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.     

Clinical predictors of nonresponse to anti‐TNF‐α agents in psoriatic patients: A retrospective study

Although the heterogeneity of the therapeutic response to TNF‐α blockers seems to be mainly due to genetic factors, several studies showed that a range of factors may influence it. The aim of our study was to investigate the impact of patients' demographic and clinical characteristics on primary response to an anti‐TNF‐α therapy in psoriatic patients. We retrospectively examined the relationship between various clinical and demographic features and response to treatment with etanercept, adalimumab, and infliximab, evaluated as PASI75 and average PASI improvement at weeks 12, 16, and 14, respectively. We analyzed data obtained from 199 patients. A better response to the treatment was significantly associated with male gender (OR = 2.59), coexistence of psoriatic arthritis (OR = 1.97), and PASI ≤15 at baseline (OR = 0.91). The present study supports that some clinical factors may be potential predictors of response to anti‐TNF‐α agents in psoriatic patients.     

Tropisetron via α7 nicotinic acetylcholine receptor suppresses tumor necrosis factor‐α‐mediated cell responses of human keratinocytes

Tropisetron is a serotonin receptor (5‐HT‐R)‐modulating agent and approved as an antiemetic for patients undergoing chemotherapy. In the gut, it acts via specific serotonin receptors, 5‐HT₃‐R, to elicit its beneficial effects against nausea. We investigated whether tropisetron can affect inflammatory cell responses of human primary epidermal keratinocytes (NHK) which are key cells in the regulation of skin homoeostasis. Tropisetron significantly and dose‐dependently suppressed tumor necrosis factor (TNF)‐α‐mediated mRNA expression and protein secretion of interleukin (IL)‐6 and IL‐8 in these cells. This effect of tropisetron was independent of p65/NF‐κB as shown by various NF‐κB signal transduction read‐outs. Importantly, the anti‐inflammatory tropisetron effect on NHK was neither mediated by 5‐HT₃‐R nor 5‐HT₄‐R since these receptors were absent in NHK. In contrast, NHK expressed α7 nicotinic acetylcholine receptors (α7nAchR) which previously were found to bind tropisetron. The α7nAchR antagonist α‐bungarotoxin neutralized, whereas AR‐R17779, a specific α7nAchR agonist, mimicked the suppressive effect of tropisetron on TNF‐α‐mediated IL‐6 and IL‐8 expression in NHK. Our findings suggest that tropisetron and probably other α7nAchR‐activating agents could be useful for the future therapy of inflammatory skin diseases.     

Impact of anti‐tumor necrosis factor‐α agents on serum levels of KL‐6 and surfactant protein‐D in patients with psoriasis

We longitudinally examined the influence of anti‐tumor necrosis factor (TNF)‐α treatment on serum levels of KL‐6 and surfactant protein‐D (SP‐D). The study group comprised 22 patients with psoriasis treated with infliximab or adalimumab and with no history of interstitial lung disease (ILD). KL‐6 and SP‐D levels were measured in serum samples. Twelve of the 22 patients (55%) showed at least a 20% increase in KL‐6 levels compared with baseline. Of these 12 patients, none exhibited any signs of ILD on chest computed tomography and nine who showed an increase in KL‐6 levels (75%) showed at least a 20% increase in SP‐D levels. Some patients showed simultaneous increases in KL‐6 and SP‐D levels after treatment with anti‐TNF‐α agents. Although these patients may have undetectable or subtle alveolar damage, careful observation is needed.     

Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti‐tumour necrosis factor agents: subanalysis of BELIEVE

Background Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti‐TNFs) is likely to improve psoriasis in patients with prior anti‐TNF treatment. Objective The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti‐TNF treatment. Methods The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16‐week, double‐blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1–15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti‐TNFs. Results Of 730 patients enrolled, 282 (38.6%) had prior anti‐TNFs and 448 (61.4%) were anti‐TNF‐naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti‐TNFs achieved PASI 75 at week 16, compared with 71.7% of anti‐TNF‐naïve patients (P = 0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti‐TNF agent had been used, the number of prior anti‐TNFs tried, or reasons for discontinuation of prior anti‐TNF therapy. Adverse event incidences were similar between patients with and without prior anti‐TNF therapy. Conclusion Adalimumab was effective and well‐tolerated in patients with psoriasis previously treated with anti‐TNF therapy.     

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.     

TNFα‐ and IL‐17A‐mediated S100A8 expression is regulated by p38 MAPK

The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non‐lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real‐time RT‐PCR analysis, we demonstrated that stimulation with TNFα and IL‐17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL‐17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα‐ and IL‐17A‐mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK‐dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα‐ and IL‐17A‐induced expression of S100A8 in cultured human keratinocytes.     

