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010 The prevalence of anxiety in patients with psoriasis: A systematic review of observational studies and clinical trials
ABSTRACTS | Clinical Outcomes 007
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Open-label, prospective pilot study on combined use of pulsed dye laser and 1% topical rapamycin in cutaneous capillary malformation E Doh1, J Ohn1, M Kim2, Y Kim2 and S Cho1 1 Dermatology, Seoul National University Boramae Hospital, Seoul, Korea (the Republic of) and 2 Mapo-Gongdeok S&U Dermatology Clinic, Seoul, Korea (the Republic of) Pulsed dye laser (PDL) is considered as treatment of choice for cutaneous capillary malformation. The regeneration or revascularization of blood vessels after PDL treatment is one of the causes of treatment failures which may be explained by angiogenesis via the induction of the hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) pathways. Recently, topical administration of rapamycin (RPM), which is also known as sirolimus, was introduced as a possible adjunctive therapeutic option to minimize post-laser revascularization in facial capillary malformations. We evaluated the effect of combined use of 1% topical RPM with PDL compared to PDL alone in cutaneous capillary malformation of trunk or extremities and tried to identify the effective length of RPM application. The study design was a prospective side-by-side comparison of 5 patients. Three adjacent areas of cutaneous capillary malformation which had never been treated before were selected in each patient and underwent the following regimens: (A) PDL alone; (B) PDL + topical RPM for 1 week post-PDL; and (C) PDL + topical RPM for 8 weeks post-PDL. Each patient was treated by PDL (Vbeam PerfectaÒ, Candela/Syneron, Wayland, MA) every 8 weeks at varied settings with the following parameters: fluence 4.75e6.25 J/cm2, pulse duration 0.45 ms, focal spot size 10 mm, 1 shot. Topical RPM was applied to the area once daily. Clinical outcomes were measured using chromameter (Minolta chromameter CR-400). Only one of five patients showed clinical improvement in color of capillary malformation with combined RPM treatment. Overall, there was no statistically significant difference in redness (p ¼ .65 at 8 weeks, p¼.87 at 16 weeks by Kruskal-Wallis test) and blanching rate between PDL alone and combined topical RPM regimens. In conclusion, topical RPM does not seem to be effective as a treatment modality for port wine stains.
Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14 SM Lwin1, C Hsu1, L Liu2, N Levell3 and J McGrath1 1 Department of Genetics and Molecular Medicine, King’s College London, London, United Kingdom, 2 St Thomas’ Hospital, Viapath, London, United Kingdom and 3 Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, United Kingdom Pityriasis rubra pilaris (PRP) represents a group of rare inflammatory papulosquamous disorders. Most cases of PRP are sporadic, but w1 in 20 cases show autosomal dominant inheritance with gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14), also known as CARD-containing MAGUK protein 2 (Carma 2). CARD14 activates the noncanonical nuclear factor-kappa B (NF-kB) pathway, thus promoting inflammation. Here, we report a mother and son with PRP due to a new missense mutation in CARD14 and the beneficial effect of ustekinumab, a monoclonal antibody against interleukins-12 and -23 (agonists of the NF-kB pathway), in the mother. A 49 year-old female and her 20 year-old son had lifelong, generalised, patchy erythematous scale with pink discolouration and a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma. Skin histology revealed psoriasiform epidermal hyperplasia. Treatment with oral retinoids, phototherapy, and topical steroids proved ineffective. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 16, c.356T>G, resulting in the missense mutation, p.Met119Arg. This mutation is predicted to be pathogenic and is located adjacent to other gain-of-function mutations between the CARD and coiled-coil domain; it was not present in unaffected family members; and does not feature in >50,000 control subjects. The mother was then treated with ustekinumab 45mg every 12 weeks after two loading doses at weeks 0 and 4. A dramatic clinical improvement was observed within a few days of the initial loading dose and persisted beyond 18 weeks’ follow-up. This report highlights the therapeutic potential of biologics that downregulate the NF-kB pathway in familial PRP with mutations in CARD14.
