Efficacy comparison of ustekinumab between anti‐tumor necrosis factor‐α drug‐naïve and anti‐tumor necrosis factor‐α drug‐resistant Japanese psoriasis cases

Ustekinumab is highly efficacious for psoriasis; however, it has not been fully clarified whether previous failure in anti‐tumor necrosis factor‐α (TNF‐α) therapy affects the treatment response with ustekinumab. Therefore, we evaluated the efficacy of ustekinumab in anti‐TNF‐α‐naïve and anti‐TNF‐α‐resistant cases and compared the clinical efficacies of adalimumab and ustekinumab in biologic naïve cases. Thirty‐five patients with plaque psoriasis who showed resistance to conventional therapies were enrolled; 26 patients, who had never been treated with biologics, were allocated to ustekinumab or adalimumab; nine patients who failed to achieve psoriasis area and severity index (PASI) 50 at week 16 with one or two TNF‐α antagonists were switched to ustekinumab. The end of the study was defined as 52 weeks after starting the first biologic for anti‐TNF‐α‐naïve patients and after switching to ustekinumab for anti‐TNF‐α‐resistant patients. The primary outcome measurement was the percentage of patients achieving PASI75 at week 16. In patients treated with ustekinumab, 87.5% of anti‐TNF‐α‐naïve and 77.8% of anti‐TNF‐α‐resistant cases achieved a PASI75 response at week 16, and no statistically significant difference was found between the treatment response rates (P = 0.60). When comparing the treatment efficacy of ustekinumab and adalimumab among anti‐TNF‐α‐naïve patients, there was also no statistically significant difference in PASI75 achievement rates (87.5 vs. 83.3%, P = 0.79). Our study suggests that ustekinumab can be considered as a first‐line biologic for psoriasis and a rescue therapy for anti‐TNF‐α‐resistant cases.     

Responses to ustekinumab in the anti‐TNF agent‐naïve vs. anti‐TNF agent‐exposed patients with psoriasis vulgaris

Background Approximately 20–30% of patients with psoriasis treated with anti‐tumour necrosis factor α (TNFα) agents will discontinue treatment within 2 years due to loss of efficacy or side‐effects. Switching to another anti‐TNFα agent produces clinical responses inferior to previously untreated patients. Ustekinumab binds to the p40 subunit of interleukin (IL)‐12 and IL‐23 and provides a mechanism of action independent of TNFα. Objective To investigate the efficacy of ustekinumab in a clinical practice setting and to compare treatment responses to ustekinumab in patients previously treated with TNFα inhibitors and anti‐TNFα‐naïve patients. Methods Patients receiving either ustekinumab (n = 71) or the subcutaneous TNFα inhibitors adalimumab or etanercept (n = 108) were identified through the registry of psoriasis patients in our Institutions. Efficacy effect outcome was a 75% improvement in the psoriasis area severity index (PASI75). Kaplan–Meier statistics evaluated the adherence to the treatments expressed as drug survival rate. Results PASI75 was achieved in 80% of the ustekinumab‐treated patients after a median time of 112 days. There was no difference in efficacy in anti‐TNFα‐naïve patients compared with anti‐TNFα unresponsive patients. Patients treated with ustekinumab showed a superior adherence to treatment in comparison with adalimumab and etanercept. Limitations Patients were non‐randomly assigned to treatment, which potentially may lead to biases. Observation time was short (1 year). Conclusion In clinical practice, the short‐term efficacy and patient adherence to ustekinumab are excellent and comparable to the data obtained in clinical trials. Lack of response to previous anti‐TNF treatment does not impair clinical response to ustekinumab.     

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.     

Anti‐tumor necrosis factor‐alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6‐month prospective study

The aim of the present study was to determine if the use of the anti‐tumor necrosis factor (TNF)‐α monoclonal antibody adalimumab could improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. This was a prospective study on a series of consecutive patients with moderate to severe psoriasis who completed 6 months of therapy with adalimumab. Patients with history of cardiovascular events, diabetes mellitus, kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Assessment of endothelial function by brachial artery reactivity measuring flow‐mediated endothelial dependent vasodilatation (FMD%), and carotid arterial stiffness by pulse wave velocity (PWV) was performed at the onset of treatment (time 0) and at month 6. Twenty‐nine patients were studied. Anti‐TNF‐α adalimumab therapy yielded a significant improvement of endothelial function. The mean ± standard deviation (SD) FMD% values increased from 6.19 ± 2.44% at the onset of adalimumab to 7.46 ± 2.43% after 6 months of treatment with this biologic agent (P = 0.008). Likewise, following the use of adalimumab, PWV levels decreased from 6.28 ± 1.04 m/s at the onset of adalimumab to 5.69 ± 1.31 m/s at 6 months (P = 0.03). In conclusion, patients with moderate to severe psoriasis exhibit improvement of endothelial function and arterial stiffness following anti‐TNF‐α therapy. These findings are of potential relevance due to increased risk of cardiovascular disease in patients with severe psoriasis.     

