Body weight increment in patients treated with infliximab for plaque psoriasis

Background Psoriasis is frequently associated with overweight and obesity. Anti‐TNF‐α therapies are effective in the treatment of psoriasis. TNF‐α is highly involved in body weight regulation. Objective Our objective was to evaluate the increase in weight throughout the treatment with infliximab and the association of weight gain with the body mass index (BMI). Methods Thirty‐five patients affected with severe plaque psoriasis receiving infliximab were included. A control group consisted of 16 patients affected with severe plaque psoriasis and treated with cyclosporine, methotrexate, or acitretin. Assessment of PASI score, body weight and BMI were performed at a 1 and 3‐year follow‐up. Results We observed a body weight increment of 2.5 ± 4.4 kg (mean ± SD) (i.e. + 3.6% of baseline) and 0.1 ± 5 kg (i.e. + 1.2%) in patients treated with infliximab and the control group, respectively (P = 0.046), after 1 year of treatment. After 3 years of infliximab administration, weight gain was 4.8 ± 5 kg (n = 16) (i.e. + 6%) (P = 0.005). Moreover, as classified by BMI, normal weight patients experienced a 4 ± 3.7 kg weight gain (i.e. + 6%) whereas overweight and obese patients had gained 1.3 ± 4.8 kg (i.e. + 1.2%) (P = 0.039) after 1 year of anti‐TNF‐α therapy. Percentual changes in body weight were larger in normal weight patients at baseline than in overweight/obese counterparts (P = 0.0149). Conclusion All patients, including normal weight patients, should receive a dietary intervention.     

Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris

Background Adherence to treatment is an indicator of treatment success. Long‐term data on adherence to biologic treatment in psoriasis are lacking. Objectives To compare the tumour necrosis factor (TNF)‐α inhibitors regarding drug survival rate and safety in patients with psoriasis. Methods This study is based on data from the Danish nationwide database DERMBIO covering patients with psoriasis treated with a biologic agent. All patients who received anti‐TNF‐α treatment in academic referral centres were included. Baseline data, adverse events, time on treatment and reason for stopping treatment were recorded. Hazard ratios (HRs) for factors determining drug survival were calculated by logistic regression. Results In total, 882 treatment series with etanercept (n = 311), adalimumab (n = 427) or infliximab (n = 144) were administered to 747 patients. Significant predictors of drug survival were: sex, the anti‐TNF‐α agent and the previous response to an anti‐TNF‐α agent. In the group of anti‐TNF‐α‐naïve patients the longest drug survival was observed for infliximab, followed by adalimumab [HR vs. infliximab 3·70, 95% confidence interval (CI) 1·99–6·89] and etanercept (HR vs. infliximab 3·18, 95% CI 1·72–5·86). The 4‐year drug survival is in the range of 40% for etanercept or adalimumab vs. 70% for infliximab. There was no difference in number of adverse events. Conclusions The overall efficacy of anti‐TNF‐α drugs diminishes with time, as envisaged by the progressive loss of patient adherence to treatment. The major reasons for stopping treatment were loss of efficacy, followed by adverse events. Infliximab had the best patient retention ability, with 70% of patients still being on the drug after 4 years of treatment.     

Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks

Background A substantial portion of patients with psoriasis does not achieve a satisfactory response under antitumour necrosis factor (TNF)‐α biological therapies. Objectives We aimed to evaluate whether etanercept plus narrowband ultraviolet B (NB‐UVB) phototherapy is superior to etanercept monotherapy in the management of psoriasis. Methods In this prospective study, patients with psoriasis were treated with etanercept 25 mg twice weekly. Two marker lesions were selected for determination of the modified Psoriasis Area and Severity Index (M‐PASI). NB‐UVB was administered thrice weekly whereby one marker lesion was covered as nonirradiated control. Skin biopsies for histology and immunohistochemistry were performed in both marker lesions after a 6‐week treatment course. Results After 6 weeks of therapy, the relative M‐PASI reduction (mean ± SD) in etanercept‐treated sites (53·7 ± 36·9%) was significantly lower than the reduction in etanercept plus NB‐UVB‐treated lesions (64 ± 27·8%; P = 0·011). At the end of treatment, histology scores of etanercept‐treated psoriatic plaques were significantly higher than scores of etanercept plus NB‐UVB‐treated sites (4·6 ± 2·7 vs. 3·7 ± 2·4; P = 0·045). Epidermal immunoreactivity for CD1a, CD4 and CD8 was significantly lower in etanercept plus NB‐UVB‐treated lesions when compared with etanercept monotherapy. Conclusions Etanercept combined with NB‐UVB is more effective than etanercept monotherapy at 6 weeks as demonstrated at a clinical, histological and immunohistological level. However, as there is an increased risk for malignancy by treatment with TNF‐α blockers alone or in combination with phototherapy, we recommend to restrict this highly effective combination to short periods of time, for instance to obtain a quicker response, and to avoid long‐term treatment.     

Possible association of hepatitis C virus infection with late‐onset psoriasis: A hospital‐based observational study

Psoriasis is a chronic inflammatory disease mainly involving the skin and joints, mediated by pro‐inflammatory cytokine tumor necrosis factor (TNF)‐α. In hepatitis C, continuous inflammation mediated by TNF‐α leads to liver cirrhosis and diabetes mellitus. Hence, psoriasis and hepatitis C have pathophysiological factors in common. An epidemiological association between the two conditions has been reported, but no detailed research has yet been performed. Frequency of hepatitis C virus (HCV) infection was assessed in 717 patients with psoriasis and 38 057 with all other dermatological diseases who visited Fukuoka University Hospital in 1998–2011. HCV⁺ and HCV^? psoriatic patients were further compared. Frequency of HCV infection was significantly higher in psoriasis (7.5%) than in controls (3.3%) in overall ages. When stratified by age at the first visit, the frequency was significantly higher in patients with psoriasis than in controls aged in their 60s (11.8% vs 6.6%, respectively, P = 0.0215) and 70s (19.5% vs 7.3%, P < 0.0001). HCV⁺ psoriatic patients were significantly older at onset than HCV^? ones (median, 54 vs 39 years), stronger male predominance (male/female ratio, 4.4:1), similar family history of psoriasis, higher association of diabetes mellitus and hypertension, and significantly lower body mass index (22.4 ± 2.73 vs 24.2 ± 4.61), in age‐stratified (≥40 years) analysis. HCV⁺ psoriatic patients were less obese, but still had a higher frequency of diabetes mellitus and hypertension, possibly due to chronic inflammation in the liver and other organs. HCV infection may trigger psoriasis, especially late‐onset psoriasis, possibly via overproduction of TNF‐α, a common mediator of the two conditions.     

Tumour necrosis factor (TNF-α) alpha converting enzyme and soluble TNF-α receptor type 1 in psoriasis patients in relation to the chronic alcohol consumption

Background Tumour necrosis factor alpha converting enzyme (TACE) is a major sheddase of TNF‐α and its receptors, essential for the generation of soluble, mature molecules. The regulation of the TACE activity by ethanol in vitro has been suggested recently. The alcohol abuse is a frequent problem among psoriasis patients. The aim of the study was to analyse the relationship between long‐term alcohol consumption and the concentration of TACE in peripheral blood mononuclear cells (PBMC) and its substrate – soluble TNF‐α receptor type 1 (sTNF‐R1) in plasma in psoriasis patients. Methods The study has been conducted among 44 patients (aged 30–59 years) with early‐onset, plaque‐type psoriasis. Thirty‐eight patients (aged 29–61 years) with other than psoriasis chronic dermatologic disorders were controls. The data on alcohol consumption during previous 10 years were obtained with a structured questionnaire. The severity of the disease was assessed using Psoriasis Area and Severity Index (PASI), and concentrations of TACE in PBMC lysate and sTNF‐R1 in plasma was assessed with a quantitative sandwich enzyme immunoassay technique. Results The TACE concentration correlated to that of sTNF‐R1 (R = 0.52 in psoriasis patients and R = 0.56 in controls, P < 0.05). The concentrations of TACE were 2.62 ± 0.32 ng/mL in patients and 1.29 ± 0.25 ng/mL in controls (P < 0.05), and corresponding sTNF‐R1 concentrations were 2.54 ± 0.27 ng/mL and 1.79 ± 0.14 ng/mL (P < 0.05), respectively. The concentrations of TACE and sTNF‐R1 in patients correlated to the intensity of alcohol consumption (R = 0.56, and R = 0.52, P < 0.05, respectively) and were the highest in excessive drinking psoriasis patients (2.94 ± 0.34  and 2.67 ± 0.13 ng/mL). Conclusion The alcohol abuse may contribute to the increase of TACE expression in PBMC and also to the elevated plasma sTNF‐R1 concentration in psoriasis patients.     