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Activated regulatory T cells in patients with alopecia areata for supressing disease acitivity R Kubo, S Muramatsu, Y Sagawa, C Saito, S Kasuya, A Nishioka, E Nishida and A Morita Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Alopecia areata is one of refractory inflammatory skin disorders. However the precise mechanism remains obscure and appropriate treatement for severe cases should be developed even patients experience self regression. We previously evaluated the number of circulating CD4+ CD25+ regulatory T cells were increased substantially, but not stastically significant in alopecia patients compared with healthy controls (4.691.24% vs. 3.811.12%, p¼0.074). In the present study, we examined three distinct Treg subsets: activated Treg (aTreg), resting Treg (rTreg), and non-suppressive T cells (non-Treg). aTreg have the strongest suppressive activity among the three subsets and rTreg are moderately suppressive. We examined these subsets from the peripheral blood in 12 alopecia patients. aTreg levels and aTreg + rTreg levels were significantly higher than those of healthy controls (n¼11) (aTreg:1.871.27% vs 0.920.44%, p¼0.022; aTreg + rTreg:3.221.55% vs 2.380.44%, p¼0.045). In the three-group comparison, alopecia, psoriasis (n¼15) and healthy controls, aTreg + rTreg levels in alopecia were higher than those in psoriasis (3.221.55% vs 1.941.38%, p<0.05). aTreg levels in patinets not having alopecia totalis were significantly higher than that of healthy controls (2.020.95% vs 0.920.44%, p¼0.047). aTreg and rTreg levels were negatively correlated with the disease duration (aTreg:r¼-0.306; aTreg+rTreg:r¼ -0.544). These results indicated that increased aTreg+rTreg would suppress the disease activity at early phase and induce spontaneous remission to some extent in alopecia patients. Therefore, the maintenace of aTreg levels might prevent the disease progression and be a target of new treatment modality.
The prevalence of anxiety in patients with psoriasis: A systematic review of observational studies and clinical trials P Fleming1, J Bai2, M Pratt3, C Sibbald1, C Lynde1 and W Gulliver3 1 Division of Dermatology, University of Toronto, Toronto, ON, Canada, 2 MD Program, University of Toronto, Toronto, ON, Canada and 3 Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada Psoriasis and anxiety are chronic conditions with significant morbidity, and there is evidence that they may exacerbate one another. There is little data on the prevalence of anxiety in psoriasis and the effect of psoriasis treatment on comorbid anxiety. The primary objective of this study is to perform a systematic review of the literature to describe the prevalence and severity of anxiety/anxiety symptoms among adult patients with psoriasis and characterize the effect of anti-psoriatic interventions on anxiety symptoms. We searched PubMed, EMBASE, and the Cochrane Database using search terms ‘psoriasis’ and ‘anxiety’. Results were tabulated and verified by two independent reviewers. Meta-analyses were not performed due to heterogeneity of data. Of 213 publications identified, 938,194 patients from 15 papers were included. The mean age ranged from 31.9-59.4 years old, with a mean PASI score of 7.65-22.8 (reported by nine studies) and body surface area involvement of 25.9-39.8% (reported by two studies). The prevalence of anxiety in patients with psoriasis was 7-48%, which was significantly higher than healthy controls in two of three studies (HR 1.29-1.31, p¼0.001 and OR 2.91 [95% CI, 2.01-4.21], p<0.001). Four of five studies (n¼2029) demonstrated an improvement in anxiety symptoms with psoriasis treatment. This systematic review demonstrates a high prevalence of anxiety of adult patients with psoriasis, suggesting that patients would benefit from systematic screening. Although the data suggests that anxiety may be improved through various psoriasis treatments, larger prospective randomized trials are needed to confirm this effect.
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Monogenic type I interferonopathies: from diagnosis to treatment M Rodero, M Fre´mond, L Van Eyck, y Crow, B Neven and French JAKI-Interferonopathy Treatment Consortium Institut Imagine, Paris, France Mutations in genes involved in nucleic acid metabolism, sensing or associated signalling cascades can cause constitutive and sustained activation of type 1 interferon (IFN). In such monogenic diseases the skin has emerged as one of the most commonly affected organs; where cutaneous pathology, encompassing severe vasculopathy and ‘chilblains’, frequently results in extensive tissue damage and can provide a major clue to the diagnosis of this novel group of disorders. Recognition of the fundamental role of IFN in the pathogenesis of the type I interferonopathies led us to consider the blocking of IFN signalling as a logical therapeutic strategy. On this basis, we have treated patients mutated in TMEM173, encoding the cytosolic adaptor molecule STING, with the JAK1/2 inhibitor ruxolitinib. In such patients, treated for a period of up to 2.5 years, we have observed a remarkable improvement in all major aspects of the clinical phenotype including the devastating skin involvement. We have mapped these clinical effects ex vivo and in vitro by defining the kinetics of pSTAT1 status before and after drug intake in leukocytes from patients; interestingly, these data reveal an almost complete, but transient inhibition of STAT1 phosphorylation, thereby explaining the lack of infections in treated patients despite the immunosuppressive properties of the drug. In order to assess whether this treatment could be translated to other interferonopathies we have also treated cells from patients with mutations in IFIH1 and obtained similar results. Overall, our findings suggest that JAK inhibition represents a highly promising and well-tolerated therapeutic approach to the multisystem sterile inflammation associated with TMEM173-activating mutations. Considering the recognized phenotypic and pathophysiological overlap, treatment by JAK inhibition may also be relevant to other monogenic type I interferonopathies, and the still wider spectrum of diseases associated with an activation of type I IFN such as subsets of systemic lupus erythematosus and dermatomyositis.