The single‐chain anti‐TNF‐α antibody DLX105 induces clinical and biomarker responses upon local administration in patients with chronic plaque‐type psoriasis

It is not clear whether TNF‐α antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin‐produced TNF‐α would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double‐blinded, randomized, placebo‐controlled clinical trials with the novel single‐chain anti‐TNF‐α‐PENTRA^®‐antibody DLX105. Upon intra‐dermal injection, DLX105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% (P = 0.001). The clinical response was accompanied by changes in biomarkers such as reductions in K16, Ki67 and epidermal thickness as well as decreased mRNA levels of IL‐17, TNF‐α, IL‐23p19, IL‐12p40 and IFN‐γ. Next, we applied the drug topically twice daily in a 0.5% hydrogel formulation. While the local PASI did not change, topical DLX105 mediated significant reductions of mRNA levels of key proinflammatory cytokines when compared to placebo, and this effect was further enhanced after weekly tape stripping of plaques to increase drug penetration. These results suggest that longer treatment periods and/or increased local drug concentrations might result in better therapeutic efficacy of topically applied DLX105. In sum, we can show for the first time that local inhibition of TNF‐α is sufficient to mediate a biological response in psoriasis that translates into clinical efficacy.     

Cutaneous lymphocyte‐associated antigen as a novel predictive marker of TNF‐alpha inhibitor biological therapy in psoriasis

A considerable number of patients with psoriasis show secondary resistance during long‐term TNF‐alpha inhibitor therapy, necessitating the identification of reliable predictive markers. Predictive role of cutaneous lymphocyte‐associated antigen (CLA) was investigated. Thirty‐eight severe patients with psoriasis were treated for a 24‐week‐long study period. Clinical responsiveness (PASI) and changes in flow cytometry–measured peripheral lymphocyte CLA expression (week 0–2–6) were statistically analysed. Regarding 24‐week‐long treatment outcome patients were divided into two groups: During the first 6 weeks, mean CLA expression showed significant (P = 0.034604) increase among responders (32/38), while after a preliminary increase, it was significantly (P = 0.012539) decreasing in the relapsing group (6/38). Pearson's correlation analysis showed significant negative correlation between PASI and CLA changes. Responders showed (not significantly) lower initial CLA expression than relapsing patients. Our observations suggest change in CLA expression during the first 6 weeks of induction period to serve as a potential predictive marker of TNF‐alpha inhibitor therapy in psoriasis.     

Balance of Treg versus T‐effector cells during systemic treatment with adalimumab and topical treatment with calcipotriol–betamethasone dipropionate ointment

Diminished suppressive capacity of regulatory T cells (Treg) has been demonstrated in blood and in lesional skin of psoriatic patients. Treatment with anti‐TNFα restored the number and function of circulating Treg in psoriasis. We aimed to study Treg in the skin of psoriatic patients undergoing topical treatment with calcipotriol–betamethasone dipropionate (CBD) ointment (n = 12) or systemic treatment with anti‐TNFα agent adalimumab (n = 10). Skin biopsies were collected from patients with chronic plaque psoriasis who responded to the above‐mentioned treatments with a SUM‐score improvement of at least 50% (at the end of treatment). Biopsies were processed for immunohistochemistry. As Treg function is associated with a numerical balance between Treg and effector T cells, Foxp3/CD4 ratios were calculated. It appeared that both treatments cause a significant decrease in the presence of Foxp3+ cells. However, in patients that were treated with CBD ointment, we observed lower Foxp3/CD4 ratios after 8 weeks of treatment compared to baseline (t = 0: 0.41 ± 0.08; t = 8: 0.22 ± 0.04, P = 0.033), whereas in patients who were treated with adalimumab we observed an increase of the Foxp3/CD4 ratios after 1.5 and 16 weeks of treatment compared to baseline (t = 0: 0.25 ± 0.04; t = 1.5: 0.32 ± 0.06; t = 16: 0.49 ± 0.10, P = 0.15). Based on Foxp3/CD4 ratios, we can conclude that adalimumab treated skin differs from CBD treated skin with regard to the anti‐inflammatory/inflammatory balance. We suggest that, in contrast to CBD ointment, adalimumab favours local Treg function in the skin.     

