Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

Clinical characteristics of patients with psoriasis with family history: A multicenter observational study.

Previous studies on family history of psoriasis showed that patients with a family history have an earlier onset of the disease, but such studies in Japan are still limited. To elucidate the characteristics of patients with familial psoriasis, we studied the family history of patients with psoriasis using the West Japan Psoriasis Registry, a multi-institutional registry operated by 26 facilities in the western part of Japan, including university hospitals, community hospitals, and clinics. This study enrolled 1847 patients registered between September 2019 and December 2021, with 199 (10.8%) having a family history of psoriasis. Patients with a family history of psoriasis had significantly earlier onset of the disease than those without a family history. Furthermore, patients with a family history of psoriasis had significantly longer disease duration. Psoriatic arthritis (PsA) was significantly more common in patients with a family history (69/199, 34.7%) than in those without a family history (439/1648, 26.6%) (adjusted P = 0.023). A subanalysis of patients with PsA revealed a significant difference in the patient global assessment (PaGA) score in Fisher's exact test and adjusted test. The numbers of patients with PaGA 0/1 were 29 (43.3%) and 172 (39.9%) in patients with PsA with and without family history of psoriasis, respectively, whereas the numbers of patients with PaGA 3/4 were 13 (19.4%) and 145 (33.6%) in patients with PsA with and without family history of psoriasis, respectively. Other disease severity variables did not show a difference between the two groups. Our findings suggest that genetics play a larger role in the development of PsA than in the development of psoriasis vulgaris. Most cases of PsA occur in patients who already have psoriasis, therefore dermatologists should pay attention to joint symptoms, especially in patients with psoriasis who have a family history of psoriasis.

Real-world efficacy and safety of interleukin-17 inhibitors for psoriasis: A single-center experience.

We evaluated the efficacy and safety of interleukin (IL)-17 inhibitors (IL-17i) by analyzing 66 patients with psoriasis treated with secukinumab (n = 25), ixekizumab (n = 17) and brodalumab (n = 24) at Kurume University Hospital between December 2014 and June 2019. The mean Psoriasis Area and Severity Index (PASI) scores at baseline were 12.9, 13.4 and 9.9 in the secukinumab, ixekizumab and brodalumab groups (SECg, IXEg and BROg), respectively. At the 6-month evaluation, the mean PASI scores were 1.7, 1.1 and 0.5 in SECg, IXEg and BROg, respectively. The proportion of patients achieving PASI of 3.0 or less was significantly lower in SECg. Drug survivals showed no significant difference among the groups. Although one patient in IXEg died due to an unknown cause, no serious IL-17i-associated adverse event was observed. This study showed high efficacy and relatively low risk of the treatment with IL-17i.

Mycobacterium tuberculosis infection in psoriatic patients treated with biologics: Real-world data from 18 Japanese facilities.

Although rare, tuberculosis has been reported with biologic treatment against psoriasis in Japan, a tuberculosis medium-burden country. Mycobacterial infection often develops after a long incubation period and might not have been adequately identified in clinical trials or post-marketing surveillance. To determine the real-world incidence of tuberculosis in psoriatic patients treated with biologics, we conducted a retrospective, multicenter, observational study in 18 facilities in Western Japan. Psoriatic patients who visited a participating facility between 2010 and March 2017 and received biologic reagents were enrolled. Information on sex, age at first biologic treatment, results of interferon-γ release assay (IGRA) for Mycobacterium tuberculosis, treatment history with isoniazid, and onset of active and/or latent tuberculosis was collected. A total of 1117 patients (830 men and 287 women) were enrolled. The mean duration of biologic treatment was 3.54 years. Sixty-five patients (5.8%) showed positive IGRA results at screening. Active tuberculosis developed in two patients after the administration of tumor necrosis factor inhibitors (both involved miliary tuberculosis). Latent tuberculosis was observed in two patients treated with anti-interleukin-12/23p40 antibody. The incidence rate of tuberculosis, including latent tuberculosis, in this survey was 0.36%. Although the incidence rate of tuberculosis was low considering the observation period of biologic treatment, active tuberculosis was found in both the screening-negative group and a screening-positive subject after isoniazid prophylaxis (both miliary tuberculosis), concluding that negative screening or isoniazid treatment does not always assure that an individual has no tuberculosis. Hence, dermatologists still need to pay careful attention to tuberculosis at every patient visit.

Cross-sectional multicenter observational study of psoriatic arthritis in Japanese patients: Relationship between skin and joint symptoms and results of treatment with tumor necrosis factor-α inhibitors.

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross-sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti-tumor necrosis factor (TNF)-α antibodies being prescribed first to 157 of them. Anti-TNF-α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti-TNF-α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti-TNF-α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti-TNF-α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed.

A retrospective observational study on biological drug treatment in a daily practice serving patients with psoriasis in Japan.

