Dermatological side effects rarely interfere with the continuation of checkpoint inhibitor immunotherapy for cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPIs) is an emerging anticancer treatment strategy, which may cause a variety of skin reactions. In this study, we sought to analyze and classify the cutaneous side effects (CSE) of the CPIs nivolumab, pembrolizumab, and ipilimumab with respect to prevalence, type, and severity, and to review their potential interference with CPI immunotherapy. METHODS: In this retrospective analysis, medical records were analyzed with respect to incidence, type, and severity of CSE in patients on CPI immunotherapy for cancer. The implications for immunotherapy maintenance were scrutinized. RESULTS: From 2012 to 2019, 352 consecutive patients were treated with CPIs for cancer, of which 46 patients (13.1%) experienced CSE. The incidence of CSE was less with nivolumab (n = 16; 9.5%) and pembrolizumab monotherapy (n = 9; 9.6%) as compared to ipilimumab (n = 10; 23.3%) and combination therapy (n = 11; 23.9%); P < 0.05. Skin toxicity could be stratified by rash/eczema (n = 28; 60.9%), autoimmune (n = 8; 17.4%, vitiligo n = 5, lichen sclerosus n = 2, psoriasis guttata n = 1), lichenoid reaction (n = 5; 10.9%), pruritus (n = 4; 8.7%), and a miscellaneous group (n = 3; 6.5%). The limited severity grades of CSE caused immunotherapy disruption in only three (0.9%) cases. Interestingly, 80% of melanoma patients who developed vitiligo during immunotherapy had stable disease or disease remission. CONCLUSION: CPIs in cancer patients may result in a distinct set of CSE, with drug rash and eczematous rash being the most common. CTLA-4 blocker ipilimumab and combination therapy are more prone to elicit skin toxicity than the PD-1 inhibitors nivolumab and pembrolizumab, although this rarely interferes with the continuation of immunotherapy.

Initial Results of Secukinumab Drug Survival in Patients with Psoriasis: A Multicentre Daily Practice Cohort Study.

Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials. However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan-Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least one episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practice.

Continuous Wave Potassium Titanyl Phosphate Laser Treatment is Safe and Effective for Xanthelasma Palpebrarum.

BACKGROUND: Although not an accepted standard treatment, the 532-nm continuous wave potassium titanyl phosphate (CW-KTP) laser might be a powerful device to treat xanthelasma palpebrarum (XP). OBJECTIVE: To determine the safety and efficacy of CW-KTP laser treatment for XP. MATERIALS AND METHODS: Between January 2013 and January 2015, 30 consecutive patients with XP were treated with a 532-nm CW-KTP laser (spot size: 0.9 mm, power: 5.0 W, fluence: 36-38 J/cm, pulse width: 46 milliseconds, frequency: 2.0 Hz, passes per session: 3). In a retrospective study design, safety and efficacy data were collected and analyzed. RESULTS: Overall, 29/30 (97%) of patients had an excellent cosmetical result. Downtime was 1 week with crusted lesions. Although slight hypopigmentation was common, only 1/30 (3%) patients had hypopigmentation that was more than expected. Recurrences (13/30; 43%) were frequent, so that yearly maintenance therapy was warranted. No major side effects were noticed. CONCLUSION: Continuous wave KTP laser therapy is safe and highly effective for XP, although regular follow-up treatments are often necessary to maintain the achieved cosmetic results.

NRAS-mutated melanocytic BAP1-associated intradermal tumor (MBAIT): a case report.

Melanocytic BAP1-associated intradermal tumors (MBAITs) are epithelioid spitzoid looking, mostly intradermally located melanocytic tumors that often have tumor-infiltrating lymphocytes and a common nevus component. They occur sporadically but also in the context of an underlying BAP1 germline mutation. Recognition of these lesions is important because they can be a marker for an underlying BAP1-associated cancer syndrome. Most cases reported in the literature thus far were found to have both a BRAF and BAP1 mutation. Here, we report an unusual case of an MBAIT lesion with a combined NRAS and BAP1 mutation. A BAP1 germline mutation was excluded. Our case is the second case reported until now with this combination of mutations in this subset of lesions. In the other reported NRAS-/BAP1-mutated MBAIT case, presence of a BAP1 germline mutation was not tested. Our case confirms that the mutational spectrum in MBAITs is broader than previously thought. Just as in the BRAF-mutated cases, it is likely that a subset might be associated with a BAP1 germline mutation. In case of suspicion of an MBAIT lesion based on histological examination, diagnostic work-up should include assessment of protein expression and/or mutation analysis of at least BRAF, NRAS, and BAP1. Work-up should not be limited to analyzing only BRAF protein expression or mutation, since NRAS-mutated MBAITs might be missed.

