A real-world, non-interventional, prospective study of the effectiveness and safety of apremilast in bio-naïve adults with moderate plaque psoriasis treated in the routine care in Greece - the 'APRAISAL' study.

BACKGROUND: Real-world data in patients with moderate psoriasis treated with apremilast is limited. OBJECTIVES: To evaluate the effectiveness and safety of apremilast in bio-naïve patients with moderate psoriasis in real-world clinical settings. METHODS: This was a 52-week multicenter, observational, prospective study of adult outpatients with moderate psoriasis {[10% < body surface area < 20% or 10 < psoriasis area severity index (PASI) < 20] and 10 < dermatology quality of life index (DLQI) < 20} initiated on apremilast ≤7 days before enrollment. Missing data were imputed using the last observation carried forward method. RESULTS: A total of 287 eligible patients (median age: 54.2 years; median psoriasis duration: 9.8 years) were consecutively enrolled. At baseline, the median DLQI and PASI scores were 12.0 and 11.8, respectively. The 52-week DLQI ≤ 5 and PASI75 response rates were 68.3% and 61.0%. At 52 weeks, 70.8% and 72.7% of the patients shifted from moderate/severe/very severe to clear/minimal scalp and palmoplantar psoriasis involvement, respectively; the pruritus severity state improved in 67.2%. The 52-week Kaplan-Meier estimated drug continuation rate was 85.3%. The adverse drug reaction rate was 19.9%. CONCLUSIONS: Apremilast is a safe and effective treatment for bio-naïve patients with moderate psoriasis and specific psoriasis manifestations.

Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Effectiveness and safety of apremilast in biologic-naïve patients with moderate psoriasis treated in routine clinical practice in Greece: the APRAISAL study.

BACKGROUND: Apremilast is an oral phosphodiesterase-4 inhibitor indicated for patients with moderate-to-severe chronic plaque psoriasis and active psoriatic arthritis. OBJECTIVES: To examine the effectiveness of apremilast on Dermatology Life Quality Index (DLQI), Psoriasis Area and Severity Index (PASI) and nail, scalp and palmoplantar involvement, when administered prior to biologics. METHODS: This 52-week real-world study included biologic-naive adults with moderate psoriasis (psoriasis-involved body surface area 10% to <20%, or PASI 10 to <20 and DLQI 10 to <20). Apremilast was initiated ≤7 days before enrolment. Data from the first 100 eligible patients who completed 24 weeks (W24) of observation (or were prematurely withdrawn) are presented in this interim analysis using the last-observation-carried-forward imputation method. RESULTS: Eligible patients (mean age: 49.9 years; 71.0% males; median disease duration: 8.0 years) were consecutively enrolled between April and October 2017, by 18 dermatology specialists practising in hospital outpatient settings in Greece. Baseline DLQI (median: 12.0) and PASI (median: 11.7) scores improved (P < 0.001) at all postbaseline timepoints (Weeks 6, 16 and 24; W24 median decreases: 9.0 and 9.4 points respectively). At W24, DLQI ≤5, DLQI 0 or 1, and PASI-75 response rates were 63.0%, 25.0% and 48.0% respectively. The Nail Psoriasis Severity Index score in patients with baseline nail involvement (n = 57) decreased at all postbaseline timepoints (P < 0.001; W24 median decrease: 20.0 points). At W24, 50.0% and 51.7% of patients with baseline scalp (n = 76) and palmoplantar (n = 29) involvement respectively achieved postbaseline Physician's Global Assessment (PGA) score of 0 or 1 if baseline score was ≥3, or 0 if baseline score was 1 or 2. The adverse drug reaction rate was 21.0% (serious: 2.0%). CONCLUSIONS: These interim results indicate that through 24 weeks, apremilast improved quality of life and reduced disease severity in biologic-naive patients with moderate plaque psoriasis, while demonstrating safety consistent with the known safety profile.

Causality evaluation of bacterial species isolated from patients with community-acquired lower leg cellulitis.

