Conventional Systemic Drugs Research Articles

Histone modifications associated with biological drug response in moderate-to-severe psoriasis.

Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate-to-severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). Peripheral blood mononuclear cells (PBMCs) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMCs. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA. Data were analysed by IBM-SPSS v.23. Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non-significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non-responders to biological drugs at 3months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non-responders to biological drugs at 3 and 6months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients' response to biological drugs in psoriasis.

Association between clinical factors and dose modification strategies in the treatment with ustekinumab for moderate-to-severe plaque psoriasis

Purpose: The aim of this study was to identify clinical factors associated with dose reduction and dose escalation in the treatment with ustekinumab in patients with moderate-to-severe plaque psoriasis.Materials and methods: An observational, longitudinal and retrospective study was conducted using patients with moderate-to-severe plaque psoriasis. We reviewed clinical histories and variables were recorded on a database (patients’ characteristics, pharmacotherapeutics, effectiveness and safety). We evaluated correlation between dose reduction, dose escalation and used dose with other variables.Results: Of the study’s 62 patients, Ustekinumab dose was adjusted in 45.2% (22.6% with reduced doses and 22.6% with increased doses). We found a statistically significant correlation between extending the dosing interval and the absence of psoriatic arthritis, no concomitant systemic therapies, treatment time with ustekinumab, lower PASI at week 28 and achieving PASI75 at week 28. There was also a statistically significant correlation between dose escalation and diabetes mellitus, psoriatic arthritis, prior biological treatments, concomitant systemic therapies, concomitant phototherapy and not achieving PASI75 at week 28.Conclusions: Dose-reduction strategies would increase ustekinumab efficiency in patients that achieve PASI 75 without psoriatic arthritis, diabetes mellitus, previous BT and concomitant treatment with conventional systemic drugs.

PDT for onychomycosis.

In this issue, Gilaberte et al. present data on methyl aminolevulinate–photodynamic therapy (MAL-PDT) for onychomycosis. Poor treatment results and evolving drug resistance with the conventional topical and systemic antifungal drugs have initiated a search for alternative treatments, and PDT is such an alternative. There are several reports on successful use of PDT for onychomycosis in the literature.1, 2 The treatment results with MAL-PDT in Gilaberte et al.'s study are poor, and not different from placebo. Onychomycosis without total dystrophy, however, responded better to MAL-PDT and was associated with a higher microbial cure rate than placebo-PDT and showed a better clinical outcome as measured using the onychomycosis severity index. Twenty-four weeks after initial MAL-PDT, three of nine dermatophyte-infected had achieved microbial cure, but at the end of the study, at week 36, positive dermatophyte cultures had increased to eight. As MAL is not in itself a photosensitizer but needs to be taken up and metabolized to photoactive porphyrins, a necessary capability of a susceptible fungus is that it has uptake capacity and an enzymatic repertoire capable of converting MAL to photoactive porphyrins. This capability was demonstrated for Trichophyton rubrum in laboratory studies, and aminolevulinate–PDT was shown to have growth-inhibiting effect.3 Gilaberte et al. cultured 10 different species of fungi in their study, and the question arises whether all these species have the same capabilities as shown for Trichophyton rubrum. There might be differences which have considerable influence on their susceptibility to MAL-PDT. Further studies are needed to elucidate this. Treatment of onychomycosis is difficult, and recurrences are the rule rather than the exception. No fungal resistance and genotoxic or mutagenic effect to fungus or human cells have so far been reported using PDT with various photosensitizers.1 It therefore seems to be a safe therapy option which can be used in selected cases.

Superiority in Quality of Life Improvement of Biologics over Conventional Systemic Drugs in a Swiss Real-Life Psoriasis Registry

Background: Randomized controlled trials have shown the efficacy of systemic treatments in moderate-to-severe psoriasis. Clinical outcomes in psoriasis patients under real-world conditions are less well understood. Objective: This study compared Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI) improvement in all psoriasis patients registered in the Swiss Dermatology Network for Targeted Therapies. We asked whether outcomes differed between 4 treatment strategies, namely biologic monotherapy versus conventional systemic monotherapy, versus combined biologic and conventional systemic drugs, and versus therapy adaptation (switching from one type to another). Methods: PASI and DLQI within 1 year after onset of systemic treatment, measured at 3, 6, and 12 months, were compared among the 4 groups using generalized linear mixed-effects models. Results: Between March 2011 and December 2014, 334 patients were included; 151 received conventional systemic therapeutics, 145 biologics, 13 combined treatment, and 25 had a therapy adaptation. With regard to the absolute PASI, neither the biologic cohort nor the combined treatment cohort significantly differed from the conventional systemic therapeutics cohort. The odds of reaching PASI90 was significantly increased with combined therapy compared to conventional systemic therapeutics (p = 0.043) and decreased with a higher body mass index (p = 0.041). At visits 3 and 4, the PASI was generally lower than at visit 2 (visit 3 vs. visit 2, p = 0.0019; visit 4 vs. visit 2, p < 0.001). After 12 months, patients with biologic treatment had a significantly lower DLQI than those with conventional systemic therapeutics (p = 0.001). Conclusion: This study suggests that after 1 year of treatment, biologics are superior in improving the subjective disease burden compared to conventional systemic drugs.