TNF‐alpha‐Antagonisten in der Therapie der Psoriasis – Nutzen und Risiken

Summary: Anti‐TNF‐α agents including etanercept, a fusion protein of the p75 TNF receptor and IgG1 and infliximab, a chimeric human‐mowie monoclonal antibody. They have been approved for the treatment of rheumatoid arthritis and/or Crohn's disease. New understanding of the importance of the inlammatory cytokine TNF‐α in the pathophysiology of psoriasis led to the use in open‐label and randomized studies in patients with psoriasis and psoriatic arthritis. Although larger randomized trials are needed to confirm early results, both anti‐TNF‐α agents, have demonstrated activity in improving the signs and symptoms of psoriatic arthritis and psoriasis. Further investigations will fully elucidate the role of infliximab in these and other dermatological diseases.     

Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)‐α level and the efficacy of TNF‐inhibitor therapy in psoriasis

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)‐α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF‐α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab‐treated patients and 29.6% of adalimumab‐treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody‐positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF‐inhibitor concentration and elevated plasma TNF‐α level.     

Anti‐tumor necrosis factor‐alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6‐month prospective study

The aim of the present study was to determine if the use of the anti‐tumor necrosis factor (TNF)‐α monoclonal antibody adalimumab could improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. This was a prospective study on a series of consecutive patients with moderate to severe psoriasis who completed 6 months of therapy with adalimumab. Patients with history of cardiovascular events, diabetes mellitus, kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Assessment of endothelial function by brachial artery reactivity measuring flow‐mediated endothelial dependent vasodilatation (FMD%), and carotid arterial stiffness by pulse wave velocity (PWV) was performed at the onset of treatment (time 0) and at month 6. Twenty‐nine patients were studied. Anti‐TNF‐α adalimumab therapy yielded a significant improvement of endothelial function. The mean ± standard deviation (SD) FMD% values increased from 6.19 ± 2.44% at the onset of adalimumab to 7.46 ± 2.43% after 6 months of treatment with this biologic agent (P = 0.008). Likewise, following the use of adalimumab, PWV levels decreased from 6.28 ± 1.04 m/s at the onset of adalimumab to 5.69 ± 1.31 m/s at 6 months (P = 0.03). In conclusion, patients with moderate to severe psoriasis exhibit improvement of endothelial function and arterial stiffness following anti‐TNF‐α therapy. These findings are of potential relevance due to increased risk of cardiovascular disease in patients with severe psoriasis.     

Development of MGUS in psoriatic patients: a possible undiagnosed event during anti‐TNF‐α‐treatment

Background Monoclonal gammopathies are haematological conditions characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin that accumulates in the blood. They have already been reported during treatment with a range of drugs but never before during treatment with the anti‐TNF‐α treatments: adalimumab, etanercept and infliximab currently used in the therapy of moderate‐severe psoriasis and psoriatic arthritis. Objective This is a case series describing the development of MGUS in psoriatic patients treated with anti‐TNF‐α. Methods Three hundred patients receiving an anti‐TNF‐α treatment for chronic plaque psoriasis or psoriatic arthritis in a clinical setting in Italy, These patients were screened through serum protein electrophoresis to investigate the possible development of MGUS. Results Eight patients were found to have developed monoclonal gammopathy of undetermined significance. The median treatment duration for the eight patients was 1 year with excessive IgG present in five patients, IgM accumulation in one patient and a double monoclonal component in two patients. Conclusion Our data suggest that there may be an association between anti‐TNF‐α therapy and development of MGUS.     

