Aram Boada

A new era in the management of psoriasis? The biologics: facts and controversies ☆

During the last 30 years, the tremendous progress in our knowledge of the pathogenesis of psoriasis has led to the development of new agents, the so-called biologics, that have revolutionized the management of severe psoriasis. Dermatologists and patients see this emerging therapy as a new perspective in the state of the art in managing moderate to severe psoriasis. After a few years of use in daily practice, we may begin to analyze the power of the currently available biologic agents in the management of severe psoriasis from the perspective of facts.

Perniosis: Clinical and Histopathological Analysis

Perniosis are inflammatory cutaneous lesions, located on acral skin, which present in association with cold exposure. They can appear as an idiopathic dermatosis or with an underlying autoimmune disease. The use of cutaneous biopsy to distinguish between both types is controversial. We analyze the histological findings in 9 cases of idiopathic perniosis (IP) and compare them with those obtained from 11 cases of perniosis associated with an autoimmune disease (autoimmune perniosis). The most frequent histopathological features observed in cases of IP were a lymphocytic infiltrate with perivascular (8 cases, 89%) and perieccrine distribution (6 cases, 66%), dermal edema (5 cases, 55%), and necrotic keratinocytes (5 cases, 55%), whereas those found in perniosis associated with an autoimmune disease were lymphocytic infiltrate with perivascular distribution (11 cases, 100%) but without perieccrine distribution (3 cases, 27%), vacuolation of the basal layer (7 cases, 63%), and necrotic keratinocytes (5 cases, 45%). The only significant difference between both groups was the perieccrine distribution of the lymphocytic infiltrate in cases of IP, which, as mentioned in previous studies, could be considered a histopathological clue to differentiate both types of perniosis.

Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer.

Importance New targeted therapies for cancer have been released in recent years, opening new horizons in the treatment of patients with cancer. However, their related adverse events (AE) are not fully characterized. Hair repigmentation (HR) is a nondescribed effect secondary to anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1 ) therapy for treatment of lung cancer (LC), in opposition to the vitiligo reactions that develop during melanoma treatment. Objective To describe a new adverse event occurring during anti–PD-1/anti–PD-L1 therapy for LC. Design, Setting, and Participants A case series from a descriptive observation of 14 patients with HR after anti–PD-1/anti–PD-L1 treatment, recruited between September and December, 2016, who were followed up to detect whether they developed cutaneous AE at the time HR was detected. The patients had all been treated in the dermatology department at Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Main Outcomes and Measures Clinical observation of HR during anti–PD-1/anti–PD-L1 therapy for LC, proved by comparing old pictures provided by the patients and recent pictures taken during the follow-up. Results Fourteen patients (13 men and 1 woman; mean age, 64.9 years) receiving anti–PD-1 or anti–PD-L1 therapy for non–small-cell lung cancer (NSCLC) presented hair repigmentation during follow-up. This hair repigmentation consisted in a diffuse darkening of the hair in 13 of 14 patients, or in black patches between white hairs in 1. Thirteen of 14 patients presented a good clinical response to the treatment, with at least stable disease, and only 1 had to stop the therapy after only 4 cycles of treatment owing to a life-threatening progression of the disease. Conclusions and Relevance We present to our knowledge the first report of hair repigmentation owing to anti–PD-1/anti–PD-L1 therapy for lung cancer in a series of 14 patients. Hair repigmentation may be a good response marker in patients receiving anti-PD1/anti–PD-L1 therapy for LC.

CCL4L polymorphisms and CCL4/CCL4L serum levels are associated with psoriasis severity.

Psoriasis is a common inflammatory skin disease with key immunological and genetic components. Recruitment of leukocytes into the skin is a central step in its pathogenesis, mediated by cytokines. Among the cytokines expressed in psoriatic lesions, C-C chemokine ligand 4 (CCL4) and C-C chemokine ligand 4-like (CCL4L) chemokines appear to be pivotal elements for the skin recruitment of proinflammatory cells. The aim of this study is to evaluate the relationship between CCL4L polymorphisms (including single-nucleotide polymorphisms (SNPs) and copy number variation (CNV)) and the course and prognosis of psoriasis. We analyzed the CNV and the rs4796195 SNP in 211 psoriatic patients and 234 controls; sera from both populations were also quantified for CCL4/CCL4L protein. Our results showed that a high CNV (≥3 copies) is associated with psoriasis severity, whereas moderate disease correlated with a lower CNV (≤2 copies); specifically, the CCL4L1 allele frequency is higher in severe psoriasis, whereas CCL4L2 is more frequent in patients with a milder disease. In addition, we found a positive correlation between the CNV and sera protein levels. Our results suggest that CCL4L genotyping could not only allow a better understanding of the psoriatic pathogenesis but could also be used as a prognostic tool, even helping to modulate the efficacy of treatments.

