Prevalence and factors associated with sleep disturbance in adult patients with psoriasis.

BACKGROUND: Sleep, which is crucial for restoring of physiological functions and health, is reportedly impaired in psoriasis. The role of different potential sleep confounding factors, including detailed pruritus characteristics, and the complex interplay between psychological variables (anxiety and depression), pruritus and sleep disturbance in psoriasis remain insufficiently investigated. OBJECTIVES: To investigate sleep characteristics and to identify clinical, demographic and psychological factors associated with sleep disturbance in psoriasis. METHODS: This cross-sectional study included 334 psoriasis patients (response rate 86%) and 126 control subjects (response rate 82%). Measures included sleep quality [Pittsburgh Sleep Quality Index (PSQI)], psoriasis severity, pruritus characteristics, including average pruritus intensity [visual analogue scale (VAS)], severity of comorbidities, anxiety and depression (Hospital Anxiety and Depression Scale - HADS) and quality of life (Dermatology Life Quality Index - DLQI, and Short Form 12 - SF12). RESULTS: Fifty-nine per cent of patients and 34% of control subjects (P < 0.001) suffered from sleep disturbance (PSQI > 5). Patients slept 1 h less than control subjects (median 6 vs. 7 h, P < 0.001). Patients without pruritus had less impaired sleep (global PSQI) than patients with strong (P < 0.001) and very strong pruritus (P < 0.001). Anxiety (HADS-A) and depression (HADS-D) levels were the strongest predictors of sleep impairment, followed by pruritus exacerbation at night, age, female sex, pruritus exacerbation in the morning, average pruritus intensity (VAS), diagnosed depression and gastroesophageal reflux disease, altogether explaining 32%-37% of the variance in global sleep quality. Both anxiety (HADS-A) and depression (HADS-D) were significant mediators explaining the association between pruritus intensity (VAS) and sleep impairment in 42% and 37% respectively. CONCLUSIONS: Sleep disturbance in patients with psoriasis is highly prevalent. Patients with psoriasis should be assessed for sleep impairment, pruritus, anxiety and depression. Reduction in pruritus should be considered as an important therapeutic goal, along with therapies aimed at reducing anxiety and depression.

A comprehensive, tri-national, cross-sectional analysis of characteristics and impact of pruritus in psoriasis.

BACKGROUND: Pruritus is prevalent in psoriasis but still many features of pruritus, its response to therapy and its burden in psoriasis remain to be better characterized. OBJECTIVE: To investigate characteristics and burden of pruritus in an international cohort of patients with psoriasis. METHODS: This cross-sectional study included a total of 634 patients and 246 controls from Germany, Poland and Russia. Physicians examined and interviewed participants, recording clinical characteristics, such as severity, therapy and localization of psoriatic lesions. Participants filled out self-reported questionnaires including questions on pruritus severity and impact, characteristics, and response to therapy, and quality of life (QoL). Localization patterns of pruritus and skin lesions were visualized using body heat maps. RESULTS: Most patients (82%) experienced pruritus throughout their disease, and 75% had current pruritus. The majority of patients (64%) perceived pure pruritus, and those who reported additional painful and/or burning sensations (36%) reported overall stronger pruritus. The scalp was the most frequently reported localization of pruritus, even in the absence of skin lesions. Body surface area (BSA) of pruritus was not linked to pruritus intensity, but to BSA of psoriatic lesions (rho = 0.278; P < 0.001). One third of patients (31%) reported impaired sex-life, and 4% had suicidal ideations due to pruritus. In up to one third of patients, psoriasis therapies had little or no effect on pruritus. The only therapeutic option offered to some of these patients were antihistamines, which appeared to be effective in most cases. CONCLUSION: Pruritus is highly prevalent in psoriasis and is linked to a significant burden. Current psoriasis therapies are frequently insufficient to control pruritus. Managing psoriasis should include the assessment and control of itch. Efficient antipruritic therapies should be developed and be made available for patients with psoriasis.