Genetic prediction of the effectiveness of biologics for psoriasis treatment

Anti‐tumor necrosis factor (TNF)‐α therapy is used for the treatment of psoriasis, with varying outcomes. However, the specific cause of inadequate response or treatment failure remains unknown. The aim of the present study was to identify useful clinical biomarkers for predicting therapeutic responses or to serve as new drug targets for refractory psoriasis cases. We performed a genome‐wide association study (GWAS) of 65 psoriasis patients who were prospectively followed after beginning anti‐TNF‐α therapy using Human Omni Express‐8 v1.2 Beadchips. Patients were enrolled at the dermatology departments of Kobe University Hospital and six collaborative hospitals. Associations between single nucleotide polymorphisms (SNP) and changes in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment were evaluated. After genome data collection and quality control, a total of 731 442 SNPs were identified in 65 Asian psoriasis patients who were treated with adalimumab or infliximab. Here, we present 10 SNPs, such as those in JAG2 and ADRA2A, that were associated with treatment responses to anti‐TNF‐α agents (strongest effect, P < 7.11E‐06). This is the first GWAS to examine SNP associated with treatment responses in psoriasis patients. In addition, we identified other SNP that exhibited potential associations with anti‐TNF‐α treatment response, which merit further study. Of these, rs11096957 on TLR10, which is associated with increased TNF‐α production, was previously reported to be associated with treatment responses to TNF‐α inhibitors.     

Safety of anti‐tumour necrosis factor‐α agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature

Background Issues concerning the potential risks of reactivating chronic hepatitis B virus arise when the use of anti‐Tumour Necrosis Factor‐α (TNFα) agents is imperative in patients with concurrent psoriasis and hepatitis B virus infection. Objective The aim of this study was to report the experience regarding safety in the management of patients with coexisting psoriasis and chronic hepatitis B with the anti‐TNFα agents: infliximab, etanercept and adalimumab. Methods The psoriasis outpatient database of our dermatological department was searched for psoriasis and hepatitis B diagnoses and the medical records of these patients were reviewed for use of anti‐TNFα agents. Results Seven cases (four women and three men) were identified, with mean age of 51 years (34–65 years). Three patients received adalimumab, three patients were given etanercept and one infliximab. All patients received lamivudin, 100 mg/day, which started 2 weeks before the initiation of anti‐TNFα medication and went on during the whole treatment period. Follow‐up period extended from 6–24 months. All patients were inactive HbsAg (+) carriers. Liver function tests – at baseline and at the end of follow‐up period – were within the normal range. There was no considerable rise in the viral load in any case, from baseline until the last available measurement, although a patient receiving infliximab showed an increase that reached 600 IU/mL. Conclusion Successful treatment of psoriasis with anti‐TNFα agents in patients who are inactive HBsAg carriers is possible and could be safe under the conditions of concomitant lamivudin administration and intensive monitoring. Larger randomized controlled studies are needed to confirm these findings.     

Effects of anti‐TNF‐α agents on circulating endothelial‐derived and platelet‐derived microparticles in psoriasis

Psoriasis involves TNF‐α secretion leading to release of microparticles into the bloodstream. We investigated the effect of TNF blockers on microparticles levels before and after treatment in patients (twenty treated by anti‐TNF‐α agents and 6 by methotrexate) with severe psoriasis. Plasmatic microparticles were labelled using fluorescent monoclonal antibodies and were analysed using cytometry. Three months later, 70% of patients treated with anti‐TNF‐α agents achieved a reduction in PASI score of at least 75%. The clinical improvement in patients treated with anti‐TNF‐α agents was associated with a significant reduction of the mean number of platelet microparticles (2837/μl vs 1849/μl, P = 0.02) and of endothelial microparticles (64/μl vs 22/μl, P = 0.001). Microparticles are significantly decreased in psoriatic patients successfully treated by anti‐TNF‐α. Microparticles levels as circulating endothelial cells represent signs of endothelial dysfunction and are elevated in psoriasis. Then, TNF blockade may be effective to reduce cardiovascular risk through the reduction of circulating microparticles.     

