Antonella Di Cesare

The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis

Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.

The IL23R R381Q Gene Variant Protects against Immune-Mediated Diseases by Impairing IL-23-Induced Th17 Effector Response in Humans

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohns disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

A Role for Th17 Cells in the Immunopathogenesis of Atopic Dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease. Both epidermal barrier dysfunction and immunodysregulation are suggested to influence the pathogenesis of AD. AD has been considered a paradigmatic T helper cell (Th) 2-mediated disease, with a switch to a Th1 cell environment during the chronic phase of the disease. Previously unreported findings now suggest a possible role for Th17 cells as well.

Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiol® gel) in the treatment of scalp psoriasis: results from a study in 885 patients

Background: Previous studies showed the efficacy of a formulation containing calcipotriol and betamethasone dipropionate for the treatment of psoriasis. Objective: To investigate maintenance strategies of a formulation containing calcipotriol (50 µg/g) and betamethasone dipropionate (0.5 mg/g) for the treatment of scalp psoriasis. Materials and methods: Nine-hundred and four patients were screened and randomised on a 1:1 basis in two groups: maintenance of two applications per week (group A) versus on-demand therapy (group B). Clinical evaluation was performed at weeks 0, 2, 4, 8 and 12. Results: Eight-hundred and eighty-five patients were randomised: 441 in group A and 444 in group B. From week 2, both groups showed a significant clinical improvement compared with baseline; at weeks 8 and 12, group A demonstrated a higher clinical response compared with group B (p < 0.05). This difference was statistically significant (OR 0.47, 95% CI 0.37, 0.60). Conclusions: The maintenance of twice-weekly application versus on-demand treatment of calcipotriol/betamethasone dipropionate gel is more effective and is associated with a lower rate of relapse.

The spectrum of dermatoscopic patterns in blue nevi.

BACKGROUND Blue nevi are congenital or acquired, dermal dendritic melanocytic proliferations that can simulate melanocytic and nonmelanocytic lesions including melanoma, cutaneous metastasis of melanoma, Spitz/Reed nevi, and basal cell carcinoma. OBJECTIVE We sought to investigate global and local dermatoscopic patterns of blue nevi compared with melanomas and basal cell carcinomas. METHODS We retrospectively analyzed global and local features in 95 dermatoscopic images of blue nevi and in 190 melanomas and basal cell carcinomas that were selected as control lesions on the basis of similar pigmentation. Lesion pigmentation was classified as monochromatic, dichromatic, or multichromatic. RESULTS A global pattern characterized by homogeneous pigmentation was observed in all of 95 (100%) blue nevi. Eighty of 95 (84.2%) blue nevi presented a homogeneous pattern consisting of one color (blue, black, or brown) or two colors (blue-brown, blue-gray, or blue-black). Fifteen of 95 (15.8%) blue nevi had a multichromatic (blue, gray, black, brown, and/or red) pigmentation. In all, 47 of 95 (49.5%) blue nevi were characterized by pigmentation in the absence of pigment network or any other local dermatoscopic features. And 48 of 95 (50.5%) blue nevi showed local dermatoscopic patterns including whitish scarlike depigmentation, dots/globules, vascular pattern, streaks, and networklike pattern. LIMITATIONS The study was retrospective and involved only Caucasian people of Italian origin. CONCLUSION The characteristic feature of blue nevi is a homogeneous pigmentation that is blue, blue-gray, blue-brown, or blue-black. We showed that a wide spectrum of local dermatoscopic features (whitish scarlike depigmentation, dots/globules, peripheral streaks or vessels) may also be present. In such cases, clinical and dermatoscopic distinction from melanoma or nonmelanocytic lesions may be difficult or impossible, and surgical excision is necessary.

Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments

Several immune-related markers have been implicated in basal cell carcinoma (BCC) pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL)-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ) treatment or photodynamic therapy (PDT). IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular) from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT). Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response during IMQ and MAL-PDT treatments.

Cutaneous hyperpigmentation induced by apremilast

Apremilast is an oral inhibitor of phosphodiesterase-4 (PDE4) recently approved for the treatment of psoriasis and psoriatic arthritis (PsA). We report the case of a 70-year-old female patient affected with severe psoriasis and PsA for more than 30 years, who developed cutaneous skin hyperpigmentation while treated with oral apremilast 30 mg/bid (Fig. 1). Over decades, she had been variously treated with PUVA, acitretin, cyclosporine-A, and methotrexate. She was also treated with infliximab first and then adalimumab with optimal response of cutaneous and articular symptoms; however, during both biologics she developed ANA-positivity with levels up to 1:1280 that were completely reversible after treatment suspension. Eight weeks after adalimumab discontinuation, the patient presented with a psoriasis area and severity index (PASI) score of 5, severe morning stiffness, visual analog scale (VAS) pain 6, important functional limitation with tender, swollen, and painful II, III, IV-distal interphalangeal (DIP) and metacarpophalangeal (MCP) joints of both hands, and ultrasonographic active tenosynovitis of all the involved articulations. In addition, she developed new PsA symptoms at the right ankle and metatarsal sites of the right foot. The patient had a BMI > 30, arterial hypertension, atrial fibrillation, osteoporosis, hypovitamin D levels, and depressive syndrome, respectively treated with atenolol, cardioaspirin, propafenone, cholecalciferol, and escitalopram. Of note, the patient had seriously photo damaged skin with multiple solar lentigines at photo-exposed sites (upper and lower arms, dorsa of hands, face, and back-trunk). Typically, she had no photodamaged skin where she performed UV-protection with clothes. Treatment with apremilast was started and as soon as week 4 of treatment, the patient experienced almost complete clearance of cutaneous plaques with a little benefit on pain (VAS 4) and morning stiffness. At week 8 of treatment, PASI response was maintained with further improvement of PsA symptoms (morning stiffness, VAS pain 3, reduction of swollen and tender DIP-MCP joint count, and amelioration of metatarsal and ankle limitation of function). The patient did not report side effects other than weight loss (almost 5 kg), however we noticed a general cutaneous dark hyper pigmentation of the whole body, especially of the severe photo damaged areas, of the solar lentigines and seborrheic keratoses of the trunk as for intense UV exposure. We could not check hair color since the patient usually dyed her hair. Notably, the patient denied use of sun beds or sun exposure. PDE4 is a key regulator of intracellular signaling by degrading of the second messenger cyclic adenosine-30,50-monophosphate (cAMP), which in turn activates transcription of pro-inflammatory mediators and inhibits anti-inflammatory cytokines including IL-10. Apremilast inhibits PDE4 thus increasing the intracellular cAMP levels and reducing all the major players in the

Safety and efficacy of HCV eradication during etanercept treatment for severe psoriasis

Treatment of severe psoriasis in HCV positive patients is challenging, because several psoriasis medications have a toxic effect on the liver, and interferon alpha, used to treat hepatitis, can induce worsening of psoriatic lesions. TNF‐alpha inhibitors seem to be a safe and effective option in HCV positive psoriatic patients, but there are concerns about long‐term safety, impact on liver fibrosis progression and risk of immune‐mediated liver injury. With regard to HCV treatment, new direct‐acting antiviral therapies (DAA) seem to be extremely effective, with minimal side effects, but little is known about possible interactions with other medications, particularly with biologics. We report the case of a psoriatic patient, in treatment with Etanercept, who needed to undergo HCV eradication with Daclastavir and Sofosbuvir because of worsening liver fibrosis due to chronic hepatitis C. The present treatment produced excellent results in terms of HCV eradication and control of psoriatic lesions, without side effects.