Factors associated with increased suicidality risk following referral for isotretinoin commencement.

OBJECTIVE: To establish whether there is a significant change in suicidality risk following psychiatric assessment for commencement of isotretinoin and identify factors that underpin any potential risk change. METHOD: Retrospective cohort study. Suicidality risk was defined as a combination of the following: (i) actual/intended self-harm and/or attempted/completed suicide, and (ii) increased service utilisation associated with suicidal ideation/behaviour. All patients referred to Psychiatry for assessment prior to commencement of isotretinoin between 2014 and 2019 were examined. Inclusion criteria: >16 years of age, assessed for commencement of isotretinoin, complete clinical records. Data were collected by reviewing the Electronic Patient Records. Fifty-seven patients were eligible. We employed descriptive statistics, parametric/non-parametric/normality tests and logistic regression analysis, using socio-demographic and clinical characteristics as independent parameters, and suicidality risk as the dependent parameter. RESULTS: Actual/intended self-harm/attempted suicide decreased significantly following assessment without significant change in service utilisation. Female gender, absence of protective factors and assessment by Consultation-Liaison Psychiatry were linked to increased suicidality risk, after controlling for age, ethnicity, recommendation for isotretinoin, and substance misuse. CONCLUSIONS: Psychiatric assessment is helpful before commencing isotretinoin. Female gender, and absence of ongoing psychopharmacological and/or psychological intervention and/or regular psychiatric follow-up predict increased suicidality risk among patients assessed for prescription of isotretinoin.

Staphylococcus aureus Carriage in Hidradenitis Suppurativa: Impact on Response to Adalimumab.

BACKGROUND: Several patients with hidradenitis suppurativa (HS) present flare-ups during treatment with adalimumab (ADA), the cause of which is not clear. ADA is the only FDA-approved biologic for the therapy of moderate-to-severe HS. A previous study of our group has shown that Staphylococcus aureus stimulation of whole blood affects the production of human ß-defensin 2 and modulates HS severity. It is, therefore, hypothesized, that carriage of S. aureus may drive HS flare-ups. OBJECTIVE: To explore the association between carriage of S. aureus and loss of response to ADA. PATIENTS AND METHODS: Among patients with moderate-to-severe HS without carriage of S. aureus at start of treatment with ADA, we investigated for carriage of S. aureus from the nares when flare-ups occurred. Flare-ups were pre-defined as at least 25% increase of inflammatory lesions (sum of inflammatory nodules and abscesses) from baseline. Samplings were also done after completion of 12 weeks of ADA treatment from all patients who did not present flare-ups. Clinical response to ADA was assessed by the HS Clinical Response score (HiSCR). RESULTS: Thirty-nine patients were studied; 24 with Hurley II stage HS and 15 with Hurley III stage HS. Twenty-nine patients achieved HiSCR after 12 weeks of treatment without any flare-ups; 10 patients had flare-ups and failed HiSCR. Three (10.3%) and 5 (50%) patients, respectively, had nasal carriage of S. aureus (odds ratio 8.67; 95% CI 1.54-48.49; p = 0.014). Among 32 patients reaching follow-up week 48, 20 patients achieved HiSCR and 12 had flare-ups leading to ADA failure; 2 (10%) and 5 (41.7%) patients, respectively, had positive culture for S. aureus (odds ratio 6.42; 95% CI 1.00-41.20; p = 0.05). CONCLUSION: Nasal carriage of S. aureus may be associated with loss of response to ADA. Findings need confirmation in larger series of patients.

Long-term safety of adalimumab for patients with moderate-to-severe hidradenitis suppurativa.

Introduction: Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disorder that affects regions rich in apocrine glands. Although the etiology of HS is not clear, inflammatory cytokines, like tumor necrosis factor (TNF)-α, participate in pathogenesis. Adalimumab (ADA), a human IgG1 monoclonal antibody that selectively targets TNFα, is the only EMA/FDA-approved biologic agent available for the therapy of moderate-to-severe HS.Areas covered: A comprehensive literature search was conducted to present existing studies with an emphasis on the safety profile of ADA for the treatment of moderate-to-severe HS. ADA is prescribed for more than 15 years for varied indications and has improved the therapeutic outcomes of many diseases. Clinical trials and real-life safety data from ADA administration in HS were presented, with particular attention to special populations, such as children, elderly, and pregnant women.Expert opinion: Existing data advise for limited safety concerns with long-term ADA treatment provided that patients are thoroughly screened for infections, latent tuberculosis, and history of malignancy before the start of treatment.

Childhood Vitiligo.