BACKGROUND: In Japan, more than five years have passed since emergence of the first three biologics, infliximab, adalimumab, and ustekinumab, became available in daily practice; however, no data for drug survival was reported from Japan. OBJECTIVE: To study the long-term drug survival of infliximab, adalimumab, and ustekinumab used for Japanese psoriatic patients. METHODS: We retrieved data on all patients treated with biological agents and calculated the long-term drug survival for infliximab, adalimumab, and ustekinumab using our psoriasis registry (Kurume Psoriasis Registry: KURUPR) consisted of 343 patients by the end of March 2017. We analyzed 103 treatment courses of 83 patients with all types of psoriasis, as well as 79 treatment courses of 62 patients with psoriasis vulgaris using the Kaplan-Meier method. RESULTS: Drug survival was higher for ustekinumab than infliximab and adalimumab in both settings, although there were no statistical differences. CONCLUSIONS: Previous studies of long-term drug survival in patients with psoriasis vulgaris showed significantly higher drug survival for ustekinumab than infliximab, and adalimumab. Our data showed similar tendency. Besides randomized clinical trials, drug survival data is useful because it reflects real-world management.

Real-world data on the efficacy and safety of apremilast in Japanese patients with plaque psoriasis.

Background: Real-world data differ from clinical trial data. Although some real-world data regarding apremilast use for psoriasis treatment has been reported in Western countries, no such data has been reported in Asian countries. Objective: To study the efficacy, including Psoriasis Area and Severity Index (PASI) and drug survival, and safety of apremilast in Japanese patients with psoriasis. Methods: Data on all the patients treated with apremilast in Kurume University Hospital between May 2017 and June 2018 were retrieved, with June 30 2018, as the data lock date. Efficacy was analyzed by PASI50, PASI75, and PASI90; drug survival by Kaplan-Meier analysis; and drug safety by the proportion of adverse events (AEs). Results: Fourteen of 42 (33.3%) patients achieved PASI75/90; 16 (32%) patients had discontinued apremilast by the data lock date. Drug survival at week 28 was 70%. No serious AEs were reported; the most prevalent one was loose stools/diarrhea (60%), followed by nausea (38%). The most common reason for apremilast discontinuation was primary/secondary failure. Conclusions: Apremilast is safe and effective in Japanese patients with psoriasis. Higher occurrence of loose stools/diarrhea was noted in our cohort than that reported in Western real-world studies on apremilast.

RAC1 activation drives pathologic interactions between the epidermis and immune cells.

Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

Four cases of mucous membrane pemphigoid with clinical features of oral lichen planus.

BACKGROUND: Mucous membrane pemphigoid (MMP) and oral lichen planus (OLP) show similar clinical features on the oral mucosa. As clinical manifestations of oral mucosal lesions, MMP shows blisters and erosions, whereas OLP shows lace-like whitish lesions in an annular arrangement with erythema and erosions. Histopathologically, MMP shows subepithelial bullae with infiltrates of lymphocytes and neutrophils, whereas OLP shows band-like interface infiltration of lymphocytes with damage in basal cells. However, these two diseases are frequently difficult to distinguish both clinically and histopathologically. OBJECTIVES: We report four patients with oral MMP who showed OLP-like clinical and histopathological lesions. METHODS: We performed direct immunofluorescence, indirect immunofluorescence of normal human skin and 1 m NaCl-split skin, enzyme-linked immunosorbent assays for BP180, BP230, and desmogleins 1 and 3, and immunoblotting of normal human epidermal and dermal extracts, recombinant proteins of BP180-NC16a and -C-terminal domains, concentrated culture supernatant of HaCaT cells, and purified laminin-332. RESULTS: The results of various immunological studies suggested the diagnoses of various types of MMP for all four patients. CONCLUSIONS: Because MMP and OLP require different treatments, all dentists and dermatologists should have knowledge about the disease entity and the serological diagnostic methods for various types of MMP.

Comparative Study of Direct Immunofluorescence in Discoid Lupus Erythematosus and Bullous Pemphigoid.

Immunoreactants are found in the epidermal basement membrane in both lupus erythematosus and bullous pemphigoid (BP). To our knowledge, there are no comparative studies on direct immunofluorescence (DIF) of discoid lupus erythematosus (DLE) and BP. The authors studied DIF of lesional skins in 9 patients (2 males and 7 females) with DLE and 29 patients (11 males and 18 females) with BP to disclose the difference between these 2 diseases. IgG deposition was significantly more frequent at the epidermal basement membrane zone (BMZ) in the BP group than in the DLE group; however, IgA and IgM depositions were significantly more frequent at both the epidermal and follicular BMZs in the DLE group than in the BP group. In addition, the mean number of positive immunoreactants at both the epidermal and follicular BMZs was significantly larger in the DLE group than in the BP group. On an average, ≥3 immunoreactants were seen at the epidermal and follicular BMZs in DLE, whereas ≤2.5 immunoreactants were seen in BP. DIF may contribute to the differentiation between these 2 diseases.

Autoantibodies Against Multiple Epitopes in Bp180 and Laminin Gamma-1 in Subepidermal Blistering Skin Disease Associated with Psoriatic Erythroderma.