Use of biological drugs in patients with psoriasis and psoriatic arthritis in Italy: Results from the PSONG survey

This Italian multicenter retrospective study compared the drug survival and efficacy of different anti‐TNF agents in psoriasis (PsO) and psoriatic arthritis (PsA) patients. A database of PsO/PsA patients treated with adalimumab, etanercept, and infliximab from May 2013 to May 2014 was analyzed. PASI 75, 90, and 100 was calculated at each time point to evaluate efficacy. Drug survival rate and probability of maintaining PASI response were evaluated. The impact of dependent variables on probability of PASI 75 loss was evaluated by logistic regression. 1,235 patients were included, 577 with PsO and 658 with PsA. Highest survival rates were observed with adalimumab followed by etanercept and infliximab in PsO and PsA patients. The probability of maintaining PASI response was significantly higher for adalimumab followed by infliximab. For PsO patients, the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 8.1; 95% CI: 4.2–15.6, p < .001) or infliximab (OR: 6.6; 95% CI: 2.6–16.3, p < .001) vs. adalimumab. Likewise, for PsA patients the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 2.3; 95% CI: 1.4–3.8, p = .01) or infliximab (OR: 2.2; 95% CI: 1.1–4.1, p = .018) vs. adalimumab. Adalimumab could be the best therapeutic option over other anti‐TNF agents for the treatment of PsO and PsA patients.     

Ustekinumab does not increase body mass index in patients with chronic plaque psoriasis: a prospective cohort study

Background Chronic plaque psoriasis is frequently associated with metabolic disorders including obesity. Antitumour necrosis factor α treatments can induce body‐weight increase in patients with psoriasis. Information on the effect of ustekinumab on body weight is not available. Objectives To investigate whether therapy with ustekinumab is associated with changes in body mass index (BMI) in patients with chronic plaque psoriasis. Methods A prospective, multicentre study comparing the changes in BMI in two closed cohorts of patients with psoriasis during 7‐month treatment with ustekinumab (n = 79) or infliximab (n = 83). Results Patients treated for 7 months with infliximab showed a significant (P < 0·001) increase in mean BMI (2·1 ± 4·5%) and body weight (2·5 ± 3·3 kg) compared with patients treated with ustekinumab (0·1 ± 3·3%; 0·6 ± 1·1 kg). Some 45% of patients treated with infliximab had a BMI increase > 2%, compared with only 11% of those receiving ustekinumab (P = 0·01). In the multivariate analysis, all other clinical parameters predicted the BMI increase, except for the use of infliximab. At month 7, 96% of patients treated with infliximab and 82% of patients treated with ustekinumab achieved at least a 50% improvement from their baseline psoriasis area and severity index (PASI 50), and 69% of the infliximab group compared with 58% of the ustekinumab group achieved at least PASI 75. There was no difference in the proportion of PASI 50 and PASI 75 responders between the two groups. Conclusions In contrast to infliximab, ustekinumab does not increase BMI in patients with chronic plaque psoriasis. This difference could be taken into account in the selection of biologics when treating patients with psoriasis.     