Graduated compression stockings for runners: friend, foe, or fake?

OBJECTIVE: To assess the effect of graduated compression stockings (GCS) on lower leg volume and leg complaints in runners during and after exercise. DESIGN: Cross-sectional study. SETTING: Radboud University Nijmegen Medical Centre and an outdoor running track in Nijmegen, The Netherlands. PATIENTS OR OTHER PARTICIPANTS: Thirteen Dutch trained recreational runners. INTERVENTION(S): Participants used a GCS on 1 leg during running. MAIN OUTCOME MEASURES: (1) Lower leg volume of both legs was measured at baseline, directly after running, and at 5 minutes and 30 minutes after running using a validated perometer. (2) Leg complaints were reported on questionnaires at set intervals. RESULTS: (1) In both experiments, the legs with GCS showed a reduction in mean (± SEM) leg volume directly after running, as compared with the leg without GCS: -14.1 ± 7.6 mL (P = .04) for the 10-km running track and -53.5 ± 17.8 mL (P = .03) for the maximum exercise test. This effect was not observed at 5 and 30 minutes after running. (2) No differences in leg complaints were reported in either experiment. CONCLUSIONS: The GCS prevented an increase in leg volume just after the running exercise. However, this result was not accompanied by a reduction in subjective questionnaire-reported leg complaints. The practical consequences of the present findings need further study.

Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin.

Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor γt (RORγt). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORγt levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORγt levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy.

Cutaneous complication after BCG vaccination: case report and review of the literature.

The bacille Calmette-Guérin (BCG) vaccination protects against tuberculosis (TB)-related meningitis and disseminated tuberculosis. While severe complications after BCG vaccination are relatively rare, different cutaneous reactions have been reported. We report a patient with a 7-mm erythematous nodule at a distance of 4 cm from the BCG injection site. Histopathologically, a necrotizing granulomatous reaction pattern was seen in the dermis. Although complementary stainings did not detect acid fast bacilli, we suspected the lesion was caused by the attenuated strains of Mycobacterium bovis from the vaccine. This specific complication is called BCG-itis in the literature. After the excisional biopsy, the lesion disappeared and further treatment was not necessary. In defining the best treatment for this boy, we discovered a lack of knowledge on BCG-related lesions and their subsequent treatment options in the literature. We will list existing literature on this topic and demonstrate that treatment of BCG-related complications is poorly defined.

Extensive segmental acanthosis nigricans form of epidermal nevus.

Eight cases of the acanthosis nigricans form of epidermal nevus have been described in literature. The present case is impressive and has an extensive segmental distribution. Although etiological factors, such as mutations in the FGFR3 gene, are becoming recognized, treatment options remain limited. We present a case of a 14-year-old male with multiple hyperpigmented, hyperkeratotic plaques on the upper body, axillae, and groin with a segmental distribution following Blaschko lines. Histopathological investigation showed aspects of both acanthosis nigricans and epidermal nevus. So far, screening has not revealed any internal abnormalities. As previous cases show a clear association with internal diseases, repetitive screening for internal diseases and syndromes is suggested in the case of the acanthosis nigricans form of epidermal nevus. Treatment of the condition remains a challenge.

Two adjacent nodules on the leg.

Poroma is a rare benign neoplasm (derived from the intraepidermal part of the eccrine or apocrine duct), which may clinically mimic malignant tumors such as (amelanotic) malignant melanoma and porocarcinoma. Histopathological examination is the key to the correct diagnosis, which is illustrated in the present case, in which a pigmented basal cell carcinoma and a poroma are in close proximity to each other. Despite a clinical differential diagnosis of melanoma, histopathology showed the typical characteristics of a poroma, a rare but much more favorable tumor. Histopathological features of poroma are discussed.

Dimethylfumarate for psoriasis: Pronounced effects on lesional T-cell subsets, epidermal proliferation and differentiation, but not on natural killer T cells in immunohistochemical study.

