Cutaneous findings in patients with acromegaly and its relationship with concomitant endocrinopathies.

OBJECTIVES: Skin changes in acromegaly are often the first sign of the disease. The aim of this study was to describe the cutaneous findings in patients with acromegaly. In addition, a secondary aim was to investigate the possible association of these findings with remission status and concomitant endocrinopathies. DESIGN, PATIENTS, AND MEASUREMENTS: In this prospective multicenter study, 278 patients over the age of 18 years with acromegaly who were followed up in 14 different tertiary healthcare institutions were included. These patients, who were followed up by the Endocrinology Department, were then referred to a dermatologist for dermatological examination. The frequency of skin lesions was investigated by detailed dermatologic examination. Dermatological diagnosis is reached by clinical, dermatological and/or dermoscopic examination, and rarely skin punch biopsy examinations in suspicious cases. The possible association of the skin findings between remitted and nonremitted patients and with concomitant endocrinopathies were evaluated. RESULTS: The most common skin findings in patients with acromegaly in our study were skin tags (52.5%), cherry angiomas (47.4%), seborrhoea (37%), varicose veins (33%), acneiform lesions (28.8%), hyperhidrosis (26.9%) and hypertrichosis (18.3%). Hypertrichosis was significantly more prevalent in patients nonremitted (p: .001), while xerosis cutis was significantly more prevalent in patients remitted (p: .001). The frequency of diabetes mellitus and hypothyroidism was significantly higher in patients with varicose veins and seborrhoeic keratosis than those without. Additionally, the coexistence of hypothyroidism, hyperthyroidism and galactorrhea was significantly higher in patients with Cherry angioma than in those without Cherry angioma (p-values: .024, .034 and .027, respectively). The frequency of hypogonadism in those with xerosis cutis was significantly higher than in those without (p: .035). CONCLUSIONS: Cutaneous androgenization findings such as skin tag, seborrhoea, acne and acanthosis nigricans are common in patients with acromegaly. Clinicians should be aware that skin findings associated with insulin resistance may develop in these patients. It can be said that the remission state in acromegaly has no curative effect on cutaneous findings. Only patients in remission were less likely to have hypertrichosis. This may allow earlier review of the follow-up and treatment of acromegaly patients presenting with complaints of hypertrichosis. Additionally, it can be said that patients with skin findings such as cherry angioma may be predisposed to a second endocrinopathy, especially hypothyroidism. Including dermatology in a multidisciplinary perspective in acromegaly patient management would be beneficial to detect cutaneous findings earlier.

Risk of skin cancers in mycosis fungoides patients receiving PUVA therapy: A real-life experience from a single tertiary center.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Skin-directed therapies, including phototherapy, are the first-line treatment modalities. Psoralen plus ultraviolet A light photochemotherapy (PUVA) is quite effective in controlling the disease; however, long-term adverse effects, particularly carcinogenesis, are the cons of this treatment. OBJECTIVE: There are various studies on the negative impact of PUVA on skin cancer in patients with autoimmune skin diseases. The data on the long-term effects of phototherapy on MF patients are scarce. METHODS: All MF cases that received PUVA alone or combined with other treatments at a single tertiary center were analyzed. This study compared the development of non-melanoma skin cancers, melanoma, and solid organ tumors in MF patients with at least 5-year follow-up data with age- and sex-matched controls. RESULTS: A total of 104 patients were included in the study. Ninety-two malignancies were detected in 16 (15.4%) patients, and six developed multiple malignancies. Skin cancers consisted of 56 basal cell carcinomas, 16 Bowen's disease, four squamous cell carcinomas, three melanomas, two basosquamous cell carcinomas, one Kaposi sarcoma, and one keratoacanthoma were found in nine (8.7%) patients. Eight patients developed three solid cancers and six lymphomas. The risk of developing skin cancer was associated with the total number of PUVA sessions (<250 vs ≥250 sessions; hazard ratio (HR) 4.44, 95% confidence interval (CI) 1.033-19.068; p = .045). 9 (13.2%) of 68 patients who had follow-ups for at least 5 years developed skin cancer. Compared to an age- and sex-matched cohort, the prevalence of new skin cancer was considerably greater (p = .009). CONCLUSIONS: Patients with MF are predisposed to develop secondary malignancies, and continual exposure to PUVA may potentiate this risk. Annual digital dermoscopic follow-up in MF patients treated with UVA is advised for early diagnosis and treatment of secondary cutaneous malignancies.