Activity and components of the granulocyte colony-stimulating factor pathway in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent and destructive skin alterations in intertriginous areas. OBJECTIVES: We investigated the expression and role in HS of granulocyte colony-stimulating factor (G-CSF), the regulator of neutrophil biology, as clinical signs of a neutrophilic granulocyte-driven inflammation are distinctive in the disease. METHODS: Skin and blood samples obtained from different cohorts of patients with HS and control individuals were assessed by RNA sequencing, quantitative polymerase chain reaction on reverse transcribed mRNA, and/or enzyme-linked immunosorbent assay. Mechanistic studies using keratinocytes, dermal fibroblasts, immune cell populations and skin biopsies were performed. RESULTS: G-CSF was abundant in HS skin, particularly in inflamed nodules and abscesses. Its levels even exceeded those found in other inflammatory skin diseases. Interleukin (IL)-1 and IL-17, respectively, induced G-CSF production by fibroblasts and keratinocytes. These effects were enhanced by tumour necrosis factor (TNF)-α and IL-36. Accordingly, fibroblasts separated from HS lesions expressed G-CSF, and IL-1 receptor antagonist reduced G-CSF levels in explanted HS skin. G-CSF blood levels positively correlated with severity of HS. Elevated lesional G-CSF receptor levels were linked to upregulation of molecules that contribute to prolonged activation of neutrophils by components of bacteria and damaged host cells [formyl peptide receptor 1 (FPR1), FPR2 and free fatty acid receptor 2 (FFAR2)], neutrophil survival [TNF receptor superfamily member 10C (TNFRSF10C/TRAIL-R3) and TNF receptor superfamily member 6B], kinases (tyrosine-protein kinase HCK and hexokinase 3), and skin destruction [MMP25 (matrix metalloproteinase 25) and ADAM8 (disintegrin and metalloproteinase domain-containing protein 8)]. G-CSF elevated the expression of FPR1, FFAR2, and TNFRSF10C/TRAIL-R3 in neutrophils and synergized with bacterial components to induce skin-destructive enzymes. CONCLUSIONS: The G-CSF pathway engages both tissue and immune cells, is strongly activated in HS lesions, and offers the opportunity to target the neutrophil-driven inflammation.

A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS).

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic skin disease with painful erythematous scaly or crusty lesions and pustules on the palms and soles. Apremilast is a phosphodiesterase 4 inhibitor that has proven effective in the therapy of psoriasis, psoriatic arthritis and in oral ulcers associated with Behcet's disease. OBJECTIVE: To explore the efficacy of apremilast in PPP. METHODS: APLANTUS was a phase 2 single-arm multicentre study of apremilast in 21 subjects with moderate-to-severe PPP. Primary endpoint was the per cent change of the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 20 compared to baseline. RESULTS: 20 weeks of oral treatment with apremilast in patients with moderate-to-severe PPP resulted in a significant decrease of the PPPASI with a median reduction of 57.1% (p < 0.001), and 61.9% of patients achieved at least a 50% improvement of the PPPASI relative to baseline. The total number of pustules per patient decreased significantly relative to baseline with 76.2% of patients achieving at least a 50% reduction in total pustules count at week 20. Improvement of PPP was also apparent in a significant decrease of the dermatologic life quality index (DLQI). The median DLQI score dropped from 8.5 at baseline to 2.0 at week 20 (p = 0.030). Apremilast was generally well tolerated, and no serious adverse events occurred. CONCLUSIONS: Patients with PPP treated with apremilast showed benefit both in objective and subjective disease parameters. Apremilast should be investigated further in this difficult-to-treat skin condition. EudraCT number: 2016-005122-11.

[Pathogenesis of hidradenitis suppurativa/acne inversa]. / Pathogenese der Hidradenitis suppurativa/Acne inversa.

Hidradenitis suppurativa/acne inversa (HS) has a multifactorial pathogenesis. In addition to a sporadic form, a familial form is reported in around 40% of patients, for whom an autosomal dominant (AD) inheritance with reduced gene penetrance is assumed. The phenotype of the disease with inflammatory nodules, abscesses and secreting sinus tracts suggests an infectious origin, but the exact role of the bacteria detected in HS pathogenesis remains unclear. Smoking and metabolic syndrome are regarded as important trigger factors in HS, with obesity and hormonal changes playing a pathogenic role in the latter. Ultimately, Toll-like receptors, antimicrobial peptides, immune cells and key cytokines are involved in the excessive inflammatory reaction of HS and are also the targets of future therapies.