Responses to ustekinumab in the anti‐TNF agent‐naïve vs. anti‐TNF agent‐exposed patients with psoriasis vulgaris

Background Approximately 20–30% of patients with psoriasis treated with anti‐tumour necrosis factor α (TNFα) agents will discontinue treatment within 2 years due to loss of efficacy or side‐effects. Switching to another anti‐TNFα agent produces clinical responses inferior to previously untreated patients. Ustekinumab binds to the p40 subunit of interleukin (IL)‐12 and IL‐23 and provides a mechanism of action independent of TNFα. Objective To investigate the efficacy of ustekinumab in a clinical practice setting and to compare treatment responses to ustekinumab in patients previously treated with TNFα inhibitors and anti‐TNFα‐naïve patients. Methods Patients receiving either ustekinumab (n = 71) or the subcutaneous TNFα inhibitors adalimumab or etanercept (n = 108) were identified through the registry of psoriasis patients in our Institutions. Efficacy effect outcome was a 75% improvement in the psoriasis area severity index (PASI75). Kaplan–Meier statistics evaluated the adherence to the treatments expressed as drug survival rate. Results PASI75 was achieved in 80% of the ustekinumab‐treated patients after a median time of 112 days. There was no difference in efficacy in anti‐TNFα‐naïve patients compared with anti‐TNFα unresponsive patients. Patients treated with ustekinumab showed a superior adherence to treatment in comparison with adalimumab and etanercept. Limitations Patients were non‐randomly assigned to treatment, which potentially may lead to biases. Observation time was short (1 year). Conclusion In clinical practice, the short‐term efficacy and patient adherence to ustekinumab are excellent and comparable to the data obtained in clinical trials. Lack of response to previous anti‐TNF treatment does not impair clinical response to ustekinumab.     

Combination of adalimumab with traditional systemic antipsoriatic drugs – a report of 39 cases

Background: Monotherapy with TNF‐α inhibitors does not always produce a sufficient response in psoriasis patients. Combinations of TNF‐α antagonists such as adalimumab with systemic antipsoriatic therapies such as methotrexate are not approved for use in psoriasis, and the published data are scarce. Patients and methods: The charts of 39 psoriasis patients from 6 dermatology departments were reviewed retrospectively. All patients were given adalimumbab with another systemic antipsoriatic drug. Results: Combination therapy with methotrexate was most common (n = 32), followed by acitretin (n = 4) and cyclosporine (n = 3). Combination therapy with methotrexate lasted 10.8 ± 11.2 months (mean), with cyclosporine for 6.8 ± 3.3 months, and with acitretin 12.9 ± 12.4 months. Combinations were effective in the majority of patients: 30/39 (76.9 %) had a good (n = 9) or excellent (n = 21) response. Two patients had a moderate response and 7 patients had a poor response and were switched to another treatment. Overall, safety was very good. Eighteen patients experienced 24 adverse events; none was severe and/or required hospitalization. Of these, 10/24 adverse events were infections, most often infections of the upper respiratory tract (n = 5), bronchitis (n = 2), and influenza (n = 1). Conclusions: Combinations of adalimumab with traditional systemic antipsoriatic treatments offer a promising method for managing severe or recalcitrant psoriasis. More data are needed to determine the long‐term safety and efficacy of these combinations.     

Elevation of serum KL‐6 in patients with psoriasis treated with anti‐tumour necrosis factor‐α therapy

We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)‐6 increased during therapy with anti‐tumour necrosis factor (TNF)‐α. A diagnosis of early‐phase or subclinical interstitial pneumonia was made in two patients, and their KL‐6 level decreased after anti‐TNF‐α discontinuation. The rise in KL‐6 in the other patient was attributed to methotrexate. We propose that serum KL‐6 should be monitored routinely in patients treated with anti‐TNF agents.     

Reduction of inflammatory slan (6‐sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept

Dermal dendritic cells (DCs) play a central role in the immunopathology of psoriasis. We previously identified slanDCs as pro‐inflammatory TNF‐α, IL‐23‐ and IL‐12‐producing DCs in human blood and as prominent inflammatory dermal TNF‐α secreting and CD11c‐positive DC subset in psoriasis. Here, we ask for the effects of TNF‐α‐inhibition on inflammatory slanDCs in skin and blood of 10 patients with psoriasis during 24 weeks of treatment with etanercept. Treatment with etanercept reduced the frequency of dermal slanDCs but did not induce apoptosis as determined by lack of increased active caspase‐3‐expression. In parallel, we found increased frequencies of slanDCs in blood which expressed lower levels of HLA‐DR. Stimulating slanDCs isolated from the blood of healthy donors in vitro induced a strong production of IL‐1β, IL‐6, IL‐23 and IL‐12p70. This capacity was efficiently reduced in the presence of etanercept, thereby indicating that TNF‐α is an autocrine stimulus for maturation and pro‐inflammatory cytokine production of slanDCs. In vivo, we noticed that treatment with etanercept did reduce the number of dermal slanDCs in parallel to the overall expression of TNF‐α and IL‐23p19. However, successful treatment did not down‐regulated the percentage of dermal slanDCs that stained positive for TNF‐α and IL‐23p19 indicating that remaining slanDCs kept their pro‐inflammatory capacity. This study provides novel insights into the immune regulatory properties of etanercept at the level of inflammatory slanDCs in vivo in skin and blood as well as in vitro.     

Antinuclear antibodies associate with loss of response to antitumour necrosis factor‐α therapy in psoriasis: a retrospective,observational study

Background An increasing number of patients with severe psoriasis are failing to respond to antitumour necrosis factor (TNF)‐α therapy (etanercept, infliximab and adalimumab). Objectives We observed that many of these patients developed antinuclear antibodies (ANA) and antidouble‐stranded DNA (anti‐dsDNA) antibodies while on treatment prompting us to investigate whether their development is associated with anti‐TNF treatment failure. Methods All patients with psoriasis who had received anti‐TNF therapies were identified and their blood results and treatment histories were obtained from electronic patient records and case notes. Results A total of 97 patients had been treated with anti‐TNF agents (60 were on their first agent, 22 had been on and stopped one agent, nine had been on and stopped two agents and six had been on and stopped all three agents). ANA developed in 17% of patients on their first treatment, 54% of patients who had failed one treatment, 78% of patients who had failed two treatments and 83% of patients who had failed all three treatments. Anti‐dsDNA antibodies developed in 2%, 27%, 33% and 83% of patients from the same respective groups. Significantly, the antibodies developed before treatment had failed with all three agents and their development was not related to the total time that patients had been on anti‐TNF therapy. Conclusions This study suggests that the development of ANA and anti‐dsDNA antibodies on anti‐TNF treatment may act as a marker of forthcoming treatment failure. Large‐scale prospective studies are required to assess the importance of this observation.     

Benefit‐risk assessment of tumour necrosis factor antagonists in the treatment of psoriasis

Background Safety of tumour necrosis factor (TNF) antagonists is a primary concern for clinicians prescribing them to patients with psoriasis. Objectives To determine the benefit‐risk balance of TNF antagonists in psoriasis. Methods Through integrated analyses of published literature, we calculated the number needed to treat (NNT) for various efficacy measures and the number needed to harm (NNH) for various adverse events for approved dosing regimens of adalimumab, etanercept and infliximab. Integrated analyses that included open‐label safety data from TNF‐antagonist clinical trials were also conducted. Results PASI 75 treatment effect data from the literature result in NNT values of 1·6 (95% confidence interval, CI 1·5–1·7) for adalimumab 40 mg every other week; 3·2 (95% CI 2·8–3·7) for etanercept 50 mg weekly or 25 mg twice weekly, and 2·3 (95% CI 2·1–2·5) for etanercept 50 mg twice weekly; and 1·4 (95% CI 1·3–1·5) for infliximab 5 mg kg^?1 dosing. For serious noninfectious, serious infectious and malignant adverse events, point estimates of the NNHs are generally at least two orders of magnitude larger than the NNTs, and the 95% CIs for the NNHs for adalimumab, etanercept and infliximab overlap. Analyses that included open‐label data corroborated, with increased exposure to study agents, the low risk of adverse events observed in placebo‐controlled periods. Conclusions These analyses demonstrated that, during the initial year of treatment, the likelihood of success with anti‐TNF therapy for psoriasis was several orders of magnitude greater than the likelihood of serious toxicity.