Allogeneic hematopoietic stem cell transplantation for heavily pretreated patients with mycosis fungoides and Sezary syndrome.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of heavily pretreated mycosis fungoides/Sezary syndrome (MF/SS). Herein, we aimed to evaluate the outcomes of AHSCT for heavily pretreated patients with MF/SS retrospectively. This analysis included consecutive 19 patients with MF/SS who received 20 AHSCT between 2012-2021 in our transplant center. Eight patients have been previously reported. Fifteen patients had diagnosis of MF and referred to SS in five patients. In our cohort, all cases had advanced disease (stages IIB: n = 1, IIIA: n = 7; IIIB: n = 4, IVA: n = 4, and IVB: n = 3). Nine patients (47.4%) had developed large cell transformation. Only two patients received AHSCT in complete response, one very good partial response and two partial response while the others had progressive disease (n = 15) before transplant. Seven (35%) patients were alive at the time of analysis, with a median follow up of 10.5 months (range, 0.3-113 months) after AHSCT. Nine patients (47.4%) died without disease relapse or progression. Non-relapse mortality was 35.9% at 1 year and 26.9% at 3 years and thereafter. For all patients the probability of overall survival was 48.5% and 32.3% at 1- and 5-year post-transplant, respectively. AHSCT for MF/SS resulted in an estimated progression free survival of 45.4% at 1 year. Given the poor prognosis of patients not receiving transplants and in the absence of curative non-transplantation therapies, our results support that AHSCT is able to effectively rescue 32.3% of the population of transplant eligible, heavily pretreated patients in 5 years.

Isotretinoin Treatment Practices and Outcomes in Acne Patients During the COVID-19 Pandemic: A Single Center, Retrospective, Comparative Study.

INTRODUCTION: The COVID-19 pandemic drastically changed the priorities in healthcare services; outpatient management of acne has changed during this period. OBJECTIVES: We aimed to investigate treatment practices, outcomes and identify modified follow-up schedules applied during the pandemic. METHODS: The patients who were admitted to dermatology outpatient clinic between March 13 and July 13, 2020, were included. Patients who were admitted between March 13 and July 13, 2019, were served as controls for the study. For each patient, age, gender, treatment protocols, treatment intervals, compliance with the treatment, treatment modifications, and adverse events were recorded. RESULTS: The total number of acne patients admitted to dermatology outpatient clinics during the pandemic period was 278 and consisted of 12.3% (278) of all admissions. Isotretinoin treatment was started in only 16 (5.8%) of the patients. The proportion of patients who were under follow-up was significantly higher during the pandemic period (P < 0.005). There was no difference between the pandemic period and the non-pandemic period in terms of starting isotretinoin treatment (P > 0.05). During pandemic period, 79% of the patients who used isotretinoin were followed-up every two or more months. Extended follow-up intervals showed no difference for detecting side effects (P > 0.05). CONCLUSIONS: Acne patients constitute an important part of dermatology outpatient clinics. During the pandemic period, majority of acne patients came for follow-up. Extended follow-up periods were adopted by physicians and were found safe and effective in the current study. Thus, isotretinoin treatment seems efficacious and safe during pandemic period.

Development and preclinical evaluation of virus-like particle vaccine against COVID-19 infection.

BACKGROUND: Vaccines that incorporate multiple SARS-CoV-2 antigens can further broaden the breadth of virus-specific cellular and humoral immunity. This study describes the development and immunogenicity of SARS-CoV-2 VLP vaccine that incorporates the four structural proteins of SARS-CoV-2. METHODS: VLPs were generated in transiently transfected HEK293 cells, purified by multimodal chromatography, and characterized by tunable-resistive pulse sensing, AFM, SEM, and TEM. Immunoblotting studies verified the protein identities of VLPs. Cellular and humoral immune responses of immunized animals demonstrated the immune potency of the formulated VLP vaccine. RESULTS: Transiently transfected HEK293 cells reproducibly generated vesicular VLPs that were similar in size to and expressing all four structural proteins of SARS-CoV-2. Alum adsorbed, K3-CpG ODN-adjuvanted VLPs elicited high titer anti-S, anti-RBD, anti-N IgG, triggered multifunctional Th1-biased T-cell responses, reduced virus load, and prevented lung pathology upon live virus challenge in vaccinated animals. CONCLUSION: These data suggest that VLPs expressing all four structural protein antigens of SARS-CoV-2 are immunogenic and can protect animals from developing COVID-19 infection following vaccination.