Aetiology and pathogenesis of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder. Patients develop inflamed nodules and abscesses and, at later stages of disease, epithelialized tunnels and scars in skinfolds of axillary, inguinal, gluteal and perianal areas. Quality of life is affected due to severe pain, purulent secretion, restricted mobility and systemic involvement. Genetics and lifestyle factors including smoking and obesity contribute to the development of HS. These factors lead to microbiome alteration, subclinical inflammation around the terminal hair follicles, and infundibular hyperkeratosis, resulting in plugging and rupture of the follicles. Cell-damage-associated molecules and propagating bacteria trigger inflammation and lead to massive immune cell infiltration that clinically manifests as inflamed nodules and abscesses. The immune system plays a key role also in the progression and chronification of skin alterations. Innate proinflammatory cytokines (e.g. interleukin-1ß and tumour necrosis factor-α), mediators of activated T helper (Th)1 and Th17 cells (e.g. interleukin-17 and interferon-γ), and effector mechanisms of neutrophilic granulocytes, macrophages and plasma cells are involved. Simultaneously, skin lesions contain anti-inflammatory mediators (e.g. interleukin-10) and show limited activity of Th22 and regulatory T cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction and scarring. Chronic inflammation in patients with HS is also frequently detected in organs other than the skin, as indicated by their comorbidities. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. This scholarly review focuses on the causes and pathogenetic mechanisms of HS and the potential therapeutic value of this knowledge.

Association of CCL2 with systemic inflammation in Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)-1 system, but the exact pathophysiological pathways remain largely unknown. OBJECTIVES: To identify and characterize the pathogenetic players in SchS. METHODS: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme-linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse-transcriptase polymerase chain reaction and ELISA. RESULTS: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL-1ß (immune cells, fibroblasts) and tumour necrosis factor (TNF)-α (fibroblasts) were important CCL2 inducers. TNF-α, but not IL-17, strengthened the CCL2-inducing effect of IL-1ß in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF-α and IL-1ß serum levels in patients with SchS. Therapeutic IL-1ß blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. CONCLUSIONS: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS.

[Drug therapy of acne inversa]. / Medikamentöse Therapie der Acne inversa.

Acne inversa is a chronic inflammatory destructive skin disease that affects about 1% of the population. The therapy should be personalized and consists of surgical and conservative procedures. Antibiotics are administered either topically or systemically. Combination therapy with clindamycin and rifampicin for 10-12 weeks can be very effective. Furthermore, TNF-α inhibitors show adequate efficacy and can be recommended. Adalimumab is the only approved drug product for systemic treatment of acne inversa. The efficacy of retinoids is controversial. Isotretinoin cannot be recommended for the treatment of acne inversa; however, acitretin has been proven to be more effective. Immune-modulating substances, like dapsone, cyclosporine A, methotrexate, colchicine, or corticosteroids, can be considered; however, the study data are insufficient for recommendation. Hormonal therapies can influence the course of the disease. Antiseptics are applied independent of the stage of disease. Patients should be informed about triggering factors.

Lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa.

BACKGROUND: Acne inversa (AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae. OBJECTIVES: This study aimed to identify and characterize the key players in AI pathogenesis. METHODS: Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry. RESULTS: Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 (LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 (n = 18) vs. 41·8 ± 4·2 (n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (rs = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity (rs = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars. CONCLUSIONS: LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus.

Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity.

BACKGROUND: A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking. OBJECTIVES: To develop and validate a novel dynamic scoring system to assess the severity of HS. METHODS: A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round. RESULTS: Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36). CONCLUSIONS: The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting.

[Acne inversa/hidradenitis suppurativa: A challenge for the future]. / Acne inversa/Hidradenitis suppurativa: Eine Herausforderung für die Zukunft.

Acne inversa (AI)/hidradenitis suppurativa is a chronic recurrent inflammatory dermatosis with signs of a systemic disease. AI is characterized by typical skin alterations in body areas bearing apocrine glands. The care of the AI patients in Germany is still inadequate. This situation might be significantly improved through the following efforts: (i) shortening of the time between the disease onset and the diagnosis/start of therapy; (ii) the in-depth investigation of AI pathogenesis with the aim of identifying innovative therapeutic targets and blood biomarkers; (iii) establishing a method for quantifying the severity of the disease, which takes into account both the clinical assessment and objective laboratory parameters and the self-assessment of the patient (e.g., Dermatology Life Quality Index [DLQI]); (iv) the elaboration of a clear algorithm for the interdisciplinary treatment of patients, which, in addition to the therapy of skin lesions, also includes lifestyle-modification measures and takes into consideration the systemic character of AI. This article describes the current problems of medical care for AI patients and outlines how we can achieve the predetermined goals.

[Acne inversa/hidradenitis suppurativa: An update]. / Acne inversa/Hidradenitis suppurativa: Ein Update.

Acne inversa (AI)/hidradenitis suppurativa is a chronic, recurrent, immune-mediated dermatosis characterized by deep inflammatory nodules, abscesses, fistulas, and undermined scars in skin areas bearing apocrine glands. In addition to the cutaneous manifestation, numerous AI patients show metabolic changes, spondyloarthritis, and depression. AI leads to a strong reduction in the quality of life and an impairment of the sexual life of affected individuals and often culminates in social withdrawal, stigmatization, unemployment, and suicidal thoughts. In this overview, we summarized the most important facts about AI and propose a simple algorithm for therapy.