Efficacy and Survival of Systemic Psoriasis Treatments: An Analysis of the Swiss Registry SDNTT

Background: The Swiss psoriasis registry SDNTT (Swiss Dermatology Network for Targeted Therapies) records the long-term safety and effectiveness of systemic treatment regimens for psoriasis. Patients and Methods: Patients with moderate to severe psoriasis are included in the SDNTT when treatment with a conventional systemic agent or biologic is initiated that was not previously used by the respective patient. Patients are followed over a 5-year period. Clinical data are obtained every 3-6 months using standardized case report forms. Here, baseline data and follow-up data for 1 year of patients included from October 2011 until December 2014 were analyzed. Results: Within 39 months, 323 patients from 7 tertiary dermatology centers in Switzerland were recruited in the SDNTT; 165 patients received biologics and 158 conventional systemic therapies. Patients treated with biologics had a significantly higher severity (PASI 11.3 vs. 9.2, BSA 15.6 vs.11.9, psoriatic arthritis 36.4 vs. 10.8%; p ≤ 0.005, p ≤ 0.013, p ≤ 0.001) and a longer duration of illness (19.2 vs. 14.4 years, p ≤ 0.003) compared to patients starting a conventional systemic treatment. PASI reduction was satisfying in both treatment groups, with 60.6% of patients treated with biologics achieving PASI75 after 1 year compared to 54.2% of patients receiving conventional systemic drugs (nonsignificant). On average, the drug survival in patients receiving a biologic therapy was significantly longer than those receiving conventional systemic treatments (30.5 vs. 19.2 months, p ≤ 0.001). Conclusions: In the real-world setting of a prospective national therapy registry, the application of current therapeutic guidelines for patients with moderate to severe psoriasis resulted in a PASI reduction of approximately 70% within the first year of treatment, but current therapeutic targets of PASI75 and PASI90 were reached in only 58 and 36% of patients, respectively, at 1 year, highlighting a gap in efficacy between selective clinical trials and the real-world setting.

The role of biologics in the treatment of moderate-to-severe plaque psoriasis

Psoriasis is a chronic, relapsing, inflammatory skin disease requiring long-term treatment and in many cases involving a reduction in the quality of life. Treatment with biologics is indicated in patients with moderate-to-severe psoriasis who do not respond or cannot be treated with conventional systemic drugs, and the therapeutic goal is an improvement of 90% (or at least 75%) with respect to baseline PASi at the end of the induction phase, which should be maintained long-term in the mainternance phase of treatment. Before starting treatment with a biological agent it is necessary to review the contraindications and precautions, rule out latent tuberculosis infection and complete the pending immunizations. Biological agents have a more favorable safety profile than classical systemic treatments; the most common side effects are mild and rarely involve the discontinuation of treatment. The treatment decision will be based on individual characteristics and patient preferences, functional limitation, expected speed of onset of effect, adverse reactions, availability and cost of treatment.

Anti-Candida activity and cytotoxicity of a large library of new N-substituted-1,3-thiazolidin-4-one derivatives

On the basis of the recent findings about the biological properties of thiazolidinones and taking into account the encouraging results about the antifungal activity of some (thiazol-2-yl)hydrazines, new N-substituted heterocyclic derivatives were designed combining the thiazolidinone nucleus with the hydrazonic portion. In details, 1,3-thiazolidin-4-ones bearing (cyclo)aliphatic or (hetero)aromatic moieties linked to the N1-hydrazine at C2 were synthesized and classified into three series according to the aromatic or bicyclic rings connected to the lactam nitrogen of the thiazolidinone. These molecules were assayed for their anti-Candida effects in reference to the biological activity of the conventional topic (clotrimazole, miconazole, tioconazole) and systemic drugs (fluconazole, ketoconazole, amphotericin B). Finally, we investigated the selectivity against fungal cells by testing the compounds endowed with the best MICs on Hep2 cells in order to assess their cell toxicity (CC50) and we noticed that two derivatives were less cytotoxic than the reference drug clotrimazole. Moreover, a preliminary molecular modelling approach has been performed against lanosterol 14-α demethylase (CYP51A1) to rationalize the activity of the tested compounds and to specify the target protein or enzyme.

