Traditional Systemic Treatments Research Articles

Secondary failure of TNF-α inhibitors in clinical practice.

Tumor necrosis factor alpha (TNF-α) is a leading inflammatory cytokine that plays a pivotal role in the pathogenesis of psoriasis. In case of a severe course of psoriasis and moderate-to-severe disease in which traditional systemic treatments are ineffective or contraindicated, TNF-α inhibitors (iTNF-α) are used. This class of drugs includes monoclonal antibodies and a fusion protein (etanercept) and can induce a humoral or cell-mediated immune response, leading to formation of anti-drug antibodies (ADAs). The immunogenicity may affect iTNF-α drug pharmacokinetics, which would lead to hampering the clinical response (secondary drug failure), so a need to increase the drug dose arises. Antibodies against monoclonal antibodies (adalimumab, infliximab) have been associated with diminished clinical response, while against etanercept are non-neutralizing and appear to have no significant effect on clinical response and treatment safety. Switching of biologic agents may be one strategy in ADA-associated secondary failure of iTNF-α. However researches are needed to identify risk factors for ADA development and investigate management strategies for optimized treatment response. The authors reviewed the literature on the effectiveness of iTNF-α and pointed out the prevention of secondary failure in clinical practice.

A psoriasis hagyományos szisztémás kezelése

A psoriasis hagyományos szisztémás kezelése

Psoriasis in Israel: demographic, epidemiology, and healthcare services utilization.

Updated data regarding the epidemiology of psoriasis and related healthcare utilization are lacking. To investigate the epidemiology, comorbidities, healthcare services utilization, and drug use in a large group of patients with psoriasis from Clalit Health Services (CHS) database. A controlled cross-sectional study was performed. Case patients were defined when there was at least one documented diagnosis of psoriasis registered by a CHS dermatologist between the years 1998-2016. The extracted data included metabolic, cardiovascular and psychiatric comorbidities; community clinic visits; in- and outpatient services utilization profiles and drug use data, which included pharmacy claims of topical and systemic treatments, including phototherapy and climatotherapy. Comparative analysis was performed by a univariate and multivariate analysis, adjusting for age, gender, obesity, and smoking. The study included 118,680 patients with psoriasis (prevalence of 2.69%) and 118,680 age- and gender-matched controls. Patients with psoriasis had increased prevalence of metabolic, cardiovascular, and psychiatric illnesses. Psoriasis was significantly associated with an increased healthcare utilization. The mean (SD) number of annual dermatologist clinic visits and emergency room visits was 7.2 ± 12.4 and 2.9 ± 7.7 in psoriasis patients as compared to 2.9 ± 7.9 and 2.7 ± 7.4 in the control group (P < 0.001). Topical steroids were the most applied treatment in psoriasis patients (15.5%), and topical vitamin D analogs were second in use (14.6%). Traditional systemic treatment for psoriasis was used in 3.8% of the patients, and biologic treatments were used in 1.6% of the patients. Our study quantifies healthcare services utilization and drug use in patients with psoriasis.

Infectious risk of biological drugs vs. traditional systemic treatments in moderate-to-severe psoriasis: a cohort analysis in the French insurance database.

The aim of this study was to compare the infectious risk between a group of psoriasis patients treated by biological drugs (BD) and a group treated by traditional systemic treatments (TST). We built a retrospective observational cohort study from the French health insurance database in the Midi-Pyrénées area (2.9 million inhabitants, southwest of France) using data from 01/01/2010 to 12/31/2013. We compared the infectious risk between 'exposed' patients treated with BD (adalimumab, etanercept, infliximab, or ustekinumab) and 'unexposed' patients treated by TST (phototherapy, acitretin, methotrexate, or cyclosporine). We realized a survival analysis on the first infectious event, defined as an anti-infective drug delivery or a hospital diagnosis of infection. We selected 101 'exposed' and 788 'unexposed' patients. In our multivariate Cox model, 'exposure' did not seem to decrease the time frame of the first infectious event compared with 'nonexposure' (HR=0.94, P=0.62). Among all treatment, the safest seemed to be ustekinumab while the least safe was etanercept. We found factors statistically associated with the risk of infection: gender (female vs. male), economic deprivation, chronic hepatitis B or C, history of cancer, at least one infectious event, and the number of different drugs during the 6-month period before the study. We did not find any difference of infective risk between the BD and the TST. This result enhances the recent PSONET registries conclusions.

Medication adherence among patients with psoriasis on traditional systemic and biologics treatment.