A multicentre prospective analysis of the incidence of pemphigoid diseases in Turkey.

BACKGROUND: The differentiation between the pemphigoid diseases is essential for treatment and prognosis. In Turkey, data on the incidence of these diseases are insufficient. Our aim in this study is to determine the incidence, demographics and clinical characteristics associated with diseases of the pemphigoid group. METHODS: We prospectively analysed 295 patients with pemphigoid who visited dermatology clinics of tertiary referral hospitals in 12 different regions of Turkey within a year. The diagnosis was based on clinical, histopathological, direct immunofluorescence (DIF) and serological (multivariant enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence and mosaic-based BIOCHIP) examinations. Clinical and demographic findings, aetiological factors and concomitant diseases observed in the patients were recorded. RESULTS: A total of 295 (female/male ratio: 1.7/1) patients with pemphigoid were diagnosed in 1-year period. The overall incidence rate of pemphigoid diseases was found to be 3.55 cases per million-years. The ratio of pemphigoid group diseases to pemphigus group diseases was 1.6. The most common pemphigoid type was bullous pemphigoid (BP, 93.2%). The others were epidermolysis bullosa acquisita (3.1%), pemphigoid gestationis (2.4%), linear IgA disease (1%) and mucous membrane pemphigoid (0.3%). The most common (26.8%) possible trigger of the bullous pemphigoid was gliptin derivative drugs. The most common concomitant diseases with pemphigoid were cardiovascular (27.8%) and neurological diseases (23.7%). CONCLUSIONS: This study showed that the increased frequency of bullous pemphigoid reversed the pemphigoid/pemphigus ratio in Turkey. Further studies are warranted regarding the reasons for this increase.

Folliculotropic mycosis fungoides: Clinical characteristics, treatments, and long-term outcomes of 53 patients in a tertiary hospital.

Folliculotropic mycosis fungoides (FMF) is characterized by a broad clinical spectrum and worse prognosis compared to classical MF. This study aimed to evaluate the clinical characteristics, treatment modalities and long-term outcome and risk factors for progression and survival of FMF patients. We conducted a single-center retrospective study and reviewed 53 patients diagnosed with FMF between 1990 to 2019 in a referral center at Ankara University, Turkey. Regarding to stage at diagnosis, 24 patients (45.3%) had advanced-stage disease (≥IIB). Follicular papules was observed in 66% and alopecia in 49.1% of the cases. Forty-three patients (81.1%) suffered from pruritus. The majority of the patients (92.4%) had at least one systemic therapy. Complete remission was achieved in 24.5% of the patients. The median time of overall survival (OS) was 50 months (range 9-324 months) and 5-year and 10-year OS was 83% and 69%, respectively. Twenty-eight (52.3%) patients progressed to more advanced stages and seven (13.2%) patients died due to MF during the follow-up period. FMF is associated with a progressive course and in most patients, skin-directed therapies were found to be inefficient to control the disease and multiple systemic therapeutic agents were required to control the disease.

CD8+ cytotoxic mycosis fungoides: a retrospective analysis of clinical features and follow-up results of 29 patients.

