Deepak Balak

Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review

Glatiramer acetate and interferon-beta are approved first-line disease-modifying treatments (DMTs) for multiple sclerosis (MS). DMTs can be associated with cutaneous adverse events, which may influence treatment adherence and patient quality of life. In this systematic review, we aimed to provide an overview of the clinical spectrum and the incidence of skin reactions associated with DMTs. A systematic literature search was performed up to May 2011 in Medline, Embase, and Cochrane databases without applying restrictions in study design, language, or publishing date. Eligible for inclusion were articles describing any skin reaction related to DMTs in MS patients. Selection of articles and data extraction were performed by two authors independently. One hundred and six articles were included, of which 41 (39%) were randomized controlled trials or cohort studies reporting incidences of mainly local injection-site reactions. A large number of patients had experienced some form of localized injection-site reaction: up to 90% for those using subcutaneous formulations and up to 33% for those using an intramuscular formulation. Sixty-five case-reports involving 106 MS patients described a wide spectrum of cutaneous adverse events, the most frequently reported being lipoatrophy, cutaneous necrosis and ulcers, and various immune-mediated inflammatory skin diseases. DMTs for MS are frequently associated with local injection-site reactions and a wide spectrum of generalized cutaneous adverse events, in particular, the subcutaneous formulations. Although some of the skin reactions may be severe and persistent, most of them are mild and do not require cessation of DMT.

Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study

Abstract Background: Mixtures of fumaric acid esters (FAE) are used as an oral systemic treatment for moderate to severe psoriasis. Large clinical studies with dimethylfumarate (DMF) monotherapy are scarce. Objectives: The objective of this study is to assess the effectiveness and long-term safety of high-dose DMF monotherapy in moderate to severe psoriasis. Methods: A prospective single-blinded follow-up study was performed in a cohort of patients treated with DMF. Patients were followed-up at fixed intervals. Assessment of consecutive photographs was performed by two observers. Primary outcome was a change in static physician global assessment (PGA) score. Safety outcome was defined as incidences of (serious) adverse events. Results: A total of 176 patients with moderate to severe psoriasis were treated with DMF for a median duration of 28 months. The median daily maintenance dosage of 480 mg was reached after a median of 8 months. Psoriasis activity decreased significantly by 1.7 out of five points. A total of 152 patients reported one or more adverse events, such as gastrointestinal complaints and flushing. Conclusions: High-dose DMF monotherapy is an effective and safe treatment option in moderate to severe psoriasis. It can be suggested that 50% of all patients may benefit from high-dose DMF monotherapy.

Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial.

Fumaric acid esters (FAEs) are considered an effective and safe long‐term treatment for psoriasis. However, 30–40% of patients need to discontinue FAE treatment due to intolerable adverse events.

Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: A cross-sectional study

BackgroundGlatiramer acetate (GA) and interferon-beta (IFN-β) are disease-modifying therapies (DMTs) for multiple sclerosis that are administered through subcutaneous (SC) or intramuscular (IM) injections. Skin reactions associated with DMTs are common and may influence patient’s health-related quality of life (QoL). We aimed to determine the prevalence of cutaneous adverse events associated with long-term DMT use, and to assess the impact of cutaneous adverse events on QoL.MethodsA cross-sectional study among patients with multiple sclerosis who had been treated with their first DMT for at least 2 years. Cutaneous events were assessed from photographs of injection-sites by dermatologists blinded for DMT. Generic and dermatology-specific health-related QoL were assessed using validated patient-reported questionnaires.ResultsA total of 229 patients were enrolled, of whom 156 (68%) had at least one skin reaction. The prevalence of cutaneous adverse events was higher for SC DMTs (75-82%) compared to IM DMT (41%) (P < 0.001). Erythema and lipoatrophy were the most common skin reactions, observed in 156 (68%) and 45 (20%) patients, respectively. Dermatology-specific, but not generic, QoL was significantly lower among patients with skin reactions compared to those without.ConclusionsThe prevalence of cutaneous adverse events was high in long-term DMT-treatment. Patients with cutaneous adverse events had a lower perceived dermatology-specific QoL.

