Alexandros Katoulis

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca2+ handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies.

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.

Frontal fibrosing alopecia: treatment with oral dutasteride and topical pimecrolimus

© 2008 The Authors JEADV 2009, 23, 570–620 Journal compilation

The role of inflammatory markers in assessing disease severity and response to treatment in patients with psoriasis treated with etanercept

Background.  Psoriasis is a chronic, systemic, inflammatory disease. Inflammatory markers are used in clinical practice to detect acute inflammation, and as markers of treatment response. Etanercept blocks tumour necrosis factor (TNF)‐α, which plays a central role in the psoriatic inflammation process.

A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis

Summary Background Treatment failures and relapses are not uncommon in onychomycosis. Therefore, it is worthwhile to consider the combination of systemic and topical antifungals to improve the cure rates further and to reduce the duration of systemic treatment.

Development of Two Primary Malignant Melanomas after Treatment with Adalimumab: A Case Report and Review of the Possible Link between Biological Therapy with TNF-α Antagonists and Melanocytic Proliferation

Biologics, such as tumor necrosis factor α (TNF-α) antagonists, have revolutionized treatment of several significant inflammatory autoimmune diseases. Nevertheless, issues concerning long-term safety remain to be clarified. There is growing evidence linking biological treatments with the occurrence of malignancies or reactivation of latent ones, including malignant melanoma. We report the case of a 75-year-old male patient who developed 2 primary malignant melanomas (MM) after treatment with adalimumab for rheumatoid arthritis. He was under adalimumab treatment for approximately 12 months before the diagnosis of MM on his right lower leg. After surgical removal and staging, no evidence of metastases was found. A few months later, a second MM developed on the patient’s scalp. The short duration of treatment with adalimumab and the unclear temporal relationship cannot adequately support a probable link between this double MM occurrence and the adalimumab-induced immunosuppressive state. The result of a literature search regarding the possible association between anti-TNF drugs and melanocytic proliferation is provided.

Papulonodular Lichenoid and Pseudolymphomatous Reaction at the Injection Site of Hepatitis B Virus Vaccination

Immunization with the hepatitis B virus (HBV) is effective and safe with an estimated incidence of adverse reactions, either local or systemic, of less than 0.1%. Cutaneous side effects are rare and include lichen planus (LP) and lichenoid reactions. We report the case of a 21-year-old female, in whom a persistent, papulonodular lesion developed at the site of the injection, 6 weeks after the second dose of the HBV. Histological examination revealed lichenoid and pseudolymphomatous features. In addition, sensitization to thiomersal, a vaccine constituent, was documented by patch testing. The association of LP with chronic liver disease is well established. Furthermore, less than 20 cases of lichen or lichenoid reactions, following HBV vaccination, have been reported. Although several arguments have been presented, it is still debated whether there is a causal association or the occurrence of LP following HBV vaccination is a simple coincidence. It has been speculated that a T-cell-mediated, graft-versus-host-like reaction, triggered by a sensitizing protein, is directed against keratinocytes expressing an epitope of hepatitis B surface antigen or a similar epitope. Our case may represent a localized lichenoid reaction to HBV vaccination, a local reactive hyperplasia or a persisting delayed hypersensitivity reaction to a vaccine constituent. This is the first case of a local lichenoid reaction at the injection site of the HBV vaccine, providing further documentation for a causal association linking the HBV vaccine with LP.

Poikiloderma of Civatte: a clinical and epidemiological study.

Background  Although a common dermatosis, idiopathic poikiloderma of the face and neck has not been studied in depth for decades.

Evaluation of the role of contact sensitization and photosensitivity in the pathogenesis of poikiloderma of Civatte

Background Poikiloderma of the face and neck (Civatte) is a rather common, indolent, chronic dermatosis, most often affecting menopausal females. Cumulative excessive sun exposure, a phototoxic or a photoallergic reaction, hormonal changes of menopause and genetic factors have all been incriminated in its obscure aetiopathogenesis.

Erythema Multiforme following Vaccination for Human Papillomavirus

Erythema multiforme (EM) is an acute self-limited immune-mediated reaction manifested by target skin lesions with mucous membrane involvement. The most common causes are infections and drugs. Vaccinations have been reported as a triggering factor, and they may be a frequent cause of EM in childhood. A 19-year-old female developed several target lesions of the hands and feet 10 days after the second dose of human papillomavirus (HPV) vaccine. Clinico-histologically, a diagnosis of EM minor was made. Treatment with topical corticosteroids and oral antihistamines resulted in complete clearance of the rash. Four months later, she received the last booster dose of the vaccine. A few subtle lesions appeared and disappeared spontaneously after a few days. Gardasil® is a non-infectious vaccine, developed for the prevention of cervical cancer, precancerous genital lesions and genital warts. It delivers the major capsid (L1) protein of HPV types 6, 11, 16 and 18. Mild local reactions are the main adverse events. The only serious events are very rare cases of anaphylaxis. In our patient, the temporal relationship between the development of EM and the vaccination suggests that the HPV vaccine probably was the causal agent. This is the first published case of EM following HPV vaccination.