We report a 79-year-old Japanese man who developed subepidermal blistering skin disease after an 8-year history of psoriasis. Histology of a bullous lesion revealed a subepidermal blister with a mixed inflammatory cell infiltrate and fibrin nets. Indirect immunofluorescence using normal human skin sections revealed IgG and IgA autoantibodies in the patient serum, which bound to the epidermal side of 1M NaCl-split skin sections. Immunoblot analysis revealed that both IgA and IgG antibodies reacted with the BP180 NC16a domain and the 120-kDa LAD-1 and that IgG antibodies also reacted with the BP180 C-terminal domain and laminin gamma-1. These findings indicated that autoantibodies to laminin gamma-1 and multiple epitopes in BP180 ectodomain played a role in the pathogenesis of this unique autoimmune subepidermal blistering skin disease associated with psoriasis.

Various peroxisome proliferator-activated receptor (PPAR)-γ agonists differently induce differentiation of cultured human keratinocytes.

Peroxisome proliferator-activated receptors (PPARs) are potentially useful for the treatment of skin diseases, because they stimulate keratinocyte differentiation, exert anti-inflammatory effects and improve barrier function. We examined five PPAR-γ agonists, including four thiazolidinediones (ciglitazone, troglitazone, rosiglitazone and pioglitazone) and an angiotensin-II receptor blocker (telmisartan), for their ability to upregulate filaggrin and loricrin expression at both mRNA and protein levels in cultured normal human keratinocytes (NHKs). Troglitazone, rosiglitazone, pioglitazone and telmisartan significantly increased filaggrin expression at both mRNA and protein levels in calcium-induced differentiated NHKs. Rosiglitazone and pioglitazone, but not troglitazone nor telmisartan, also significantly increased loricrin expression at both mRNA and protein levels in differentiated NHKs. These effects were not found in undifferentiated NHKs nor differentiated NHKs treated with ciglitazone. This study revealed differential effects of various PPAR-γ agonists on epidermal differentiation, and the most potent of those are rosiglitazone and pioglitazone.

Antibodies to the amino-terminal domain of desmoglein 1 are retained during transition from pemphigus vulgaris to pemphigus foliaceus.

BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two blistering skin diseases mediated by antibodies to desmoglein 3 (Dsg3) and/or Dsg1. Phenotypic transition from PV to PF is rarely reported. OBJECTIVES: To determine the immune response to extracellular (EC) domains of Dsgs during this transition. MATERIALS AND METHODS: We report two PV patients who subsequently developed a PF phenotype. To map the conformational epitopes in these cases, we examined the reactivity of the sera of two patients by immunoprecipitation-immunoblotting analysis, using five Dsg1/Dsg3 domain-swapped molecules on a backbone of Dsg2. RESULTS: Reactivity exclusively with the EC1 domain of Dsg1 was maintained in both PV and PF stages. No reactivity to Dsg3 in the PF stage was found in patient 1. Various changes in immunoreactivity to Dsg3 were found and the EC1 and EC2 domains of Dsg3 reacted weakly to serum taken at remission and PF stages in patient 2. CONCLUSIONS: Our findings suggest that amino-terminal pathogenic antibodies to the EC domain of Dsg1 were retained, while considerable epitope changes occurred in response to Dsg3 during the shift from PV to PF, with an absolute or significant decrease in pathogenic antibodies to the EC1 domain of Dsg3.

B-cell activating factor detected on both naïve and memory B cells in bullous pemphigoid.

B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells (DCs) and monocytes, BAFF expression on B cells has not been well documented. In the present study, BAFF molecules on DCs and naïve and memory B cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid (BP), were analysed by flow cytometry. Compared with healthy controls (HC), BAFF expression on naïve and memory B cells increased significantly in BP. No difference in BAFF receptor expression in naïve and memory B cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B cells of BP, but not HC, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B cells may play a pathogenic role in autoimmune bullous diseases, particularly BP.

Distinct protein expression and activity of transglutaminases found in different epidermal tumors.

We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrhoeic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein. Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.

Combination therapy of fexofenadine and montelukast is effective in prurigo nodularis and pemphigoid nodularis.

In this study, we report on the efficacy of combination therapy of second-generation antihistamine antagonist, fexofenadine hydrochloride, and leukotriene receptor inhibitor, montelukast sodium, for the treatment of 15 prurigo nodularis or pemphigoid nodularis patients, in whom conventional therapy was ineffective. All patients received 10 mg montelukast once a day and 240 mg fexofenadine twice a day for 4 weeks in addition to other medications they had been taking. We assessed the manifestations of the lesions and itching intensity before and after the therapy, and we evaluated each patient as (i) markedly improved, (ii) improved, (iii) slightly improved, (iv) no change, (v) worse. Two patients (13.3%) were evaluated as markedly improved, and the lesions of one patient completely disappeared. Three patients (20.0%) were evaluated as improved, and six patients (40.0%) as slightly improved. Thus, 11 of 15 cases (73.3%) improved by combination therapy of fexofenadine and montelukast, in which nine cases (75.0%) of prurigo nodularis and two cases (66.7%) of pemphigoid nodularis were involved. No patients revealed any side effects. This study revealed that combination therapy of fexofenadine and montelukast was effective for some patients with conventional therapy-resistant prurigo nodularis and pemphigoid nodularis.