Vitiligo is a common acquired depigmenting skin disease characterized by a progressive loss of functional melanocytes. It may appear from the first years of life to late adulthood. Childhood vitiligo (CV), defined as vitiligo that begins before the age of 12 years, is common and may differ from post-CV in terms of epidemiology, clinical presentation, comorbidities, and treatment options. Taking into consideration the potential significant psychosocial impact of the disease on both children and their parents, all available therapeutic options must be offered to patients who desire treatment. According to the most recent guidelines, topical corticosteroids, topical calcineurin inhibitors, and narrowband ultraviolet B phototherapy are the most commonly used treatment modalities for vitiligo in children. This review presents recent data regarding the whole spectrum of CV. Differences between CV and post-CV are also discussed.

Imiquimod 3.75% for field-directed therapy of actinic keratosis: results of a prospective case-series study in Greece.

BACKGROUND: Imiquimod 3.75% is a field-directed treatment for actinic keratosis that can detect and treat clinical and subclinical lesions across an entire sun-exposed field. The detection of subclinical lesions is evidenced by an increase in lesions to the maximum lesion count during treatment (Lmax ). We report clinical outcomes for the first 15 patients treated with imiquimod 3.75% in daily clinical practice in Greece. METHODS: Fifteen patients with actinic keratosis lesions were treated with imiquimod 3.75% in an outpatient setting in two 2-week treatment cycles separated by a 2-week treatment-free interval. Actinic keratosis lesions were counted before treatment, at the end of the first treatment cycle (Week 2; Lmax ), and 2 weeks after the second treatment cycle (Week 8). Local skin reactions (LSR) were also evaluated at Weeks 2 and 8. RESULTS: The median baseline actinic keratosis lesion count was 25, which increased to a median Lmax of 29 at Week 2 and decreased to a median of 5 at Week 8. The median percentage and absolute reduction in actinic keratosis lesions from Lmax to Week 8 were 87% and 23%, respectively. Most of the LSR were mild-to-moderate in intensity at Week 2 and had resolved by Week 8. CONCLUSION: Imiquimod 3.75% effectively detected and cleared both the clinical and subclinical actinic keratosis lesions across the entire sun-exposed field in this cohort of Greek patients. Treatment was well tolerated.

A retrospective study of the characteristics of patients with early-onset compared to adult-onset hidradenitis suppurativa.

BACKGROUND: The mean age of onset of hidradenitis suppurativa (HS) is between 20 and 24 years. Very few data about patients with early-onset HS exist. OBJECTIVE: To investigate the association of early-onset HS with the clinical characteristics: age, gender, body mass index (BMI), smoking, family history of HS, Hurley stage, and number of areas affected. METHODS: This was a retrospective study of the reported early age at HS onset (≤17 years old) with clinical characteristics and with the severity of HS at first consultation visit. RESULTS: In 166 patients, 42 patients (25.3%) reported early-onset HS. Compared to adult-onset HS, patients with early-onset HS were younger (mean age: 37 years vs. 27 years, P < 0.0001), had a significantly younger mean age of onset (28.2 years old vs. 14.5 years old, respectively, P < 0.0001), longer mean disease duration (8.8 years vs. 12.6 years, respectively, P = 0.011) and were less frequently smokers (P < 0.001), whereas there was no association with gender (P = 0.177) or BMI (0.086). Patients with a family history had increased risk for early-onset HS (OR: 2.45, 95% CI: 1.08-5.56). Early-onset HS was not associated with Hurley stage (OR: 1.12, 95% CI: 0.33-3.74) or with the number of body areas affected (OR: 1.54, 95% CI: 0.49-4.83). CONCLUSION: Early-onset HS was frequent and associated with a family history of HS. There was no difference in the severity of HS in adult life for patients with an onset of HS at ≤17 years, compared to patients with adult-onset, which may be reassuring information for these younger patients.

Methotrexate: an effective monotherapy for refractory generalized morphea.

INTRODUCTION: Morphea is an inflammatory skin disorder characterized by excessive collagen deposition. Although treatment algorithms for morphea subtypes have been suggested, no consistent recommendations are available. This study attempts to evaluate the clinical efficacy of methotrexate (MTX) as monotherapy in refractory generalized morphea. METHODS: It is a retrospective study, including 20 patients who had already been treated with various topical and systemic therapies with minimal clinical improvement. Patients received orally MTX at a of dosage 15 mg once weekly. Duration of the use, dosage of MTX, and adverse events were recorded. Clinical assessment of skin lesions was performed and documented. RESULTS: The mean disease duration was 27 months before the initiation of MTX treatment. After 12 months of therapy, very good response was achieved in 6 patients (30%), good response in 10 patients (50%), and fair response in 2 patients (10%), while 2 patients (10%) had failed treatment. Patients were followed up for a mean time interval of 21 months. No serious adverse event was recorded. CONCLUSION: MTX has been already proved to be an effective and well-tolerated treatment in pediatric patients with morphea. The majority of the group of adult patients showed very good and good improvement when treated with MTX. Although this is an uncontrolled study, MTX monotherapy was considered a safe and effective treatment for the management of this specific clinical subset of morphea in adults.

Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial.

IMPORTANCE: Hidradenitis suppurativa (HS) is a common skin disorder in which excessive inflammation is believed to have an important role. There is no specific therapy for HS. OBJECTIVE: To investigate the safety and efficacy of the anti-inflammatory biological therapy anakinra in HS. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled clinical trial with a 12-week treatment phase and a 12-week follow-up phase. The setting was Attikon University General Hospital, a tertiary care institution in Athens, Greece. Participants were 20 patients with Hurley stage II or III HS. The study and the analysis were conducted between March 1, 2012, and February 28, 2014. INTERVENTIONS: Patients were randomized to receive injections from identical syringes containing placebo or anakinra subcutaneously once daily for 12 weeks. Peripheral blood mononuclear cells were isolated and stimulated for cytokine production before the beginning of treatment and at week 12 (the end of treatment) and week 24. MAIN OUTCOMES AND MEASURES: The primary end point was the effect of anakinra on HS disease severity. Secondary end points were the time to a new exacerbation and the production of cytokines. RESULTS: Among the 20 trial participants, 10 each were randomized to the group to receive anakinra or the placebo group. The mean (SD) ages were 42.8 (13.8) and 36 (11.3) years in the anakinra and placebo groups, respectively. The disease activity score was decreased at the end of treatment in 20% (2 of 10) of the placebo arm compared with 67% (6 of 9) of the anakinra arm (P = .04). Hidradenitis suppurativa clinical response at 12 weeks was achieved in 30% (3 of 10) of the placebo arm and in 78% (7 of 9) of the anakinra arm (P = .04). The production of interferon-γ by peripheral blood mononuclear cells in the anakinra arm was decreased, and the production of interleukin 22 was increased. The time to a new HS exacerbation was prolonged in the anakinra arm by log-rank test (log rank, 6.137; P = .01). No serious adverse events were reported. CONCLUSIONS AND RELEVANCE: Anakinra has the potential to be an effective and well-tolerated treatment for HS. Inhibition of interleukin 1 is a promising treatment strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01558375.

Compartmentalized Cytokine Responses in Hidradenitis Suppurativa.

BACKGROUND: Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). METHODS: Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. RESULTS: CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1ß and IL-17 by PBMCs at week 8. CONCLUSIONS: Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF.

Serum soluble urokinase plasminogen activator receptor as a screening test for the early diagnosis of hepatocellular carcinoma.

BACKGROUND & AIMS: Early detection of hepatocellular carcinoma (HCC) before imaging signs appear remains an unmet medical need. Former publications suggest that soluble urokinase plasminogen activator receptor (suPAR) is a non-specific cancer marker. suPAR was validated for the detection of patients at risk for HCC. METHODS: After an initial training set in 23 patients with extreme disease phenotypes, a prospective test set was conducted in which 267 patients without any imaging signs of HCC were followed up for 7 years. Patients were divided into low risk and high risk for the development of HCC by the EASL criteria. suPAR was measured at the beginning of follow-up. All patients underwent liver biopsy to define staging of fibrosis. The primary study endpoint was to define a cut-off among high-risk patients by the EASL criteria that can early discriminate those at real risk for HCC. RESULTS: The training set showed that suPAR was significantly greater in patients with HCC even in the absence of underlying cirrhosis compared with patients with minimal liver inflammation because of fatty deposition. The test set showed that among the high-risk EASL subgroup, suPAR more than 9.56 ng/ml had sensitivity 76.0%, specificity 90.4%, positive predictive value 54.3% and negative predictive value 96.2% for the development of HCC (odds ratio: 29.88, P < 0.0001). In survival analysis, patients with suPAR above 9.56 ng/ml at baseline progressed earlier to HCC. CONCLUSIONS: The specificity and negative predictive value make serum suPAR a potential screening tool for the early detection of HCC in patients with chronic liver disorders.

The level of endotoxemia in sepsis varies in relation to the underlying infection: Impact on final outcome.

Former studies of our group have shown that the innate and adaptive immune status may differ in relation with the causative infection. To this same end, it was investigated if kinetics of circulating lipopolysaccharide (LPS) leading to inflammatory response may differ. Blood was sampled from 189 patients with sepsis and 206 with severe sepsis/shock starting 24h from advent of sepsis and repeating on day 3. Serum LPS was measured by Limulus Amebocyte Lysate (LAL) assay. From 59 patients, circulating monocytes were isolated and incubated in the absence/presence of LPS. Concentrations of tumor necrosis factor-alpha (TNFα) were measured in supernatants by an enzyme immunoassay. In either category of severity, circulating LPS was greater among sufferers from primary Gram-negative bacteremia (BSI) and from community-acquired pneumonia (CAP) than sufferers from other underlying infections. LPS were greater among patients with BSI compared to patients with secondary Gram-negative bacteremia and patients without bacteremia. Greater decrease of circulating LPS over 48h was recorded for survivors compared to non-survivors only within sufferers from BSI and CAP. Significant endotoxemia was considered for patients with serum LPS within the upper quartile of distribution; their monocytes were less potent for release of TNFα. It is concluded that endotoxemia in sepsis varies greatly with the underlying infection; this is related with immunoparalysis of monocytes with implications on final outcome.