Fumaric acid esters in the management of psoriasis

Fumaric acid esters (FAE) are small molecules with immunomodulating, anti-inflammatory, and anti-oxidative effects. FAE were introduced as a systemic psoriasis treatment in 1959 and empirically developed further between 1970 and 1990 in Germany, Switzerland, and the Netherlands. The development of FAE as psoriasis treatment did not follow the traditional drug development phases. Nonetheless, in 1994 FAE were approved in Germany for the treatment of severe plaque psoriasis. FAE are currently one of the most commonly used treatments in Germany, and FAE are increasingly being used as an unlicensed treatment in several other European countries. To date, six randomized controlled trials and 29 observational studies have evaluated FAE in a combined total of 3,439 patients. The efficacy and safety profile of FAE is favorable. About 50%–70% of patients achieve at least 75% improvement in psoriasis severity after 16 weeks of treatment. Common adverse events of FAE include gastrointestinal complaints and flushing symptoms, which lead to treatment discontinuation in up to 40% of patients. Lymphocytopenia, eosinophilia, and proteinuria are commonly observed during FAE treatment, but rarely require treatment discontinuation. The long-term safety profile of continuous FAE treatment is favorable without an increased risk for infections, malignancies, or other serious adverse events. There are no known drug-interactions for FAE. The 2009 European evidence-based S3-guidelines on psoriasis treatment recommend FAE and suggest it as a first-line systemic treatment for moderate-to-severe plaque psoriasis. This review is aimed to give an overview of FAE treatment in the management of psoriasis.

Treatment of lupus erythematosus with fumaric acid ester derivatives: two case-reports

Fumaric acid ester derivatives, or fumarates, have immunomodulating properties [1]. For over four decades fumarates have been applied in the treatment of psoriasis with proven efficacy and long-term safety [2,3]. More recently, fumarates have been assessed in multiple sclerosis [4]. Given their favorable safety-profile, fumarates could be of value in the treatment of other immune-mediated inflammatory diseases.

Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series

Background Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Methods Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. Results All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37–46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28–111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. Conclusions FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.

Drug-induced psoriasis: clinical perspectives

Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxy)chloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of “classical” nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments.

Non-melanoma skin cancer: The hygiene hypothesis

Protection against ultra violet radiation-induced DNA-damage in the skin is not only provided by the pigmentary system. The epidermal barrier consisting of stratum corneum keratinocytes, filaggrin and other proteins is an additional component of the UV-shield. Disruption of the epidermal barrier through frequent body cleansing with soaps and cosmetics may increase the risk of non-melanoma skin cancer.

First‐line systemic treatment of psoriasis: staying conventional or going biologic?

The systemic treatment landscape of psoriasis has changed significantly in the last two decades. Introduced in 2003, biologic cytokine antagonists have become important therapies for psoriasis that are highly efficacious, fast-acting and relatively safe. Prior to the introduction of the biologics, the systemic treatment options for psoriasis were limited to methotrexate, ciclosporin, retinoids and fumaric acid esters (FAEs). These so-called conventional drugs typically have a slow onset of efficacy and may be associated with cumulative toxicity. Current psoriasis treatment guidelines recommend the use of conventional systemic agents as first-line treatment, whereas biologics are to be applied in case of treatment failure, intolerance or contraindication to a conventional therapy. This restricted second-line use of biologics is based partly on economic grounds – the costs of biologics are significantly higher compared with conventional treatments – and on a lack of data regarding the long-term safety of biologic treatments. Yet with the advent of biosimilars the biologic costs may decrease considerably, while to date no major safety issues have been observed with continuous biologic treatment. In line with this, several biologics have been granted marked authorization for first-line use in psoriasis. As a result, biologics may be prescribed to patients with psoriasis without a need for prior use of conventional therapies, but supporting evidence has been lacking. In this issue of the BJD, Sticherling and colleagues describe results from the PRIME study, a German multicentre, randomized, open-label trial that compared head-to-head the efficacy of secukinumab, an anti-interleukin-17 biologic, with that of FAEs, a conventional agent approved for first-line use in Germany. In this study, 202 patients with chronic plaque psoriasis who had been na€ive to systemic treatment were randomized to receive subcutaneous secukinumab or oral FAEs (Fumaderm, comprised mainly of dimethylfumarate) per label for 24 weeks. The primary outcome – the proportion of patients achieving at least 75% reduction in their baseline psoriasis area and severity index (PASI-75 response) at week 24 – was evaluated by blinded assessors. There was a significantly higher PASI-75 response for secukinumab than for FAEs, 90% vs. 34%, respectively. Other secondary efficacy outcomes were also in favour of secukinumab. Of note, only 43 (44%) subjects on FAEs had completed the 24-week follow-up period compared with 99 (94%) on secukinumab. Most FAE treatment withdrawals were related to gastrointestinal complaints and lymphocytopenia. The study findings of the PRIME trial confirm important differences in short-term efficacy and speed of onset of action between secukinumab and FAEs. However, long-term assessment of efficacy, safety, cost-effectiveness and patient treatment satisfaction is still needed for optimal clinical decisionmaking. For example, biologics have been linked to a gradual decrease of efficacy, whereas FAEs have shown a favourable drug survival. In the current perspective, conventional systemic treatments will likely retain their status as preferred first-line therapy. Nonetheless, the clinical superiority in short-term treatment of highly effective biologics such as secukinumab may support their use as first-line therapy in specific cases requiring rapid disease control. The PRIME trial is hopefully the first of studies that will generate high-quality evidence to better define the position of biologic therapies relative to that of the conventional systemic agents in the psoriasis treatment algorithms.