Drug safety of systemic treatments for psoriasis: results from The German Psoriasis Registry PsoBest.

The German Psoriasis Registry PsoBest was conducted in 2008 in order to investigate the long-term outcomes and safety of systemic treatments for moderate-to-severe psoriasis. Safety analysis of antipsoriatic drugs with special focus on serious adverse events (SAE) for infections, malignancies and major cardiac events (MACE) was done. Nationwide non-interventional patient treatment registry conducted in 251 active dermatology centers. Until June 2012, n = 2444 patients [40 % female; mean age 47.3 (SD 14.1) years; mean duration of disease 18.2 (SD 14.7) years] were recruited, including n = 1791 patients (3842 patient years) with conventional systemic drugs and n = 908 (3442 patient years) with biological drugs. Mean PASI (Psoriasis Area and Severity Index) at inclusion was 14.7, mean DLQI (Dermatology Life Quality Index) 11.1, mean BMI (Body Mass Index) 28.2. The overall rate of SAE per 100 patient years were 1.3 (SD 0.9) per 100 patient years in conventional systemic and 1.5 (SD 1.2) in biologics (p > 0.5, no significant difference). The rates per 100 patient years for single severe adverse events were as follows (systemic/biologics): serious infections, 0.33/0.65 [CI (confidence interval) 0.13–0.54/0.35–0.98]; MACE, 0.56/0.77 (CI 0.29–0.97/0.41–1.31); malignancies (except non-melanoma skin cancer), 0.46/0.49 (CI 0.22–0.84/0.21–0.97). There were no significant differences between single drugs in any of the safety parameters. The conventional systemic and biologic drugs for psoriasis show satisfying safety under routine psoriasis care in Germany with respect to infections, MACE and malignancies.

Infectious risk of biological drugs versus conventional systemic treatments in moderate to severe psoriasis

INfeCTIouS rISk of bIologICal drugS VerSuS CoNVeNTIoNal SySTemIC TreaTmeNTS IN moderaTe To SeVere pSorIaSIS S. Couderc; R. Bourrel; C. Paul; J.L. Montastruc; M. Lapeyre-Mestre; and A. Sommet UMR 1027, Inserm, Universite Toulouse III, Toulouse, France; Caisse Nationale d’Assurance Maladie Midi-Pyrenees, Toulouse, France; Service de Dermatologie, Centre Hospitalier Universitaire, Toulouse, France; and Pharmacologie Medicale et Clinique, Centre Hospitalier Universitaire, Toulouse, France Introduction: Moderate to severe psoriasis affects about 0.5% of the population. Its management is based on conventional systemic treatments (TSC: phototherapy, acitretin, methotrexate, and cyclosporine) and biological second-line drugs (etanercept, infliximab, ustekinumab, adalimumab, golimumab). Results of studies comparing the infectious risk of TSC and biological drugs are divergent. Objective: To compare the infectious risk associated with biological drugs versus TSC for moderate to severe psoriasis. Material and Methods: We conducted a retrospective cohort in the French Health Insurance Database for the Midi-Pyrenees region from 01/01/2010 to 31/12/2013, with patients treated incidentally for moderate to severe psoriasis. After a 6-month observation period with all patients exposed to TSC, we compared patients exposed to biological drugs (“exposed”) versus TSC (“unexposed”). We performed a Cox model on the first infectious event, for up to 6 months after the last dispensation of psoriasis drug. An infectious event was defined as delivery of any anti-infectious systemic drug or a hospital diagnosis of infection. Results: The 101 “exposed: patients and 788 “unexposed” patients were comparable in terms of socio-demographic data and comorbidities. Considering the first infectious event over a period of 2 years, no significant difference was found between “exposed” and “unexposed” (HR = 0.94; 95% CI, 0.71–1.22; P = 0.62). Being a woman (HR = 1.23), benefit from the Universal Health Coverage (HR = 1.44), suffering from chronic hepatitis B or C (HR = 2.74), history of neoplasia (HR = 1.70), a previous infectious event during the observation period (HR = 1.74), and the number of drugs consumed during the observation period (HR = 1.03) significantly increased the risk of infection. Conclusions: We did not reveal any difference in infection risk between the TSC and biological drugs in the management of moderate to severe psoriasis. This risk appears constant the first 2 years of use.