CCL7 contributes to the TNF‐alpha‐dependent inflammation of lesional psoriatic skin

Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT‐PCR, we found CCL7, a chemokine ligand known to interact with multiple C‐C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non‐lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod‐induced psoriasis‐like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro‐psoriatic cytokines such as CCL20, IL‐12p40 and IL‐17C, while its blockade led to an increase in the antipsoriatic cytokine IL‐4. In humans receiving the TNF‐α‐blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF‐α‐dependent Th1/Th17‐mediated inflammation in lesional psoriatic skin.     

TNF‐α and IL‐10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population

Backround Pemphigus vulgaris is a rare chronic autoimmune disease of skin and mucous membranes, with several cytokines participating in its development. The role of their gene polymorphisms in susceptibility to the disease is, however, not fully understood. Objective The aim of our case‐control study was to investigate whether some of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes (IL‐1α, IL‐1β, IL‐1RI, IL‐1Ra, IL‐4Rα, IL‐12, IFN‐γ, TGF‐β1, TNF‐α, IL‐2, IL‐4, IL‐6 and IL‐10) are associated with pemphigus vulgaris in the Slovak population. Methods DNA samples were obtained from 34 pemphigus vulgaris patients and 140 healthy controls of Slovak origin. Cytokine gene SNPs were determined using the polymerase chain reaction with sequence‐specific primers (PCR‐SSP) method. Results We found a weak association between pemphigus vulgaris and polymorphic variants in TNF‐α and IL‐10 genes only, with haplotypes TNF‐α–308G/–238G and IL‐10 –1082A/–819C/–592C being significantly overrepresented in pemphigus vulgaris patients (TNF‐α GG: 94.12% vs. 82.86%, P = 0.0216; IL‐10 ACC: 44.12% vs. 30.00%, P = 0.0309). Conclusions Our preliminary results suggest that certain TNF‐α and IL‐10 gene polymorphisms might contribute to genetic susceptibility to pemphigus vulgaris; however, their overall impact on disease development will be rather limited.     

TNF α‐induced leukocyte–endothelial cell interactions show marked interindividual differences independent of the clinical response to adalimumab

The responses of patients with psoriasis to TNFα‐antagonists show interindividual differences. Here, TNFα‐incubation induced endothelial adhesion molecules, a prerequisite for leucocyte recruitment to inflamed tissues. Using a standardized flow chamber system equipped with near‐confluent endothelial cells and a mobile phase containing human leucocytes, proportions of leucocytes interacting with endothelial cells were remarkably different between individual donors (up to 3.5‐fold), regardless of whether the leucocytes originated from patients with psoriasis (n = 10) or healthy donors (n = 10). Adalimumab abrogated adhesion molecule induction and interactions with leucocytes when present prior to or simultaneously with, but not after exposure of the cultures to TNFα. This pattern was seen similarly with leucocytes from healthy donors (n = 4), and patients whose psoriasis responded well to adalimumab (n = 5) and non‐responders (n = 5). Thus, although considerable interindividual differences of leucocyte–endothelial cell interactions were demonstrated ex vivo in a TNFα‐governed microenvironment, such differences are not associated with individual responses to treatment with adalimumab in vivo.     

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll‐like receptor‐2 (TLR2), a key step in comedogenesis. Tetramethyl‐hexadecenyl‐cysteine‐formylprolinate (SIG1459), a novel anti‐acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 μmol\L), minimal bactericidal concentration (MBC = 16.1 μmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 μmol\L). To assess SIG1459's anti‐inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL‐1, Pam3CSK4) that induce pro‐inflammatory cytokine IL‐8 and IL‐1α production. Results demonstrate SIG1459 inhibits TLR2‐induced IL‐8 release from TLR2/TLR2 (IC₅₀ = 0.086 μmol\L), TLR2/6 (IC₅₀ = 0.209 μmol\L) and IL‐1α from TLR2/TLR2 (IC₅₀ = 0.050 μmol\L). To assess the safety and in vivo anti‐acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head‐to‐head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti‐acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.     