Medication adherence among patients with psoriasis on traditional systemic and biologics treatment.

Management of refractory pityriasis rubra pilaris: challenges and solutions.

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous skin disease. Its clinical presentation and evolution is very variable. The most frequent clinical features are follicular papules, progressing to yellow-orange erythroderma with round small areas of normal skin and the well-demarcated palmoplantar keratoderma. Actually, six different types of PRP have been described based on clinical characteristics, age of onset, and prognosis. The pathogenesis is still unknown, and treatment can be challenging. Available treatments are mainly based on case reports or case series of clinical experience because no controlled randomized trials have never been performed because of the rarity of the condition. Traditional systemic treatment consists in retinoids, which are actually considered as first-line therapy, but refractory cases that do not respond or relapse after drug interruption do exist. In recent years, numerous reports have demonstrated the efficacy of new agents such as biological drugs. This article is an overview on available therapeutic options, in particular for refractory forms of PRP.

Biologic drug survival in Israeli psoriasis patients

Drug survival is defined as the time period of treatment with a certain drug until its cessation. The role of previous exposure to traditional systemic treatments in biologic survival is still unknown. To investigate the drug survival rates of biologic treatments in patients with psoriasis and to identify predictor factors. Survival analysis was performed on patients with severe psoriasis who received adalimumab, infliximab, etanercept, and ustekinumab for treatment of psoriasis, drawn from the Clalit Health Services database. Multivariate analysis was performed adjusting for demographic variables; metabolic syndrome and its components; psoriatic arthritis; biologic naivety; coadministration of methotrexate, acitretin, or cyclosporine; and previous standard systemic treatment exposure. Among 907 patients treated with 1575 biologic treatments, ustekinumab had a significantly higher survival rate than tumor necrosis factor inhibitors. Biologic naivety and concomitant methotrexate intake were positive predictors for drug survival, whereas the female sex and the duration of previous systemic treatments were negative predictors. Data regarding disease severity or duration could not be drawn from the Clalit Health Services database. Ustekinumab had better retention rates in comparison with other investigated biologics inpatients with severe psoriasis, most of whom used it as a third line therapy.

Childhood psoriasis.

Psoriasis is a common chronic inflammatory skin disease. Recently, few data have been published on epidemiology, comorbidity, or therapy in children with psoriasis. Psoriasis affects up to 2% of children in Europe, even during the first months of life. The link between psoriasis and metabolic comorbidities has been highlighted, notably in relation to excessive weight and obesity. The clinical picture of psoriasis in childhood resembles adult disease, however, some clinical features are noteworthy: neonatal diaper rash is relatively specific, face involvement and guttate psoriasis are more common, plaques are often smaller, and scales are finer and softer than in adults. Napkin, guttate and palmoplantar psoriasis appear to have specific features in childhood and prevalence depends on the age of the child. Although benign, the effect of psoriasis on social interaction can be major, especially in children. Topical therapies are the first line of treatment for skin-limited disease. For chronic cases and more severe cases, phototherapy or traditional biologic systemic treatments must be discussed. The great challenge will be to propose international guidelines to manage these children.

Recommendations for managing a suboptimal response to biologics for moderate-to-severe psoriasis: A Belgian perspective

Over the past decade, biologics have become the gold standard in the treatment of moderate-to-severe psoriasis for patients who have failed or who have contraindications to traditional systemic treatments. However, although practical recommendations on how to treat a suboptimal response to biologics exist in other chronic inflammatory diseases, they are only just beginning to emerge for psoriasis. This article aims to formulate recommendations in the case of a suboptimal response of psoriasis to biologics in the Belgian setting. A Belgian taskforce of psoriasis experts was convened to review the results of a literature search and formulate recommendations based on the available evidence and provide expert opinion to address gaps in the evidence. The taskforce has proposed a treatment algorithm for patients with a primary non-response or a secondary loss of response to help address an unmet need. Expert recommendations have been developed to address treatment strategies in case of a primary or secondary suboptimal response to biologics in the treatment of moderate-to-severe psoriasis in Belgium.