S162 Journal of Investigative Dermatology (2016), Volume 136
Jumihaidokuto (Shi-Wei-Ba-Du-Tang), a Kampo Formula, decreases the disease activity of palmoplantar pustulosis M Mizawa, T Makino, C Inami and T Shimizu Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan Palmoplantar pustulosis (PPP) is a chronic skin disease characterized by sterile intraepidermal pustules associated with erythematous scaling on the palms and soles. The standard therapy for PPP patients includes topical corticosteroids, topical vitamin D3 analogs, oral cyclosporine A, psoralen plus ultraviolet A therapy (PUVA) and narrowband ultraviolet (UV)-B. However, clinicians often experience PPP that is refractory to these treatments. Jumihaidokuto (JHT) is a traditional herbal medicine composed of ten medical plants and has been administered to patients with suppurative skin disease in Japan. This study investigated the effect of JHT on the disease activity in PPP patients (n¼10). PPP patients were administered JHT (EKT-6; 6.0 g per day; Kracie Holdings, Ltd., Tokyo, Japan) for 4 to 8 weeks in addition to their prescribed medications. The disease severity of PPP was evaluated using the palmoplantar pustular psoriasis area and severity index (PPPASI). The PPPASI score was calculated as described below. Erythema, pustules and desquamation were evaluated on a scale of 0 to 4, while the area was evaluated on a scale of 0 to 6. The results showed that the average PPPASI of all patients was 8.34 9.00 before JHT treatment. Four or 8 weeks after the administration of JHT, the average PPPASI significantly decreased (5.46 7.02, p ¼ 0.01). Seven out of 10 PPP patients showed an improvement in their clinical findings. In most of these patients, the number of pustules on the palms and soles markedly decrease. In addition, some patients showed a disappearance of hyperkeratotic lesions. No adverse event was observed during the study period. Therefore, JHT is seemingly effective against PPP.
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Open-label, prospective pilot study on combined use of pulsed dye laser and 1% topical rapamycin in cutaneous capillary malformation E Doh1, J Ohn1, M Kim2, Y Kim2 and S Cho1 1 Dermatology, Seoul National University Boramae Hospital, Seoul, Korea (the Republic of) and 2 Mapo-Gongdeok S&U Dermatology Clinic, Seoul, Korea (the Republic of) Pulsed dye laser (PDL) is considered as treatment of choice for cutaneous capillary malformation. The regeneration or revascularization of blood vessels after PDL treatment is one of the causes of treatment failures which may be explained by angiogenesis via the induction of the hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) pathways. Recently, topical administration of rapamycin (RPM), which is also known as sirolimus, was introduced as a possible adjunctive therapeutic option to minimize post-laser revascularization in facial capillary malformations. We evaluated the effect of combined use of 1% topical RPM with PDL compared to PDL alone in cutaneous capillary malformation of trunk or extremities and tried to identify the effective length of RPM application. The study design was a prospective side-by-side comparison of 5 patients. Three adjacent areas of cutaneous capillary malformation which had never been treated before were selected in each patient and underwent the following regimens: (A) PDL alone; (B) PDL + topical RPM for 1 week post-PDL; and (C) PDL + topical RPM for 8 weeks post-PDL. Each patient was treated by PDL (Vbeam PerfectaÒ, Candela/Syneron, Wayland, MA) every 8 weeks at varied settings with the following parameters: fluence 4.75e6.25 J/cm2, pulse duration 0.45 ms, focal spot size 10 mm, 1 shot. Topical RPM was applied to the area once daily. Clinical outcomes were measured using chromameter (Minolta chromameter CR-400). Only one of five patients showed clinical improvement in color of capillary malformation with combined RPM treatment. Overall, there was no statistically significant difference in redness (p ¼ .65 at 8 weeks, p¼.87 at 16 weeks by Kruskal-Wallis test) and blanching rate between PDL alone and combined topical RPM regimens. In conclusion, topical RPM does not seem to be effective as a treatment modality for port wine stains.
Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14 SM Lwin1, C Hsu1, L Liu2, N Levell3 and J McGrath1 1 Department of Genetics and Molecular Medicine, King’s College London, London, United Kingdom, 2 St Thomas’ Hospital, Viapath, London, United Kingdom and 3 Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, United Kingdom Pityriasis rubra pilaris (PRP) represents a group of rare inflammatory papulosquamous disorders. Most cases of PRP are sporadic, but w1 in 20 cases show autosomal dominant inheritance with gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14), also known as CARD-containing MAGUK protein 2 (Carma 2). CARD14 activates the noncanonical nuclear factor-kappa B (NF-kB) pathway, thus promoting inflammation. Here, we report a mother and son with PRP due to a new missense mutation in CARD14 and the beneficial effect of ustekinumab, a monoclonal antibody against interleukins-12 and -23 (agonists of the NF-kB pathway), in the mother. A 49 year-old female and her 20 year-old son had lifelong, generalised, patchy erythematous scale with pink discolouration and a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma. Skin histology revealed psoriasiform epidermal hyperplasia. Treatment with oral retinoids, phototherapy, and topical steroids proved ineffective. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 16, c.356T>G, resulting in the missense mutation, p.Met119Arg. This mutation is predicted to be pathogenic and is located adjacent to other gain-of-function mutations between the CARD and coiled-coil domain; it was not present in unaffected family members; and does not feature in >50,000 control subjects. The mother was then treated with ustekinumab 45mg every 12 weeks after two loading doses at weeks 0 and 4. A dramatic clinical improvement was observed within a few days of the initial loading dose and persisted beyond 18 weeks’ follow-up. This report highlights the therapeutic potential of biologics that downregulate the NF-kB pathway in familial PRP with mutations in CARD14.
009
010
Activated regulatory T cells in patients with alopecia areata for supressing disease acitivity R Kubo, S Muramatsu, Y Sagawa, C Saito, S Kasuya, A Nishioka, E Nishida and A Morita Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Alopecia areata is one of refractory inflammatory skin disorders. However the precise mechanism remains obscure and appropriate treatement for severe cases should be developed even patients experience self regression. We previously evaluated the number of circulating CD4+ CD25+ regulatory T cells were increased substantially, but not stastically significant in alopecia patients compared with healthy controls (4.691.24% vs. 3.811.12%, p¼0.074). In the present study, we examined three distinct Treg subsets: activated Treg (aTreg), resting Treg (rTreg), and non-suppressive T cells (non-Treg). aTreg have the strongest suppressive activity among the three subsets and rTreg are moderately suppressive. We examined these subsets from the peripheral blood in 12 alopecia patients. aTreg levels and aTreg + rTreg levels were significantly higher than those of healthy controls (n¼11) (aTreg:1.871.27% vs 0.920.44%, p¼0.022; aTreg + rTreg:3.221.55% vs 2.380.44%, p¼0.045). In the three-group comparison, alopecia, psoriasis (n¼15) and healthy controls, aTreg + rTreg levels in alopecia were higher than those in psoriasis (3.221.55% vs 1.941.38%, p<0.05). aTreg levels in patinets not having alopecia totalis were significantly higher than that of healthy controls (2.020.95% vs 0.920.44%, p¼0.047). aTreg and rTreg levels were negatively correlated with the disease duration (aTreg:r¼-0.306; aTreg+rTreg:r¼ -0.544). These results indicated that increased aTreg+rTreg would suppress the disease activity at early phase and induce spontaneous remission to some extent in alopecia patients. Therefore, the maintenace of aTreg levels might prevent the disease progression and be a target of new treatment modality.
The prevalence of anxiety in patients with psoriasis: A systematic review of observational studies and clinical trials P Fleming1, J Bai2, M Pratt3, C Sibbald1, C Lynde1 and W Gulliver3 1 Division of Dermatology, University of Toronto, Toronto, ON, Canada, 2 MD Program, University of Toronto, Toronto, ON, Canada and 3 Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada Psoriasis and anxiety are chronic conditions with significant morbidity, and there is evidence that they may exacerbate one another. There is little data on the prevalence of anxiety in psoriasis and the effect of psoriasis treatment on comorbid anxiety. The primary objective of this study is to perform a systematic review of the literature to describe the prevalence and severity of anxiety/anxiety symptoms among adult patients with psoriasis and characterize the effect of anti-psoriatic interventions on anxiety symptoms. We searched PubMed, EMBASE, and the Cochrane Database using search terms ‘psoriasis’ and ‘anxiety’. Results were tabulated and verified by two independent reviewers. Meta-analyses were not performed due to heterogeneity of data. Of 213 publications identified, 938,194 patients from 15 papers were included. The mean age ranged from 31.9-59.4 years old, with a mean PASI score of 7.65-22.8 (reported by nine studies) and body surface area involvement of 25.9-39.8% (reported by two studies). The prevalence of anxiety in patients with psoriasis was 7-48%, which was significantly higher than healthy controls in two of three studies (HR 1.29-1.31, p¼0.001 and OR 2.91 [95% CI, 2.01-4.21], p<0.001). Four of five studies (n¼2029) demonstrated an improvement in anxiety symptoms with psoriasis treatment. This systematic review demonstrates a high prevalence of anxiety of adult patients with psoriasis, suggesting that patients would benefit from systematic screening. Although the data suggests that anxiety may be improved through various psoriasis treatments, larger prospective randomized trials are needed to confirm this effect.