Haplotypes of IL-12Rß1 impact on the clinical phenotype of hidradenitis suppurativa.

Antigen presentation in chronic skin disorders is mediated through the interleukin (IL)-12/IL-23 pathway and, hence, through the IL-12 receptor. Recent evidence suggesting dysregulated antigen presentation in skin lesions of hidradenitis suppurativa (HS) led to investigate the role of single nucleotide polymorphisms (SNPs) of the gene IL-12RB1 coding for the IL12-Rß1 receptor subunit. Genomic DNA was isolated from 139 patients and 113 healthy controls; nine SNPs in the transcribed region of IL12RB1 were genotyped. No significant differences of genotype and allele frequencies were found between the two groups. Two common haplotypes were recognized, namely h1 and h2. Carriage of h2 related with minor frequency alleles was associated with a greater risk for the acquisition of Hurley III disease stage and with the involvement of a greater number of skin areas. Patients with the h1 haplotype presented disease at an older age. This is the genetic study enrolling the largest number of patients with HS to date. Although SNPs of IL12RB1 do not seem to convey genetic predisposition, they are associated directly with the phenotype of the disease.

An algorithm for the management of Staphylococcus aureus carriage within patients with recurrent staphylococcal skin infections.

Recurrent skin infections of staphylococcal origin raise the question of probable skin colonization by Staphylococcus aureus and the need for eradication. Available evidence does not exist for such settings. A management algorithm was developed by a group of experts that was implemented prospectively in 125 patients admitted for recurrent staphylococcal skin infections. Patients were tested for skin carriage of S. aureus in seven body surfaces. In the event of carriage, therapy was administered consisting of hair and body washing with antiseptics for 60 days and parallel oral treatment according to the antibiogram for 30 days. Patients were followed up for 3 years. Seventy-nine patients were colonized by S. aureus, 49 by methicillin-susceptible (MSSA) and 30 by methicillin-resistant (MRSA) isolates. The eradication rate following the algorithm was 83.7% for patients colonized by MSSA and 90.0% for patients colonized by MRSA. The greater eradication rates were achieved after treatment with one antistaphylococcal penicillin or clindamycin in the case of MSSA carriage and with clindamycin or a fluoroquinolone in the case of MRSA carriage. Of the 79 treated cases, 18 relapsed. Time to relapse did not differ between MSSA carriers and MRSA carriers. It is concluded that the suggested algorithm may be clinically efficacious and achieve high decolonization and low relapse within patients with recurrent staphylococcal skin infections colonized by either MSSA or MRSA.

Polymicrobial bloodstream infections: Epidemiology and impact on mortality.

The aim of this study was to investigate the impact of polymicrobial bloodstream infections (pBSIs) on the outcome of sepsis in an area where antimicrobial resistance is of concern. This was a retrospective analysis of data collected prospectively from patients developing BSI outside of an intensive care unit (non-ICU patients) or after ICU admission. Demographics and clinical characteristics were compared for patients with pBSI versus monomicrobial BSI (mBSI) and following stratification by ICU or non-ICU and severity of sepsis status. Possible risk factors for adverse outcome were explored by multivariate analysis, and outcomes were measured by Cox regression analysis. Among 412 patients with BSI, 47 patients (11.4%) with pBSI were recorded; compared with patients with mBSI, they had significantly higher APACHE II scores and presented more frequently with severe sepsis/septic shock. The all-cause 28-day mortality was significantly higher for pBSI versus mBSI (38.3% vs. 24.7%; P=0.033), whereas appropriateness of treatment was comparable (78.7% vs. 86.6%). Primary bacteraemia by combinations of Enterococcus faecalis, Klebsiella pneumoniae and Acinetobacter baumannii was predominant among pBSIs; in mBSIs, urinary tract infections by Escherichia coli, K. pneumoniae or Pseudomonas aeruginosa predominated. Multivariate analysis demonstrated pBSI as a significant contributor to 28-day mortality (HR=1.86; P=0.039), along with presence of two or more co-morbidities (HR=2.35; P=0.004). In conclusion, pBSIs differed epidemiologically from mBSIs, with the emergence of enterococcal species, and portended an almost two-fold increased risk of 28-day mortality. Prospective studies are warranted to elucidate possibly modifiable factors.