Therapeutic Interventions for Itch in AD

Atopic dermatitis (AD) is characterized by severe pruritus, which has a negative impact on the quality of life of patients. AD pruritus is usually of high intensity, occurs predominantly during the night and leads to severe scratching. Thus, the therapy has to focus not only on the suppression of the symptom but also on improvement of sleep and therapy of scratch lesions. Today, the therapy of AD pruritus is mainly based on conventional topical and systemic anti-inflammatory drugs and off-label application of mu-opioid receptor antagonists, the antidepressant mirtazapine, and – without evidence from controlled studies – the neurokinin-1 receptor antagonist aprepitant. The pathophysiology of AD-associated pruritus is still not fully understood; however, recent identification of several key mediators and mechanisms might enable development of novel therapies such as receptor antagonists for neurokinin 1, histamine 4, interleukin 31, thymic stromal lymphopoietin (TSLP), and nerve growth factor (NGF). Controlled studies that are currently being carried out can be expected to pave the way for improved treatment options in AD pruritus.

Relevance of insulin-like growth factor 1 receptor gene expression as a prognostic factor in non-small-cell lung cancer.

Signalling through the insulin-like growth factor 1 receptor (IGF-1R) is implicated in carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. The purpose of this study was to investigate the prognostic role of IGF-1R expression in surgically resected non-small-cell lung cancer (NSCLC), and responses to IGF-1R tyrosine kinase inhibitor NVP-ADW742 in a panel of lung cancer cell lines. Insulin-like growth factor 1 receptor (IGF-1R) expression was evaluated by quantitative RT-PCR in 115 NSCLC samples and in a panel of 6 NSCLC cell lines. Cytotoxicity experiments with IGF-1R inhibitor and conventional systemic drugs such as paclitaxel in cell lines were realised. Insulin-like growth factor 1 receptor (IGF-1R) was differentially expressed across histologic subtypes, with the lowest levels observed in squamous cell tumours. Median survival was longer in patients with squamous tumour histology expressing low IGF-1R levels. In multivariable analysis, ageing and high tumour stage were significant predictors of worse overall survival. The hazard of death was lower in patients with squamous histology and low IGF-1R gene expression. There was no correlation between IGF-1R expression and response to tyrosine kinase inhibitor in cell lines tested. However, combination drug treatment resulted in synergistically enhanced antiproliferative effects on several cell lines. These findings suggest that IGF-1R is a potential target for therapy in NSCLC patients. Combination therapies will have an important role in treatment.

Acitretin in psoriasis: an evolving scenario

Acitretin, an active metabolite of etretinate, is the most widely used systemic retinoid in the treatment of psoriasis. There are several unique characteristics of this drug, which set it apart from other options in the therapeutic armamentarium of psoriasis. It is highly efficacious as monotherapy in some specific clinical subtypes of psoriasis. It has dose-sparing effects when used as combination therapy with conventional systemic drugs as well as the biologics. It is a good option for long-term maintenance therapy. Side effects are common but usually mild and can be managed by its proper dosing and monitoring. With appropriate patient selection, gradual dose escalation, and patient counseling, we can deliver good results in psoriasis with this useful drug. This review gives a comprehensive recount of acitretin use in the present era of biologics in psoriasis.

Obesity and Psoriasis: Inflammatory Nature of Obesity, Relationship Between Psoriasis and Obesity, and Therapeutic Implications

Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity.Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight.

Obesidad y psoriasis: naturaleza inflamatoria de la obesidad, relación entre psoriasis y obesidad e implicaciones terapéuticas

Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity.Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight.

Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a cost-effectiveness analysis of the ointment versus gel formulation

BackgroundPsoriasis is a chronic inflammatory skin disease with a major impact on the quality of life of affected individuals. Topical therapy has an important role in the treatment of psoriasis. Poor treatment outcomes from topical therapy regimens likely result from poor adherence and ineffective use of medication.MethodsA cost-minimization analysis was performed with the purpose of assessing the use of a gel containing calcipotriol and betamethasone dipropionate (Dovobet® gel) versus the ointment formulation (Dovobet ointment) in the treatment of psoriasis. The analysis was carried out using a Markov model with a one-year time horizon in a hypothetical cohort of patients with a Psoriasis Area and Severity Index score < 10. The model simulates different therapy adherence scenarios for the two different formulations.ResultsThe Dovobet gel strategy allows a 5% reduction in the number of patients who could potentially be treated with more expensive therapies (biologics and conventional systemic drugs) in comparison with the Dovobet ointment strategy, with a consequent impact on costs for the National Healthcare Service. The total annual cost of Dovobet gel is about €407.00 per patient, ie, 19% less that the total cost of about €500.00 of the Dovobet ointment strategy. The base case results were then examined by sensitivity analysis and budget impact analysis to correlate the various scenarios of Dovobet gel use with cost savings to the National Healthcare Service.ConclusionThe Dovobet gel strategy seems more acceptable to patients, shows better overall adherence, and appears to be favorable from the pharmacoeconomic point of view than the ointment formulation for treatment of patients with mild-to-moderate psoriasis.