Liver Injury in Psoriasis Patients Receiving Ustekinumab: A Retrospective Study of 44 Patients Treated in the Clinical Practice Setting

IntroductionThe therapy of patients with psoriasis and liver disease can be a challenge due to the increased risk of adverse effects from traditional systemic treatments; in addition, although the anti-tumor necrosis factor agents are considered safer, they have also been associated with drug-induced liver injury and reactivation of viral hepatitis. Ustekinumab has a different mechanism of action and the little that is known of its effects on the liver comes from pivotal studies. The objectives of this study were to estimate the incidence of drug-induced liver injury in patients treated with ustekinumab in daily clinical practice and to analyze liver alterations in those patients with pre-existing liver disease. MethodAll patients treated with the standard regimen of ustekinumab were included in the study. Variables gathered included age, sex, type of psoriasis, nail involvement, arthritis, previous treatments, history of liver disease, viral serology, Psoriasis Area Severity Index (at baseline and at 12, 16, and 52 weeks), transaminase levels, manifestations of liver disease, liver ultrasound, and factors such as body mass index, alcohol consumption, and ferritin levels. ResultsGrade 1 elevation of the transaminases was only observed in 6 patients; no cases of severe hypertransaminasemia were observed. None of the patients with elevation of the transaminases at baseline developed problems during treatment. ConclusionsUstekinumab-related liver injury is uncommon and mild. From a hepatic point of view, the drug appears safe, even in patients with pre-existing liver disease and those who have developed altered liver function previously with other drugs.

Análisis de la hepatotoxicidad en psoriasis tratada con ustekinumab. Estudio retrospectivo de 44 pacientes en práctica clínica habitual

IntroductionThe therapy of patients with psoriasis and liver disease can be a challenge due to the increased risk of adverse effects from traditional systemic treatments; in addition, although the anti-tumor necrosis factor agents are considered safer, they have also been associated with drug-induced liver injury and reactivation of viral hepatitis. Ustekinumab has a different mechanism of action and the little that is known of its effects on the liver comes from pivotal studies. The objectives of this study were to estimate the incidence of drug-induced liver injury in patients treated with ustekinumab in daily clinical practice and to analyze liver alterations in those patients with pre-existing liver disease. MethodAll patients treated with the standard regimen of ustekinumab were included in the study. Variables gathered included age, sex, type of psoriasis, nail involvement, arthritis, previous treatments, history of liver disease, viral serology, Psoriasis Area Severity Index (at baseline and at 12, 16, and 52 weeks), transaminase levels, manifestations of liver disease, liver ultrasound, and factors such as body mass index, alcohol consumption, and ferritin levels. ResultsGrade 1 elevation of the transaminases was only observed in 6 patients; no cases of severe hypertransaminasemia were observed. None of the patients with elevation of the transaminases at baseline developed problems during treatment. ConclusionsUstekinumab-related liver injury is uncommon and mild. From a hepatic point of view, the drug appears safe, even in patients with pre-existing liver disease and those who have developed altered liver function previously with other drugs.

Cost-of-illness in patients with moderate to severe psoriasis: a cross-sectional survey in Hungarian dermatological centres.

Despite the widespread availability of biological drugs in psoriasis, there is a shortage of disease burden studies. To assess the cost-of-illness and quality of life of patients with moderate to severe psoriasis in Hungary. Consecutive patients with Psoriasis Area and Severity Index (PASI) > 10 and Dermatology Life Quality Index (DLQI) > 10, or treated with traditional systemic (TST) or biological systemic treatment (BST) were included. Demographic data, clinical characteristics, psoriasis related medication, health care utilizations and employment status in the previous 12 months were recorded. Costing was performed from the societal perspective applying the human capital approach. Quality of life was assessed using DLQI and EQ-5D measures. Two-hundred patients were involved (females 32%) with a mean age of 51 (SD 13) years, 103 (52%) patients were on BST. Mean PASI, DLQI and EQ-5D scores were 8 (SD 10), 6 (SD 7) and 0.69 (SD 0.3), respectively. The mean total cost was €9,254/patient/year (SD 8,502) with direct costs accounting for 86%. The main cost driver was BST (mean €7,339/patient/year). Total costs differed significantly across treatment subgroups, mean (SD): no systemic therapy €2,186 (4,165), TST €2,388 (4,106) and BST €15,790 (6,016) (p < 0,001). Patients with BST had better PASI and DLQI scores (p < 0.01) than the other two subgroups. Patients with biological treatment have a significantly better quality of life and higher total costs than patients with or without traditional systemic treatment. Our study is the largest in Europe and the first in the CEE region that provides cost-of-illness data in psoriasis involving patients with BST.