Study of pro‐ and anti‐inflammatory cytokine profile in the patients with parthenium dermatitis

Background: Parthenium dermatitis is a common airborne allergic contact dermatitis induced by exposures to the weed Parthenium hysterophorus. The disease manifests as itchy erythematous papules, papulovesicular and plaque lesions on exposed areas of the body. Objectives: The aim of this study was to show the alterations in pro/anti‐inflammatory cytokines in parthenium dermatitis. Methods: The study included 50 patients with parthenium dermatitis confirmed by patch testing using aqueous extracts of P. hysterophorus and 50 age‐matched healthy controls. The levels of pro‐inflammatory [tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐17] and anti‐inflammatory (IL‐4 and IL‐10) cytokines were estimated by commercially available high sensitivity enzyme‐linked immunosorbent assay (ELISA) kits. Results: All the dermatitis patients showed significantly (P < 0.001) elevated levels of TNF‐α, IL‐6, IL‐8, and IL‐17 levels as compared to healthy controls. In contrast, the anti‐inflammatory cytokine IL‐4 showed an insignificant decrease (P < 0.217) and a decrease in level of IL‐10 was statistically significant (0.001) compared with controls. Conclusions: The present study suggests the involvement of pro‐inflammatory cytokines in the pathogenesis of parthenium dermatitis. A decrease in levels of anti‐inflammatory cytokines was demonstrated, which could not downregulate pro‐inflammatory cytokines in parthenium dermatitis.     

Asymmetric dimethylarginine but not osteoprotegerin correlates with disease severity in patients with moderate‐to‐severe psoriasis undergoing anti‐tumor necrosis factor‐α therapy

Patients with psoriasis, in particular those with severe disease, have an increased risk of cardiovascular (CV) events compared with the general population. The aim of the present study is to determine whether correlation between asymmetric dimethylarginine (ADMA) and osteoprotegerin (OPG), two biomarkers associated with CV disease, and disease severity may exist in patients with moderate‐to‐severe psoriasis. We also aimed to establish if baseline serum levels of these two biomarkers could correlate with the degree of change in the clinical parameters of disease severity following the use of anti‐tumor necrosis factor (TNF)‐α therapy in these patients. This was a prospective study on a series of consecutive non‐diabetic patients with moderate‐to‐severe psoriasis who completed 6 months of therapy with anti‐TNF‐α‐adalimumab. Patients with kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Metabolic and clinical evaluation was performed immediately prior to the onset of treatment and at month 6. Twenty‐nine patients were assessed. Unlike OPG, a significant positive correlation between ADMA and resistin serum levels was found at the onset of adalimumab and also after 6 months of biologic therapy. We also observed a positive correlation between the percent of body surface area affected (BSA) and ADMA levels obtained before the onset of adalimumab and a negative correlation between baseline ADMA levels and a 6‐month BSA change compared with baseline results. In patients with moderate‐to‐severe psoriasis, ADMA levels correlate with clinical markers of disease severity.     

Increased levels of circulating platelet‐derived microparticles are associated with metastatic cutaneous melanoma

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL^?1) than in patients with stage III (2041 μL^?1) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut‐off value (5311 μL^?1) allowing the distinction between high‐risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma.     

Efficacy and safety of guselkumab in psoriasis patients who failed ustekinumab and/or anti‐interleukin‐17 treatment: A real‐life 52‐week retrospective study

Recent major research advancements have significantly expanded our understanding of psoriasis pathophysiology, resulting in the development of highly effective, targeted therapies. Guselkumab is the first interleukin (IL)‐23 inhibitor approved for the treatment of moderate‐to‐severe‐psoriasis, providing a new therapeutical option for psoriasis. The aim of our study was to evaluate the efficacy of guselkumab in psoriatic patients who previously failed anti‐IL‐12/23 and/or anti‐IL‐17 treatment. A 52‐week single‐center retrospective study was performed enrolling moderate‐to‐severe patients attending our Psoriasis Care Center from October 2018 to May 2020. Study population included 13 patients; 46.1% have been previously treated with ustekinumab, while 69.2% have previously failed an anti‐IL‐17 treatment (38.5% secukinumab, 30.8% ixekizumab, and 38.5% both). At baseline, mean Psoriasis Area and Severity Index was 13.2 ± 6.8, reducing up to 0.5 ± 0.7 at week 52 (P < .001). Body surface area reduced from 22.3 ± 10.5 (baseline) to 0.8 ± 1.1 at week 52 (P < .001). No statistically significant differences have been found between patients previously treated with anti‐IL‐12/23 compared to anti‐IL‐17 or both. Only one patient discontinued guselkumab at week 36 due to secondary inefficacy. This is a single institution study with a relatively small sample size. Our real‐life data confirm trial results, showing guselkumab as a safe and effective option in patients with moderate‐to‐severe psoriasis even in those who previously failed ustekinumab and/or anti‐IL‐17 treatment.     

Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti‐tumour necrosis factor agents: subanalysis of BELIEVE

Background Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti‐TNFs) is likely to improve psoriasis in patients with prior anti‐TNF treatment. Objective The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti‐TNF treatment. Methods The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16‐week, double‐blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1–15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti‐TNFs. Results Of 730 patients enrolled, 282 (38.6%) had prior anti‐TNFs and 448 (61.4%) were anti‐TNF‐naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti‐TNFs achieved PASI 75 at week 16, compared with 71.7% of anti‐TNF‐naïve patients (P = 0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti‐TNF agent had been used, the number of prior anti‐TNFs tried, or reasons for discontinuation of prior anti‐TNF therapy. Adverse event incidences were similar between patients with and without prior anti‐TNF therapy. Conclusion Adalimumab was effective and well‐tolerated in patients with psoriasis previously treated with anti‐TNF therapy.     

Topical application of the adenosine A2A receptor agonist CGS‐21680 prevents phorbol‐induced epidermal hyperplasia and inflammation in mice

The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti‐inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A_2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS‐21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS‐21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS‐21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB₄ and CXCL‐1, and the inflammatory cytokine TNF‐α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS‐21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist‐treated mice. Our results showed that CGS 21680 efficiently prevents phorbol‐induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.     

Genetic prediction of the effectiveness of biologics for psoriasis treatment

Anti‐tumor necrosis factor (TNF)‐α therapy is used for the treatment of psoriasis, with varying outcomes. However, the specific cause of inadequate response or treatment failure remains unknown. The aim of the present study was to identify useful clinical biomarkers for predicting therapeutic responses or to serve as new drug targets for refractory psoriasis cases. We performed a genome‐wide association study (GWAS) of 65 psoriasis patients who were prospectively followed after beginning anti‐TNF‐α therapy using Human Omni Express‐8 v1.2 Beadchips. Patients were enrolled at the dermatology departments of Kobe University Hospital and six collaborative hospitals. Associations between single nucleotide polymorphisms (SNP) and changes in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment were evaluated. After genome data collection and quality control, a total of 731 442 SNPs were identified in 65 Asian psoriasis patients who were treated with adalimumab or infliximab. Here, we present 10 SNPs, such as those in JAG2 and ADRA2A, that were associated with treatment responses to anti‐TNF‐α agents (strongest effect, P < 7.11E‐06). This is the first GWAS to examine SNP associated with treatment responses in psoriasis patients. In addition, we identified other SNP that exhibited potential associations with anti‐TNF‐α treatment response, which merit further study. Of these, rs11096957 on TLR10, which is associated with increased TNF‐α production, was previously reported to be associated with treatment responses to TNF‐α inhibitors.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.     

Long‐term changes in nail fold capillary abnormalities and serum fibroblast growth factor 23 levels in dermatomyositis patients with anti‐melanoma differentiating antigen 5 antibody

Nail fold videocapillaroscopy (NVC) abnormalities are a characteristic finding of microangiopathy in dermatomyositis (DM). The aim of the present study was to examine long‐term changes in NVC abnormalities and serum fibroblast growth factor 23 (FGF23) and vascular endothelial growth factor (VEGF) levels in DM patients with anti‐melanoma differentiation‐associated gene 5 (MDA5) antibody (Ab). Serum levels of FGF23 and VEGF were measured by enzyme‐linked immunosorbent assay. NVC abnormalities were evaluated by capillaroscopy in 11 DM patients with anti‐MDA5 Ab at baseline and after treatment. NVC abnormalities included irregularly enlarged capillaries, reduced capillaries, hemorrhages, capillary ramifications, disorganization of the vascular array, loss of capillaries and giant capillaries. Serum FGF23 levels were significantly decreased in patients with anti‐MDA5 Ab (0.3 ± 0.3 pmol/L) compared with healthy controls (1.0 ± 0.6 pmol/L, P < 0.01). Serum FGF23 levels significantly increased after treatment (0.3 ± 0.3 vs 1.0 ± 0.7 pmol/L, P < 0.005), but serum VEGF levels were comparable between at baseline and after treatment. At baseline, irregularly enlarged capillaries were observed in 10 of 11 patients, but after treatment, they were significantly reduced in only two (91% vs 18%, P < 0.001). Hemorrhages were observed in all 11 patients at baseline, but disappeared in all after treatment (100% vs 0%, P < 0.001). These results suggest that NVC abnormalities are reversible by treatment and that serum FGF23 levels reflect the degree of microvascular damage in DM patients with anti‐MDA5 Ab.