JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs

Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy

Background: After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients. Methods: We studied 377 patients treated at Ghent University Hospital and at ST.-Elisabeth Clinic and Maternity in Namur, with adjuvant intensity modulated radiotherapy (IMRT) after breast-conserving surgery for breast cancer. Women were treated in a prone or supine position with normofractionated (25 x 2 Gy) or hypofractionated (15 x 2.67 Gy) IMRT alone or in combination with other adjuvant therapies. Patient-and treatment-related factors and genetic markers in regulatory regions of radioresponsive genes and in LIG3, MLH1 and XRCC3 genes were considered as variables. Acute dermatitis was scored using the CTCAEv3.0 scoring system. Desquamation was scored separately on a 3-point scale (0-none, 1-dry, 2-moist). Results: Two-hundred and twenty patients (58%) developed G2+ dermatitis whereas moist desquamation occurred in 56 patients (15%). Normofractionation (both p = D (p = 0.001 and p = 0.043) and concurrent hormone therapy (p = 0.001 and p = 0.037) were significantly associated with occurrence of acute dermatitis and moist desquamation, respectively. Additional factors associated with an increased risk of acute dermatitis were the genetic variation in MLH1 rs1800734 (p=0.008), smoking during RT (p = 0.010) and supine IMRT (p = 0.004). Patients receiving trastuzumab showed decreased risk of acute dermatitis (p < 0.001). Conclusions: The normofractionation schedule, supine IMRT, concomitant hormone treatment and patient related factors (high BMI, large breast, smoking during treatment and the genetic variation in MLH1 rs1800734) were associated with increased acute skin toxicity in patients receiving radiation therapy after breast-conserving surgery. Trastuzumab seemed to be protective

Novel genetic variants associated with lumbar disc degeneration in northern Europeans: A meta-analysis of 4600 subjects

Objective: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. Methods: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. Results: This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10-8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10-8) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10-4, p=0.006). Conclusions: LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway. Copyright Article author (or their employer) 2012

JAK1, JAK2, JAK3 and TYK2 immunohistochemical localization in the epidermis.

<p>Similar expression was seen in all studied diseases: JAK1, 2 and 3 were expressed in the cytoplasm of the keratinocytes and TYK2, besides cytoplasmic expression, had nuclear expression of TYK2 (arrow). Original magnification x 200. Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum.</p

Demographics of the patients.

<p>The demographics for each disease group are comparable to the control group, except for AD.</p

Immunohistochemical staining of normal keratinocytes (KCs) and psoriasis induced keratinocytes (Pso KCs) with or without tofacitinib treatment.

<p>The pJAKs expression in Pso KCs was similar and summarizes the one observed in the epidermis of the psoriasis skin biopsies. Strong pJAK3 expression and weak positive pJAK1 expression was induced by psoriasis stimulation and inhibited after treatment with tofacitinib. Phospho-JAK2 and pTYK2 expression did not change neither with psoriasis stimulation nor with the treatment. Note the cytoplasm localization of pJAK1 and pJAK3 and the nuclear localization of pTYK2 in the keratinocytes. As pJAK2 was negative in all conditions, the localization of the staining could not be analysed. Original magnification x200.</p

Percentage of JAK/STAT family positivity (in grey)/negativity in dermal inflammatory cells of ISDs comparing to controls.

<p>Percentage of JAK/STAT family positivity (in grey)/negativity in dermal inflammatory cells of ISDs comparing to controls.</p

PhosphoJAK1, pJAK2, pJAK3 and pTYK2 immunohistochemical localization in the epidermis.

<p>Cytoplasmic expression of pJAK1, pJAK3 and pTYK2. Intranuclear expression of pJAK2 and pTYK2 (arrows). Similar expression was seen in all studied diseases. Original x 200. Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum.</p