Mycophenolate Mofetil in the Treatment of Psoriasis

Psoriasis is a chronic immune-mediated disorder which, though not life-threatening, has a great impact on the quality of life. There are multiple therapeutic options available for the treatment of psoriasis based on the severity and percentage of body surface area involved which include topicals, systemic agents, and phototherapy. It is not uncommon for patients to become resistant to therapies and treatment failures can be frustrating for the physician as well as the patient. Mycophenolate mofetil, an antimetabolite and immunosuppressant, has been found to be effective and safe for treating moderate-to-severe psoriasis in several studies. It is a good alternative for patients who fail traditional systemic treatments or who have a contraindication for their use.

Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.

227 Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (&gt; 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise &gt; 50% from nadir or baseline. Primary endpoint was PSA response rate (&gt; 50% reduction from baseline). A Simon minimax design was used. PSA response of &gt; 25% was to be considered promising for further study (versus null rate of &lt; 5%); 25 patients were required. Secondary endpoints included PSA response &gt; 30%, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AE). Results: 29 patients were accrued: median age was 71 (range 55-86) and median pretreatment PSA was 76 ng/mL (range 7-11,420 ng/ml); all had prior docetaxel-based chemotherapy. 28 patients were evaluable for response; all were evaluable for toxicity. PSA response of &gt;50% was seen in 48% of patients and 59% of patients had a PSA response of &gt; 30%. Median PFS was 138 days; median duration of stable disease was 123 days. 12 patients had grade 3 or 4 toxicity on treatment. Of the 17 grade 3 AEs, only 3 were considered ‘probably’ or ‘possibly’ related to treatment, while none of the 2 grade 4 AEs were considered related to treatment. Conclusions: In docetaxel pre-treated CRPC patients, low-dose keto + HC is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response with low-dose keto appears comparable to that of abiraterone in this patient context. A prospective randomized study of available post-chemo options is needed to assess comparative efficacy. Clinical trial information: NCT00895310.

Healthcare cost impact of biological drugs compared with traditional systemic treatments in psoriasis: a cohort analysis in the French insurance database

Biological drugs have dramatically improved the management of moderate to severe psoriasis. Little is known about their economic impact in daily clinical practice. The aim of this study was to estimate the costs of biological drugs, in term of health resources consumption, and to compare it with costs induced by traditional systemic treatments. This cohort study was built from the French health insurance database in the Midi Pyrénées area (2.8million inhabitants, South West of France). We compared health care costs between 'exposed' patients treated with biological drugs (adalimumab, etanercept, infliximab or ustekinumab) and 'unexposed' patients defined as patients who received traditional systemic treatments (phototherapy, acitretin, methotrexate or cyclosporin) during a 6-month period. A total of 1924 patients met the inclusion criteria. Sixty-nine patients were 'exposed', whereas 1855 patients were 'unexposed'. 'Exposed' patients had a mean total healthcare cost of 8107€ vs. 1678€ (P<0.001) for 'unexposed' patients. They had higher costs concerning inpatient admission, medication and consultations including dermatology consultations, laboratory, non-medical care and transportation. Biological drug prescription was associated with an increase in the use of anti-infective drugs and with a reduction in the use of psychoactive drugs. The mean total health care expenditure in patients treated with biological drugs was five times higher as compared with patients treated with traditional systemic treatments. The limitation of the study is the short duration of follow-up comprising a loading dose period for some biological drugs. This may have contributed to an overestimation of drug-related costs.

Survival rate of antitumour necrosis factor-α treatments for psoriasis in routine dermatological practice: a multicentre observational study

Adherence is an overall marker of treatment success, and it depends on multiple factors including efficacy and safety. Despite the wide use of tumour necrosis factor (TNF)-α blockers in the treatment of plaque-type psoriasis, few data regarding treatment adherence in routine clinical practice are available. To estimate the long-term survival rate of anti-TNF-α therapy in a cohort of patients with psoriasis in routine clinical practice; to evaluate the reasons for and predictors of treatment discontinuation. The Outcome and Survival rate Concerning Anti-TNF Routine treatment (OSCAR) study was based on a retrospective analysis to estimate the long-term survival rate of the first anti-TNF-α treatment in patients with psoriasis, from three Italian academic referral centres. Adult patients (n = 650) with plaque psoriasis treated with a first course of adalimumab, etanercept or infliximab for ≥ 3 months were included. Global adherence to anti-TNF-α treatments after 28·9 ± 15·4 months (867 ± 462 days) of observation was 72·6%. Etanercept showed a longer survival (mean 51·4 months, 1565 days; P < 0·001) compared with infliximab (36·8 months, 1120 days) and adalimumab (34·7 months, 1056 days). Treatment discontinuation due to primary and secondary inefficacy was observed in 5·2% and 14·5% of patients, respectively, whereas discontinuation due to adverse events was reported in 29 subjects (4·5%). Independent predictors of treatment withdrawal were female gender [hazards ratio (HR) 1·3], treatment with adalimumab or infliximab compared with etanercept (HR 2·7 and 1·7, respectively), and the concomitant use of traditional systemic treatment, as a rescue therapy, compared with monotherapy (HR 1·9). Overall survival of anti-TNF-α agents in psoriasis is elevated, with drug discontinuation mostly due to inefficacy. Etanercept showed a longer adherence compared with adalimumab and infliximab.

