is demonstrated by dual delivery of a variety of molecules (methylene blue, rhodamine B, and fluorescein isothiocyanate-dextran) using pig skin and vaccination using mice with delivered ovalbumin.

Biologics for Reducing Cardiovascular Risk in Psoriasis Patients.

Psoriasis is a chronic inflammatory skin disease with a high prevalence of cardiovascular disease (CVD), obesity, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome. Among them, CVD is the most common cause of morbidity and mortality in psoriasis patients. Since CVD is associated with considerable morbidity and mortality, primary care clinicians are increasingly committed to reducing the risk of CVD in patients with psoriasis. Biologics targeting TNF-α, IL-12/23, and IL-17 are systemic therapies that can dramatically improve the condition of psoriasis. Recent studies have reported that these inflammatory cytokine signals may promote atherosclerosis, suggesting that biologics might be effective for improving psoriasis as well as reducing the risk of CVD. Here, we reviewed cardiovascular risk in psoriasis patients, the association between psoriatic inflammation and atherosclerosis, and the efficacy of biologics for reducing the risk of cardiovascular diseases.

Olaparib-Induced Purpuric Drug Eruption in a Patient with Castration-Resistant Prostate Cancer.

Olaparib is recently approved as an anti-tumor agent for several cancers, including castration-resistant prostate cancer, which inhibits poly (adenosine diphosphate-ribose) polymerase, a DNA repair factor. Since olaparib is a newly approved drug, there are few reports of skin disorders that may be triggered by olaparib administration. In this report, we present a case with an olaparib-induced drug eruption presenting multiple purpuras on the patient's fingers and fingertips. The present case suggests that olaparib might induce purpura as nonallergic drug eruption.

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.

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.

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.

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.

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.

Effect of interleukin-17A inhibitor in Japanese patients with psoriatic arthritis compared with tumor necrosis factor-alpha inhibitor.

OBJECTIVES: The patient of severe psoriatic arthritis (PsA) is mainly treated with oral methotrexate, ciclosporin, and anti-tumor necrosis factor-alpha inhibitors (TNFi). Recently, anti-interleukin-17A inhibitors (IL-17Ai) have been used in the treatment of PsA. This study aimed to evaluate the efficacy and safety of IL-17Ai in Japanese patients with PsA compared with those of TNFi. METHODS: This was a longitudinal and retrospective study. The study population included 31 Japanese patients with PsA. All enrolled patients fulfilled the Classification Criteria for Psoriatic Arthritis. All patients were treated with TNFi or IL-17Ai. The assessed clinical manifestations were C-reactive protein (CRP)-based Disease Activity Score in 28 Joints (DAS28-CRP), disease activity in psoriatic arthritis (DAPSA), 20% achievement of American College of Rheumatology core set, swollen joint count (SJC), tender joint count (TJC), and visual analog scale (VAS). Functional ability of patients with PsA was analyzed using the modified health assessment questionnaire (mHAQ) score. We evaluated the parameters at baseline and weeks 12, 24, and 52. RESULTS: The change in SJC, TJC, VAS, mHAQ, and DAPSA had no significant difference at weeks 12, 24, and 52. The improvements of CRP and DAS28-CRP were significantly higher in TNFi group only at week 12. The biologics retention rate was significantly higher in TNFi group by the log-rank test. No critical adverse events occurred. CONCLUSIONS: Our study presented that IL-17Ai had treatment effects comparable to TNFi. IL-17Ai might have the potential to become an alternative to the previous drug, but more large-scale studies are expected.

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.