INTRODUCTION: Lower leg cellulitis is a diffuse inflammation of the cutaneous connective tissue following invasion of microorganisms and with potential to recur. The causative agent is not routinely identified in clinical practice, and the empirical therapy initiated primarily targets the 'conventional' disease pathogens, Streptococcus pyogenes and Staphylococcus aureus. OBJECTIVE: To evaluate at case level, the role of bacterial species isolated from lesional skin in the pathogenesis of community-acquired lower leg cellulitis. METHODS: Two sampling methods (superficial swab and biopsy) were applied to isolate bacterial species from 40 patients hospitalized for first (N = 24 cases) and recurrent (N = 16 patients) lower leg cellulitis episodes. Subsequently, a clinical-laboratory heuristic algorithm was employed to interpret causality associations of isolated species with disease episodes at case level. RESULTS: In 37/40 cases (92.5%), at least one bacterial species was identified with either sampling method. The number of different species/specimen isolated from superficial swabs compared to punch biopsies was significantly more (P < 0.001). A causative agent was identified in 16 cases (40%); it was a 'conventional' pathogen in seven patients and strains belonging to one of six 'non-conventional' pathogens in nine cases. There was no concordance in the spectrum of isolated pathogens with the two sampling methods (kappa-index = 0.028). Another four species may have participated in five patients as co-pathogens in mixed infections. There was also no difference in microbiological disease features between patients with first and recurrent cellulitis episodes. CONCLUSIONS: The application of a clinical-laboratory causality algorithm coupled with pooled culture results of more than one sampling methods in patients with lower leg cellulitis is anticipated to permit the identification of responsible bacterial species at case level and offer incentive for therapeutic intervention studies.

Intralesional bevacizumab as in-add adjuvant to immunocryosurgery for locally advanced basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is a tumour that relies mainly on aerobic energy assimilation for growth and depends on an extensive microvascular network to support adequate oxygen supply. In this tumour, higher expression levels of vascular endothelial growth factor (VEGF) has been described to correlate with increased microvessel density and more aggressive biologic behaviour. OBJECTIVE: To report feasibility and effectiveness of intralesional bevacizumab, an anti-VEGF antibody, as an in-add adjuvant to immunocryosurgery (cryosurgery sessions during daily topical imiquimod application) for the treatment of locally advanced BCC. METHOD: Seven patients (six uncontrollable or extensive local disease; one tumour unresponsive to repeated immunocryosurgery) were treated with 1­3 sessions of intralesional injections of bevacizumab (25 mg) at the day of cryosurgery during ongoing immunocryosurgery. Follow-up after treatment was 18­48 months. RESULTS: In 4/7 cases tumours cleared completely and 3/7 remained relapse free during follow-up. A relapsed tumour and a further case that did not clear after repeated immunocryosurgery cycles were excised with significantly reduced burden of surgery. Finally, two cases with previously locally uncontrollable BCC tumours regressed significantly and stabilized. CONCLUSION: In-add intralesional bevacizumab is a feasible and potentially effective addition to minimally invasive schemes for the treatment of locally advanced BCC.

Phospholipase activity after ß-endorphin exposure discriminates Malassezia strains isolated from healthy and seborrhoeic dermatitis skin.

BACKGROUND: Phospholipase activity and its induction by ß-endorphin have been associated with pathogenic Malassezia pachydermatis animal isolates. OBJECTIVE: To evaluate Malassezia phosholipase activity in human isolates from seborrhoeic dermatitis (SD) and healthy controls before and after ß-endorphin exposure. METHODS: Eighty-four volunteers with or without SD (N = 41) were sampled. Isolated Malassezia strains were incubated in Dixon's medium with and without 100 nmol/L ß-endorphin. Subsequently, phospholipase activity was assessed in egg-yolk agar and the results were compared employing Wilcoxon sign test for paired data, chi-squared test and multinomial logistic regression analysis. RESULTS: A total of 64 Malassezia strains were isolated. SD strains tended to have decreased phospholipase activity before (P = 0.057) and increased after exposure to ß-endorphin (P = 0.061) compared to isolates from healthy skin. Phospholipase activity after ß-endorphin exposure related to basal enzyme activity as a measure of per strain phospholipase inducibility by ß-endorphin did not depend on Malassezia species (P = 0.652). However, this latter biochemical trait discriminates strains isolated from SD lesional and healthy skin (P = 0.036). CONCLUSION: ß-endorphin exposure modifies the in vitro phosholipase activity in Malassezia species isolated from SD lesional skin. This is in accordance with emerging evidence that enhanced local lipase activity is involved in the pathogenesis of SD.

Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin.