BACKGROUND AND OBJECTIVE: Less than 5% of cases of mycosis fungoides (MF) present with a cytotoxic/suppressor CD8+ phenotype. This study aimed to evaluate the clinical characteristics, treatment modalities, and clinical course in CD8+ MF patients. METHODS: In a retrospective analysis of 353 MF patients in a referral center at Ankara University, Turkey, 29 patients that were diagnosed with CD8+ MF were included in the study. RESULTS: CD8+ MF cases constituted 8.2% of all MF patients. The age at the time of diagnosis ranged between 6 and 81 years with a median value of 46 years. The female-to-male ratio was 1.41. Patients presented with erythematous scaly (69%), hyperpigmented (58.6%), poikilodermic (17.2%), and hypopigmented (17.2 %) patches/plaques. The most common sites of involvement were the trunk and lower extremities. The most common comorbidity was hypertension (24.1%, n: 7) with 13 patients (44.8%) having a history of at least one autoimmune disease. At the time of diagnosis, 93.2% of the patients had early-stage disease, and 6.8% of the patients had advanced stage. The mean follow-up period was 6.68 ± 6.04 years (range 1-28 years). Most of the patients were treated with skin-directed therapies. Complete remission was achieved in 17 (58.6%) patients, eight (27.6%) patients had partial remission, and four (13.8%) patients had stable disease. CONCLUSIONS: We concluded that CD8+ MF is associated with an indolent course and in most patients, skin-directed therapies were found to be efficient to control the disease.

A rare case of malignant syphilis after adalimumab therapy due to Crohn's disease associated with bariatric surgery.

Malignant syphilis (also known lues maligna) is a rare and severe variant of secondary syphilis. It is most commonly seen in patients who are infected with human immunodeficiency virus (HIV), and rarely, it can occur in immunocompetent individuals. The exact mechanism of the development of malignant syphilis is not clear. It could probably be associated with immunosuppression, inappropriate immune response of the host, or virulent strain of Treponema pallidum. Coexistence of immunosuppression and inappropriate immune response may predispose to develop malignant syphilis in HIV-infected patients with immune reconstitution inflammatory syndrome. Herein, we report the first case of malignant syphilis after adalimumab therapy for Crohn's disease due to bariatric surgery and discuss the underlying possible pathogenic mechanisms.

Hidradenitis suppurativa: Clinical characteristics and determinants of treatment efficacy.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder that causes a significant decline in quality of life. There are numerous treatment options; however, real-life data on the efficacy of these treatments is limited. This study was performed in two centers to describe clinical characteristics and assess treatment outcome in a cohort of 139 patients with HS. Data on demographic and clinical characteristics, Hurley stage and comorbidities were collected from patient charts and evaluated retrospectively. Treatment response was measured with HS clinical response index (HISCR). Mean body mass index was 27.8±4.88. Inflammatory comorbidities were present in 23%. Among first-line drugs systemic doxycycline resulted in 60% HISCR followed by rifampicin-clindamycin combination (46.4%). Isotretinoin had the lowest HISCR (30.7%) in this group. For second-line therapies, all acitretin treated patients achieved response and patients treated with tumor necrosis factor alpha (TNF-α) inhibitors had the highest HISCR. Currently recommended first-line therapies have moderate efficacy in HS. Acitretin appears to be a reasonable alternative for the highly effective TNF-α inhibitors in patients with severe and resistant HS. Overall, these results support that excessive inflammatory response play an important role in pathogenesis of HS.

The effect of personal, familial, and environmental characteristics on acne vulgaris: a prospective, multicenter, case controlled study.

BACKGROUND: There are only a few studies about epidemiological features of acne vulgaris in the literature. The aim of this study was to analyze demographic, clinical, familial and environmental characteristics of acne, the role of diet and aggravating factors and association of these factors with acne severity. METHODS: Patients with a diagnosis of mild-moderate to severe acne were consecutively interviewed at the participating centers during the study period. RESULTS: A total of 3826 patients and 759 control patients were involved in this study. Mild acne was the most common type of acne, and most of the lesions were localized on face followed by the trunk. The severity of acne was worse in patients who had a positive family history of acne. The most common triggering factor was psychological stress. We found a positive correlation with chocolate, bread, green tea, milk, white sugar, ripe banana, ice cream, apple, orange, and red meat consumption. As we compare the acne severity according to geographical features we detected mild- moderate acne was more common in Mediterranean region and severe acne was more common in East Anatolian region. Family history positivity was more common in Aegean region and least common in Central Anatolian region. There was statistically significant relationship as we compare acne severity and dietary factors such as chocolate, dairy products such as milk, sunflower seed consumption within the geographical regions. CONCLUSIONS: This study presents the demographic and clinical characteristics of acne patients in Asian and the European parts of Turkey. We believe that this study will provide a useful overview of acne in Turkey.