011
012
Monogenic type I interferonopathies: from diagnosis to treatment M Rodero, M Fre´mond, L Van Eyck, y Crow, B Neven and French JAKI-Interferonopathy Treatment Consortium Institut Imagine, Paris, France Mutations in genes involved in nucleic acid metabolism, sensing or associated signalling cascades can cause constitutive and sustained activation of type 1 interferon (IFN). In such monogenic diseases the skin has emerged as one of the most commonly affected organs; where cutaneous pathology, encompassing severe vasculopathy and ‘chilblains’, frequently results in extensive tissue damage and can provide a major clue to the diagnosis of this novel group of disorders. Recognition of the fundamental role of IFN in the pathogenesis of the type I interferonopathies led us to consider the blocking of IFN signalling as a logical therapeutic strategy. On this basis, we have treated patients mutated in TMEM173, encoding the cytosolic adaptor molecule STING, with the JAK1/2 inhibitor ruxolitinib. In such patients, treated for a period of up to 2.5 years, we have observed a remarkable improvement in all major aspects of the clinical phenotype including the devastating skin involvement. We have mapped these clinical effects ex vivo and in vitro by defining the kinetics of pSTAT1 status before and after drug intake in leukocytes from patients; interestingly, these data reveal an almost complete, but transient inhibition of STAT1 phosphorylation, thereby explaining the lack of infections in treated patients despite the immunosuppressive properties of the drug. In order to assess whether this treatment could be translated to other interferonopathies we have also treated cells from patients with mutations in IFIH1 and obtained similar results. Overall, our findings suggest that JAK inhibition represents a highly promising and well-tolerated therapeutic approach to the multisystem sterile inflammation associated with TMEM173-activating mutations. Considering the recognized phenotypic and pathophysiological overlap, treatment by JAK inhibition may also be relevant to other monogenic type I interferonopathies, and the still wider spectrum of diseases associated with an activation of type I IFN such as subsets of systemic lupus erythematosus and dermatomyositis.
S162 Journal of Investigative Dermatology (2016), Volume 136
Jumihaidokuto (Shi-Wei-Ba-Du-Tang), a Kampo Formula, decreases the disease activity of palmoplantar pustulosis M Mizawa, T Makino, C Inami and T Shimizu Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan Palmoplantar pustulosis (PPP) is a chronic skin disease characterized by sterile intraepidermal pustules associated with erythematous scaling on the palms and soles. The standard therapy for PPP patients includes topical corticosteroids, topical vitamin D3 analogs, oral cyclosporine A, psoralen plus ultraviolet A therapy (PUVA) and narrowband ultraviolet (UV)-B. However, clinicians often experience PPP that is refractory to these treatments. Jumihaidokuto (JHT) is a traditional herbal medicine composed of ten medical plants and has been administered to patients with suppurative skin disease in Japan. This study investigated the effect of JHT on the disease activity in PPP patients (n¼10). PPP patients were administered JHT (EKT-6; 6.0 g per day; Kracie Holdings, Ltd., Tokyo, Japan) for 4 to 8 weeks in addition to their prescribed medications. The disease severity of PPP was evaluated using the palmoplantar pustular psoriasis area and severity index (PPPASI). The PPPASI score was calculated as described below. Erythema, pustules and desquamation were evaluated on a scale of 0 to 4, while the area was evaluated on a scale of 0 to 6. The results showed that the average PPPASI of all patients was 8.34 9.00 before JHT treatment. Four or 8 weeks after the administration of JHT, the average PPPASI significantly decreased (5.46 7.02, p ¼ 0.01). Seven out of 10 PPP patients showed an improvement in their clinical findings. In most of these patients, the number of pustules on the palms and soles markedly decrease. In addition, some patients showed a disappearance of hyperkeratotic lesions. No adverse event was observed during the study period. Therefore, JHT is seemingly effective against PPP.