[Systemic treatments for psoriasis and psoriatic arthritis]. / Systemische Therapien der Psoriasis und Psoriasisarthritis.

Psoriasis is one of the most common chronic dermatoses. More than 25 % of the affected individuals require effective systemic treatment because of severe symptoms and/or the significantly restricted quality of life. Thanks to intensive research and successful cooperation between academia and the pharmaceutical industry, the options for treating psoriasis have dramatically increased in recent years. Especially targeted therapies give us the opportunity for personalized regimen. This review describes the spectrum of the systemic treatments for psoriasis and psoriatic arthritis and discusses the efficacy, safety, and particular features of the individual substances.

Efficacy of Steroid and Physiotherapy in Early Reported Lagophthalmos of Patient Affected with Leprosy. A Report from Trbal Dominated Leprosy Endemic State of India.

Lagophthalmos is one of the well-known complications of leprosy due to involvement of the facial nerve. In the present study an attempt has been made to elucidate the role of early intervention with steroids and adjunct physiotherapy in early reported lagophthalmos in patients affected with leprosy at a tertiary referral institute under the Disability Prevention and Medical rehabilitation (DPMR) programme. During April 2008 to March 2014, 62 patients affected with leprosy reported to Regional leprosy Training and Research Institute with lagophthalmos. Cases reporting within six months of difficulty in closure were categorized as early reporting group. These were either referred from a peripheral health centre (63%) or self-reported (37%). These patients were examined clinically and details were noted in a pretested Performa. The standard dosages of the steroids were given to patients as per NLEP guidelines. Lid gaps on direct gaze and with both gentle and forced closure were assessed using standard measuring technique by a physiotherapist. During the follow-up period the patients were imparted active and passive physiotherapy and any change in the lid gap was recorded. The data was analysed and appropriate test of significance was applied. Out of 62 lagophthalmos patients, 49(79.1%) were males and 13 (20.9%) were females. 56 (90.3%) cases were from MB category and 6 (9.7%) cases were from PB category. 53(85.4%) patients presented with unilateral eye involvement, while 9 (14.6%) had bilateral lagophthalmos. 53 (74.6%) of the eyes achieved complete lid closure, while the remaining 18 (25.4%) eyes had gap on gentle closure. During six month follow-up the amount of recession of lid gap among the early reported lagophthalmos was 4.15 mm with standard steroid regimen and physiotherapy. With the use of the steroid and regular physiotherapy lagophthalmos diagnosed and treated in initial stages shows significant improvement in the lid gap reduction.

Interleukin-10 receptor-1 expression in monocyte-derived antigen-presenting cell populations: dendritic cells partially escape from IL-10's inhibitory mechanisms.

Interleukin (IL)-10 is an important immunoregulatory cytokine that mediates its effects via a transmembrane receptor complex consisting of two different chains, IL-10R1 and IL-10R2. While IL-10R2 is ubiquitously expressed and does not bind IL-10 primarily, the expression of IL-10R1 determines cellular responsiveness. However, the current knowledge about the expression and regulation of IL-10R1 is still limited. Here we analyzed the expression of IL-10R1 on monocytic cells and demonstrated that human blood monocytes carried about 720 IL-10-binding sites on their surface. Compared with lymphocytes and various tissue cells and tissues, blood monocytes expressed the highest IL-10R1 levels. The in vitro differentiation of these cells into macrophages provoked a further increase of IL-10R1 surface expression. In contrast, their differentiation into myeloid dendritic cells (mDCs) resulted in reduced surface IL-10R1 levels. The different IL-10R1 levels expressed by monocyte-derived antigen-presenting cell populations were reflected in their different responsiveness toward IL-10. Importantly, also in vivo developed immature macrophages and mDCs showed different IL-10 sensitivity. These data suggest that, compared with monocytes and macrophages, mDCs partially escape from IL-10's inhibitory mechanisms by downregulating IL-10R1.

Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines.

Interferon (IFN)-lambda1, -2 and -3 (also designated as interleukin (IL)-29, IL-28alpha and IL-28beta) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-lambda1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-lambdas are still unknown. This study aimed at identifying the target cells of IFN-lambdas within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-lambda receptor expression. Interestingly, immune cells expressed high levels of a short IFN-lambda receptor splice variant (sIFN-lambdaR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-lambda1 with a moderate affinity (K(D) 73 nM) and was able to inhibit IFN-lambda1 effects. Our study suggests that IFN-lambda therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application.