Complete Decongestive Therapy Is an Option for the Treatment of Rosacea Lymphedema (Morbihan Disease): Two Cases.

BACKGROUND AND PURPOSE: Morbihan disease, also known as rosacea lymphedema, is a rare persistent form of lymphedema that is associated with the disease rosacea. Even though acne rosacea responds well to standard medical treatment, the lymphedema component of the disease is resistant to both medical and surgical therapy. Complete decongestive therapy (CDT) can be considered as a conservative alternative option for treatment of rosacea lymphedema. To date, there is no report on the use of CDT in treating facial lymphedema secondary to acne rosacea. CASE DESCRIPTION: We present 2 cases of women with a diagnosis of Morbihan disease and chronic facial lymphedema that remained resistant to drug treatment for many years before CDT was offered. The treatment program included 4 components: manual lymphatic drainage, compression bandaging, exercises to enhance lymphatic drainage, and patient education. OUTCOMES: Following 10 to 15 sessions of CDT, the first patient's facial edema had almost completely resolved. The second patient's response to treatment was assessed as moderate. DISCUSSION: To the best of our knowledge, these 2 cases of Morbihan disease treated with CDT are the first of their kind to be presented in the literature. As the treatment options for Morbihan disease remain inadequate, we believe that CDT should be considered as a treatment option in those patients who do not benefit from or refuse drug treatment, before moving on to more invasive procedures. Prospective studies should be designed to demonstrate the efficacy of CDT and provide management details.

Transformation of Mycosis Fungoides/Sezary Syndrome: Clinical Characteristics and Prognosis.

OBJECTIVE: Transformed mycosis fungoides (T-MF) is a rare variant of MF with an aggressive course. In this study, we aimed to describe characteristics of MF/Sezary syndrome (SS) patients with transformation. MATERIALS AND METHODS: Patients diagnosed with T-MF among MF/SS patients between 2000 and 2014 in a tertiary single center were evaluated retrospectively. Demographic data, clinical data, laboratory data, immunophenotype features, response to treatment, survival, and histopathologic features were analyzed. RESULTS: Among 254 MF patients, 25 patients with T-MF were identified (10.2%) and included in the study. The male-to-female ratio was 2.6/1. The median time between MF diagnosis and transformation was 32 months (range: 0-192). Nine (36%) patients were diagnosed initially with T-MF. Advanced disease stage and high serum lactate dehydrogenase (LDH) levels were indicators of poor prognosis and treatment response. Five of the 18 patients with progressive disease had undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT resulted in complete remission in three (60%) patients. Ten (40%) patients died as a result of disease progression. Mean survival time was 25.2±14.9 (2-56) months after transformation. CONCLUSION: Advanced stage, high serum LDH levels, and loss of CD26 and CD7 expression in the peripheral blood are poor rognostic factors in T-MF. Treatment-resistant tumors and nodules should be cautionary for T-MF. Patients with T-MF have a shortened survival. Some patients may respond to first-line treatments. However, the majority of patients who do not respond to first-line therapies also are unresponsive to second or third-line therapies. Allo-HSCT may be an alternative option in patients with T-MF.

Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency.

BACKGROUND: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). OBJECTIVE: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. METHODS: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. RESULTS: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. CONCLUSIONS: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.

Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene.

H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome.

A Severe Case of Lymphomatoid Papulosis Type E Successfully Treated with Interferon-Alfa 2a.

Lymphomatoid papulosis (LyP) is a benign papulonodular skin eruption with histologic features of malignant lymphoma. A new variant of LyP which was termed "type E" was recently described with similar clinical and histological features to angiocentric and angiodestructive T-cell lymphoma. LyP type E is characterized with recurrent papulonodular lesions which rapidly turn into hemorrhagic necrotic ulcers and spontaneous regression by leaving a scar. None of the available treatment modalities affects the natural course of LyP. For therapy various modalities have been used such as topical and systemic steroids, PUVA, methotrexate, bexarotene, and IFN alfa-2b. Here we present a severe and devastating case with a very rare variant of LyP type E, which is, to our knowledge, the first case successfully treated with IFN alfa-2a. Now disease has been maintaining its remission status for six months.