BACKGROUND: Preclinical data and reports of adverse skin reactions in patients treated with dipeptidyl peptidase-IV inhibitors (gliptins) have increased awareness towards skin-targeting side-effects of these anti-hyperglycaemic drugs. Bullous pemphigoid (BP), sometimes drug-induced, is the most commonly acquired autoimmune blistering dermatosis in western countries, typically a disease of the elderly people with significant morbidity and excess mortality. OBJECTIVE: To report the development of BP in five diabetics under gliptin (4 vildagliptin, 1 sitagliptin) plus metformin in fixed-dose drug combinations. CASE REPORTS: From March to August 2010 six out of nine newly diagnosed BP patients in our Department were type 2 diabetics. Five of them were on gliptin plus metformin (three different trade preparations) for 2-13 months prior to BP onset. In all cases BP was controlled after withdrawal of the suspected medication and relatively mild therapeutic interventions. In two cases the eliciting role of the preceding treatment is supported by evidence at the level 'probable/likely' according to the WHO-UMC algorithm. CONCLUSIONS: This is the first report of drug-induced BP as a group adverse event of the gliptins plus metformin combination therapy for glycaemia control in type 2 diabetes mellitus patients.

Tuberculin skin test overestimates tuberculosis hypersensitivity in adult patients with psoriasis.

BACKGROUND: Tuberculin skin testing (TST) is still the reference method for the diagnosis of latent tuberculosis infection (LTBI). OBJECTIVE: To evaluate the effect of psoriasis on TST. METHODS: Comparison of TST results of consecutive dermatology (n = 91) and internal medicine (n = 615) inpatients. TST was uniformly ordered, performed and evaluated according to the Mantoux method using purified protein derivative. RESULTS: (a) Significantly larger TST indurations were measured in dermatology (median: 7 mm) compared to internal medicine inpatients (median: <1 mm; p < 0.0001). More dermatology inpatients showed 'positive' (>5 mm) and 'strongly positive' (>or=15 mm) TST results (53 vs. 29% and 22 vs. 13%, respectively). (b) Among dermatology inpatients, the TST reactions were significantly larger (p < 0.01) in psoriatics (n = 28) compared to the remaining patients (n = 63). (c) In psoriatics, the TST correlated positively with the psoriasis area and severity index score (p = 0.015). CONCLUSION: Overt psoriasis is associated with increased TST measurements. This observation is suggestive of a possible overtreatment of these patients for LTBI.

Efalizumab-induced thrombocytopenia: report of relapse after re-administration.

Although a reversible, sometimes severe, drug-induced thrombocytopenia is a recognized adverse drug reaction (ADR) in patients with psoriasis treated with efalizumab, definite proof for the association of thrombocytopenia with efalizumab is still lacking (currently level II evidence for ADR). We report a patient with psoriasis who had two episodes of reversible thrombocytopenia during efalizumab; the first occurred 5 months after introduction of the medication and the second 4 months after re-introduction of efalizumab for relapsing psoriasis. The development of a second episode of thrombocytopenia on re-exposure to efalizumab provides, for the first time in the literature to our knowledge, definite (level I) ADR evidence for efalizumab-induced thrombocytopenia.

Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application.

BACKGROUND/AIM: Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs. METHODS: Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2-5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N(2) cryosurgery (spray, two cycles, 10-20 s) and imiquimod was continued for additional 2-12 weeks (median, 4). The outcome after at least 18 months of follow-up (18-24 months) is currently reported. RESULTS: Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%). CONCLUSIONS: 'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.

Alterations in the inflammatory cells infiltrating basal cell carcinomas during immunocryosurgery.

Immunocryosurgery, the combination modality of a cryosurgery session at day 14 of a 5-week daily imiquimod treatment cycle, has shown remarkable efficacy in the treatment of basal cell carcinoma (BCC). The modality was designed to exploit synergy of antitumor effects, including the induction of immune responses, elicited by imiquimod and cryosurgery. Herein, we report on the infiltration of the BCC by selected inflammatory cell species during an immunocryosurgery treatment cycle. The density of tissue infiltrating CD68+, CD3+ and Foxp3+ cells was studied by immunohistochemistry in 56 BCC biopsies from 28 treated sites (26 patients) at baseline and at days 12, 16 or 28 during treatment. Immunocryosurgery induces statistically significant alterations in all three cell species (p < 0.003): The density of CD68+ increased already by day 12 and remained at a higher level during the treatment thereafter. The density of CD3+ cells increased significantly between days 12 and 16 of treatment. The density of Treg (Foxp3+) cells increased in the early phase of treatment (highest at day 12) to decrease significantly already 2 days after the cryosurgery session (day 16) and thereafter up to day 28 of the treatment cycle (p = 0.033). Within the tumor tissue, these alterations result in an abrupt increase in the CD3+/Foxp3+ ratio, a finding suggesting that the cryosurgical perturbation may probably play a decisive modulating role in the cellular composition of the inflammatory infiltrate during immunocryosurgery, eventually heralding the induction of an effective tumor-destructing immune response.