Original ArticleCCL4L Polymorphisms and CCL4/CCL4L Serum Levels Are Associated with Psoriasis Severity

Psoriasis is a common inflammatory skin disease with key immunological and genetic components. Recruitment of leukocytes into the skin is a central step in its pathogenesis, mediated by cytokines. Among the cytokines expressed in psoriatic lesions, C-C chemokine ligand 4 (CCL4) and C-C chemokine ligand 4-like (CCL4L) chemokines appear to be pivotal elements for the skin recruitment of proinflammatory cells. The aim of this study is to evaluate the relationship between CCL4L polymorphisms (including single-nucleotide polymorphisms (SNPs) and copy number variation (CNV)) and the course and prognosis of psoriasis. We analyzed the CNV and the rs4796195 SNP in 211 psoriatic patients and 234 controls; sera from both populations were also quantified for CCL4/CCL4L protein. Our results showed that a high CNV (≥3 copies) is associated with psoriasis severity, whereas moderate disease correlated with a lower CNV (≤2 copies); specifically, the CCL4L1 allele frequency is higher in severe psoriasis, whereas CCL4L2 is more frequent in patients with a milder disease. In addition, we found a positive correlation between the CNV and sera protein levels. Our results suggest that CCL4L genotyping could not only allow a better understanding of the psoriatic pathogenesis but could also be used as a prognostic tool, even helping to modulate the efficacy of treatments.

Melanoma Incidence Increases in the Elderly of Catalonia But Not in the Younger Population: Effect of Prevention or Consequence of Immigration?

The remodeling of Ca2+ signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions. One particular facet of these adaptive changes is the alteration of Ca2+ fluxes through the plasma membrane, as described in several studies. In this review, we summarize the current knowledge about the expression of different Ca2+ channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca2+ signaling. In the last few years, new molecular components of Ca2+ influx pathways have been identified in melanoma cells. In addition, new links between Ca2+ homeostasis and specific cell processes important in melanoma tumor progression have been unveiled. Thus, not only do Ca2+ channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches.All cases of MM diagnosed in 23 hospitals in Catalonia, from 2000 to 2007 were recorded and melanoma incidence calculated and adjusted for the European standard population via the direct method. The age standardised rate/100,000 inhabitants varied from 6.74 in 2000 to 8.64 in 2007 for all melanomas and from 4.79 to 5.80 for invasive MMs; the Breslow thickness was stable during the period. The increase in invasive melanoma incidence in the elderly was remarkable, the crude rate/100,000 inhabitants increasing from 11.04 (2000) to 15.49 (2007) in the 60-64 year population, while remaining more stable in the 30-34 year range, from 3.97 in 2000 to 4.55 in 2007, and with a tendency to decrease from 5.1 in 2000 to 2.5 in 2007 for the age range of 25-29 years. These lower age ranges are much more affected by immigration. Despite the large immigrant population (nearly one million immigrants arrived in Catalonia during the study period from countries with a low melanoma incidence), melanoma incidence in our region has risen considerably and this trend is likely to persist in the near future.

Fatal gastrointestinal toxicity with ipilimumab after BRAF/ MEK inhibitor combination in a melanoma patient achieving pathological complete response

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

Generalized cutaneous drug eruption due to strontium ranelate

© 2008 The Authors JEADV 2009, 23 , 317–368 Journal compilation

Mucous Membrane Ulcers in an Immunocompromised Patient—Quiz Case

A 62-year-old man presented with a 10-day history of painful ulcerated lesions on his tongue and penis. His medical history was remarkable for a low-risk myelodysplastic syndrome, which had been treated with antithymocyte globulin and cyclosporine 1 month earlier. Clinical examination showed a large, deep, and exquisitely tender ulceration on the glans penis, with a purulent exudate (Figure 1). Also, 3 linear superficial erosions were detected on the dorsum of the tongue (Figure 2). Exudate cultures yielded Escherichia coli and Enterococcus faecalis. Antibiotic therapy with ciprofloxacin and metronidazole was unable to improve the clinical lesions, which enlarged after a few days. Laboratory evaluation was significant for a severe lymphocytopenia (lymphocytes, 300/μL [to convert to 10/L, multiply by 0.001]). No other cutaneous or extracutaneous signs or symptoms of visceral involvement were detected. Serologic tests were negative for human immunodeficiency virus (HIV). Skin biopsy findings are shown in Figure 3. What is your diagnosis?A 62-year-old man presented with a 10-day history of painful ulcerated lesions on his tongue and penis. His medical history was remarkable for a low-risk myelodysplastic syndrome, which had been treated with antithymocyte globulin and cyclosporine 1 month earlier. Clinical examination showed a large, deep, and exquisitely tender ulceration on the glans penis, with a purulent exudate (Figure 1). Also, 3 linear superficial erosions were detected on the dorsum of the tongue (Figure 2). Exudate cultures yielded Escherichia coli and Enterococcus faecalis. Antibiotic therapy with ciprofloxacin and metronidazole was unable to improve the clinical lesions, which enlarged after a few days. Laboratory evaluation was significant for a severe lymphocytopenia (lymphocytes, 300/μL [to convert to 10/L, multiply by 0.001]). No other cutaneous or extracutaneous signs or symptoms of visceral involvement were detected. Serologic tests were negative for human immunodeficiency virus (HIV). Skin biopsy findings are shown in Figure 3. What is your diagnosis?

Cutaneous toxicities of new treatments for melanoma

New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients’ quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.