BACKGROUND: T-cell infiltration, epidermal hyperproliferation, and disturbed keratinization are pathologic hallmarks of plaque psoriasis. Oral fumaric acid esters are an effective therapy for psoriasis and are believed to exert their effects mainly through their anti-inflammatory properties. OBJECTIVE: To investigate the differential effects of dimethylfumarate (BG-12; FAG-201) for psoriasis on lesional T-cell subsets, natural killer (NK) T cells, and keratinocyte hyperproliferation and differentiation. STUDY DESIGN: A before-and-after clinical and immunohistochemical study as part of a larger clinical trial. SETTING: Single outpatient clinic. PATIENTS: Six patients with moderate-to-severe psoriasis. INTERVENTION: Dimethylfumarate 720 mg daily for 16 weeks. METHODS: Biopsies were taken from the lesional skin of six psoriatic patients, at baseline and after 16 weeks of treatment with dimethylfumarate. Clinical severity scores were obtained (Psoriasis Area Severity Index [PASI] and psoriasis severity SUM scores). T-cell subsets (CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+), cells expressing NK receptors (CD94, CD161), an epidermal proliferation marker (Ki67), and a keratinization marker (K10) were immunohistochemically stained and, together with 'epidermal thickness,' quantified using image analysis. RESULTS: At week 16, the mean PASI and SUM scores were reduced by 55% (p < 0.01) and 49% (p < 0.01), respectively. In line with these results, epidermal hyperproliferation, keratinocyte differentiation, and epidermal thickness significantly improved. In the dermis and the epidermis, the relevant T-cell subsets significantly declined. However, in both the lesional psoriatic dermis and epidermis, cells expressing NK receptors (CD94 and CD161) persisted after 16 weeks of treatment. CONCLUSIONS: Dimethylfumarate is an effective therapy for moderate-to-severe plaque psoriasis. The drug may act by reducing lesional T-cell subsets and normalizing epidermal hyperproliferation and keratinization, but does not reduce NKT cells.

A comparative study of pulsed 532-nm potassium titanyl phosphate laser and electrocoagulation in the treatment of spider nevi.

OBJECTIVE: To assess the clinical efficacy and safety of potassium titanyl phosphate (KTP) laser treatment and electrocoagulation (EC) for the treatment of spider nevi (SN). METHOD: A randomized single-blind intrapatient comparison study was performed. A blinded observer and patients reported the clinical treatment outcome and pain on a visual analogue scale (0-10). Side effects were noted if present. RESULTS: Mean physician-rated clinical efficacy scores+/-standard error of the mean were 7.7+/-0.7 for KTP laser and 6.2+/-0.9 for EC treatment (p=.05). Patient-rated mean clinical efficacy of KTP laser was 8.3+/-0.6 and of EC was 7.3+/-0.7 (p=.09). Stratification for potential confounding bias, such as location of SN, central bulging vein, and diameter (p=.25) of the treated SN did not reveal any statistically significant differences between the treatments. Treatment with KTP or EC did not result in scarring or pigmentary changes. Pain was reported for KTP treatment (3.1+/-0.4) and EC (6.4+/-0.7) (p<.05). CONCLUSION: Clinical efficacy of KTP laser and EC for SN is comparable, although there is a tendency toward an advantage in favor of the KTP laser. KTP laser treatment was less painful.

Primary hemochromatosis presented by porphyria cutanea tarda: a case report.

We present a 27-year-old female Caucasian patient, who initially presented with extensive fragility and blistering of mainly the dorsal side of both hands. Histology and urine porphyrin analysis confirmed the diagnosis of porphyria cutanea tarda. Internal screening for underlying disease revealed C282Y mutation-associated primary hemochromatosis, a hereditary iron-overload syndrome that may cause toxicity of a variety of organs. Hemochromatosis and porphyria cutanea tarda are pathogenetically linked as iron interferes with heme synthesis pathway. Patient was successfully treated with phlebotomy and low-dose hydroxychloroquine.

Efficacy and safety of pulsed dye laser treatment for cutaneous discoid lupus erythematosus.

BACKGROUND: Treatment of chronic discoid lupus erythematosus (CDLE) with a pulsed dye laser (PDL) has shown promising results, although outcomes in previous studies were not validated and laser parameters were inconsistent. OBJECTIVE: We conducted an open prospective study to assess the efficacy and safety of PDL for the treatment of recalcitrant CDLE, using a validated scoring method and a fixed treatment schedule. METHODS: Twelve patients with active CDLE lesions were treated with PDL (585 nm, fluence 5.5 J/cm(2), spot size 7 mm) 3 times with an interval of 6 weeks followed by a 6-week follow-up period. Treatment outcomes were evaluated by 3 observers using the validated Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Cosmetic results and adverse events were recorded. RESULTS: A significant decline in "active" CLASI was observed after 6 weeks, after 12 weeks, and at follow-up. Baseline active CLASI was 4.4 +/- 0.2 (mean +/- SEM), reaching 1.3 +/- 0.3 after follow-up (P < .0001). Individual scores for erythema and scaling/hypertrophy significantly declined 6 weeks after treatment. The "damage" CLASI (dyspigmentation, scarring, and atrophy) did not show any significant change during or after therapy. The observed clinical improvement was confirmed by two independent observers by clinical assessment of photographs (r = 0.87 and r = 0.89; both P < .05). The treatment was well tolerated, only minimal pain was reported, and the cosmetic result was fair. LIMITATIONS: Small sample size and short follow-up duration were limitations. CONCLUSION: PDL treatment is an effective and safe therapy for patients with refractory CDLE.