Thyroid Dysfunction in Patients Treated with Tyrosine Kinase Inhibitors, Sunitinib, Sorafenib and Axitinib, for Metastatic Renal Cell Carcinoma

Targeted drugs are generally associated with a lower toxicity than conventional systemic cytotoxic drugs and, thus, are administered for long periods. As a result, unusual adverse effects, including thyroid dysfunction, have become important clinical issues. We retrospectively collected the data and compared the incidence and the time of onset of thyroid dysfunction in 33 patients (M/F: 26/7, age: 34-77) with metastatic renal cell carcinoma treated with the small-molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib and axitinib in Yamagata University Hospital, Japan, from 2005 to 2010. The incidence of thyroid dysfunction tended to be higher in patients treated with axitinib (6 of 6: 100%) than in those treated with sunitinib (9 of 15: 60%) or sorafenib (6 of 12: 50%) (P= 0.1113). The median thyroid dysfunction-free survival evaluated using the Kaplan-Meier product-limit method with the log-rank test was significantly shorter in patients treated with axitinib than in those treated with sunitinib/sorafenib (3 vs. 16 weeks, P=0.0198). A multivariate Cox regression model for thyroid dysfunction-free survival with several probable confounding factors as co-variables showed that patients treated with axitinib were more likely to have thyroid dysfunction than the others (hazard ratio: 4.53, 95% confidence interval: 1.40-14.63, P=0.0116). Patients treated with the tyrosine kinase inhibitors developed thyroid dysfunction frequently. Furthermore, those treated with axitinib developed thyroid dysfunction significantly more and at a faster rate than the others. Therefore, when the tyrosine kinase inhibitors, especially axitinib, are used, close monitoring of thyroid function is recommended, at least for the initial 1-2 months, to avoid clinical symptoms derived from thyroid dysfunction.

Clinical Pharmacology for Development of Topical Dermatological Products: Present and Future Opportunities for Safety and Efficacy

The development of topical products for dermatological diseases represents an untapped opportunity for the clinical pharmacologist. Assessment of bioavailability of topical drugs and its utility in weighing benefit vs. risk has been unique and challenging, compared with assessments for conventional systemic drugs. However, with continued advances in analytical methods and growing interests in discovering biomarkers, the future opportunities for clinical pharmacology to advance topical drug development processes are enormous and will be limited only by our drive and determination to push science forward.

Psoriasis: What is new in nonbiologic systemic therapy in the era of biologics?

Psoriasis is a common debilitating disease significantly affecting the quality of life of the patients. Majority of the psoriasis patients have mild disease which can be managed by topical therapies. Around 30% of the psoriasis patients require systemic therapy during the course of their disease. There is a vast array of drugs for the treatment. Methotrexate, cyclosporine and retinoids are the most commonly used conventional systemic drugs. Newer studies provide insight into their more effective and safer use and as combination therapy with biologics. In recent times, many new drugs with novel mechanisms of action other than biologics have been tried in psoriasis. In this article, we have reviewed the current developments and new found role of the conventional drugs as well as the newer nonbiologic systemic drugs in the treatment of psoriasis.

Long-term data in the treatment of psoriasis

Moderate-to-severe plaque psoriasis is associated with a considerable disease burden and treatment needs are often unmet. Several conventional systemic drugs are available as treatments, including methotrexate, cyclosporin, retinoids and psoralen ultraviolet A, which, although effective, are associated with considerable toxicity that limits their long-term use. Recent developments in more targeted therapies involving biological agents, such as anti-T-cell agents and inhibitors of tumour necrosis factor-alpha, offer an alternative treatment approach with the possibility of longer continuous therapy, which may translate into disease control and improved quality of life. Although the majority of data supporting the use of biological agents have been obtained in short-term studies of 3-6 months' duration, some agents have been evaluated for longer periods of continuous administration. Comparison of efficacy among these agents may better define their role as long-term therapy. This article discusses the data currently available on both conventional and biological systemic therapies for psoriasis, in terms of short-term and long-term use.