Etanercept for the treatment of psoriasis

Etanercept is a systemic tumor necrosis factor-α inhibitor indicated for use in the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. A considerable number of studies have demonstrated the efficacy and safety of etanercept in these indications, thus offering a new and promising treatment option. The drug was approved by the Food and Drug Administration in the United States and by the European Medicines Evaluation Agency in Europe for treating moderate-to-severe psoriasis in 2004. This article reviews the pharmacology, clinical efficacy and safety of etanercept for psoriasis and recent findings since its approval. The number of studies of medium- and long-term efficacy and safety is increasing steadily; these studies support the use of etanercept in a maintenance setting, with an apparently more favorable risk: benefit ratio than traditional systemic treatments.

Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors

Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.

Association between traditional systemic antipsoriatic drugs and tuberculosis risk in patients with psoriasis with or without psoriatic arthritis: Results of a nationwide cohort study from Taiwan

Although the link between tuberculosis (TB) and biologics use is well established, the risk of TB among patients with psoriasis exposed to traditional systemic therapies remains elusive. The aim is to investigate the association between traditional systemic therapies and TB among patients with psoriasis. We conducted a retrospective cohort study on the risk of active TB among patients with psoriasis and psoriatic arthritis, using the National Health Insurance Research Database of Taiwan, 1996 through 2008. Standardized incidence ratios of TB were analyzed in comparison with age- and gender-matched general population. Logistic regression was used in a nested case-control analysis to estimate the odds ratios of TB related to exposure to traditional systemic agents during the year before TB development. Among the 81,266 patients in the psoriasis cohort, 497 new active TB cases were identified. The incidence rate of TB was 102 cases per 100,000 person-years among patients with psoriasis (standardized incidence ratio 1.22, 95% confidence interval 1.18-1.33). The risk of TB was higher in patients with severe disease (standardized incidence ratio 1.52, 95% confidence interval 1.46-1.74). To facilitate comparisons with the 497 active TB cases, a total of 1988 matched control subjects were selected for a nested case-control study. Patients taking systemic corticosteroids and nonsteroidal anti-inflammatory drugs were associated with higher incidence of TB, especially frequent users, after adjustment for multiple TB risk factors, drug exposures, hospital visits, and level of urbanization. Stratified analyses of current users and new users of these drugs revealed similar results. Finally, traditional systemic antipsoriatic treatment was not associated with TB on any of the analyses. The National Health Insurance Research Database did not contain information regarding severity of psoriasis, smoking status, alcohol use, diet, laboratory parameters, chest radiograph, or history of recent contact with an individual with TB. Misclassification of disease cannot be ruled out in a registry-based database. The accessibility of health care may be associated with the level of urbanization, which could confound the effect of drugs in multivariate analyses. Severe psoriasis may be associated with an elevated TB risk. Traditional systemic therapies do not seem to be strongly associated with TB occurrence.

Treatment of severe nail psoriasis with acitretin: an impressive therapeutic result

Nail psoriasis is common in adult psoriatic patients. Although several new drugs have recently been introduced for the treatment of skin psoriasis, treatment of nail psoriasis still remains a challenge. Topical treatments (e.g., corticosteroids, tazarotene, 5-fluorouracil, calcipotriol) are the first line in the management of skin psoriasis. The efficacy of these drugs in nail disease, however, is limited, mainly due to the difficulty in penetrating the nail bed and nail matrix. In cases of nail disease resistant to topical treatment, methotrexate, ciclosporin, acitretin, or biological agents can be used. The present authors introduce a 73-year-old patient affected by impressive psoriatic nail disease involving all her fingernails and toenails treated by acitretin, a traditional systemic treatment. After 2 months of treatment there was a marked improvement. The clinical improvement of the nails was progressive and 6 months later it was stable and satisfactory. The remarkable response to treatment in this case suggests that oral acitretin, in association to urea nail lacquer, might be useful in the management of disabling severe nail psoriasis even in absence of severe cutaneous involvement.