Combination therapy of cyclosporine and anti‐tumor necrosis factor α in psoriasis: a case series of 10 patients

Combination therapy has become important in treating psoriasis, using synergism between different mechanisms to maximize efficacy and minimize toxicity. Little has been published on the combination of cyclosporine and anti‐tumor necrosis factor (TNF) α agents. In this study, a retrospective chart review was made of the effects of this combination therapy in 10 patients with recalcitrant psoriasis. Treatment included a conditioning phase with cyclosporine, 3.14 ± 0.37 mg/kg for 4.6 ± 2 weeks, and a combination phase during which etanercept/adalimumab were initiated and cyclosporine was tapered over 10.2 ± 3.7 weeks. Treatment success, evaluated after each phase, was classified as complete recovery (CR, more than 75% improvement), partial response (PR, 25–75% improvement), and no response (NR, less than 25% improvement). All patients reached CR at the end of the combination therapy. Two were still on combination therapy after 12 and 20 weeks. Adverse event occurred in three cases, all in the conditioning phase. We conclude that combination therapy with cyclosporine and anti‐TNF α appears to offer an effective and safe approach to treatment of psoriasis.     

Influence of tumour necrosis factor‐α polymorphism −308 and atopy on irritant contact dermatitis in healthcare workers*

Background. Chronic irritant hand dermatitis is an issue for healthcare workers and may negatively impact infection control. Objectives. We examined the effects of a G to A transition at position ?308 on the tumour necrosis factor‐α (TNF‐α) gene on chronically damaged skin of healthcare workers during exposure and recovery from repetitive hand hygiene, after intensive treatment, and on the irritant response in normal skin. Patients/Materials/Methods. In 68 healthcare workers with irritant hand dermatitis, we genotyped TNF‐α?308 and measured the epidermal response via quantitative digital imaging, erythema, dryness, and barrier integrity. Results. Excess hand erythema decreased with hand hygiene exposure and increased during time off for AA/GA genotypes, but had opposite effects for GG. AA/GA had smaller reductions in dryness with lotion treatment and larger reductions in excess erythema than GG. The atopic diathesis and heightened neurosensory irritation resulting from water and lactic acid significantly influenced the responses. Repeated exposure to water and sodium lauryl sulfate (0.05, 0.1%) produced higher erythema in normal skin for AA/GA than for GG. Conclusions. This study provides evidence that the TNF‐α polymorphism at ?308 and an atopic history impact the severity of irritation and recovery from exposure and response to treatment for common hand skin products in both chronic irritant hand dermatitis and normal skin.     

Pneumocystis jirovecii pneumonia in a patient with pustular psoriasis with an IL‐36RN deficiency treated with infliximab: Case report and review of the literature

Pneumocystis jirovecii pneumonia (PCP) is a relatively rare complication in non‐HIV patients receiving immunosuppressive treatment. Since the introduction of tumour necrosis factor‐α inhibitors cases of this complication have increased. We report the case of a 54‐year‐old, HIV‐negative patient, who presented to our department with a long history of pustular psoriasis with poor response to traditional treatments. During the last admission he developed a severe flare that was unresponsive to cyclosporine, therefore infliximab was initiated. After the third dose he developed PCP that required admission to the intensive care unit, with a positive response to i.v. administration of trimethoprim/sulfamethoxazole. During follow up a mutation in the IL36RN gene compatible with an IL‐36RN deficiency was found and anakinra was started, with rapid improvement of his psoriasis. PCP is a severe complication in patients receiving immunosuppressive therapy and is probably underreported by dermatologists. There are no clinical guidelines for PCP prophylaxis in dermatological patients who will receive immunosuppressive or biological treatments. We believe that it is necessary to report the cases of PCP to assess the real impact of this complication and develop appropriate prophylaxis guidelines.     

Treatment of nail psoriasis with adalimumab: an open label unblinded study

Background Despite numerous advances in the therapeutic management of cutaneous psoriasis, there is a lack of standardized therapeutic regimens for psoriatic nail disease. Objective An open, non‐randomized, unblinded study was designed to evaluate the efficacy and safety of adalimumab in the treatment of nail psoriasis. Patients/methods Seven patients suffering from severe plaque‐type psoriasis and 14 with psoriatic arthritis and cutaneous psoriasis with concomitant nail involvement were enrolled into the study. The applied dose regimen of adalimumab was the same as the one recommended for cutaneous psoriasis. Outcome measures were assessed at baseline and at weeks 12 and 24 using the Nail Psoriasis Severity Index (NAPSI). Patients also filled in a Greek translation of the international onychomycosis‐specific questionnaire to assess the impact of the nail improvement on their quality of life. Results All 21 patients completed the study and were eligible for statistical analysis. Significant improvement was recorded after the eighth injection. Mean NAPSI (NAPSIm) at baseline was 10.57 ± 1.21 for the fingernails and 14.57 ± 2.50 for the toenails in patients with just cutaneous psoriasis and 23.86 ± 2.00 for the fingernails and 29.29 ± 2.87 for the toenails in patients with psoriatic arthritis. NAPSIm at week 12 was 5.57 ± 0.78 for the fingernails and 9.57 ± 2.17 for the toenails in patients with just cutaneous psoriasis and 12.86 ± 1.05 for the fingernails and 19.21 ± 2.07 for the toenails in patients with psoriatic arthritis. NAPSIm after 24 weeks of treatment was 1.57 ± 0.20 for the fingernails and 4.14 ± 1.58 for the toenails in patients with cutaneous psoriasis and 3.23 ± 0.32 for the figernails and 10.00 ± 1.40 for the toenails in patients with psoriatic arthritis. Treatment was well tolerated with minimal and temporary side‐effects limited to the site of injection. All patients were satisfied, while marked improvement in their quality of life was recorded based on the reduction of the scores obtained from the international quality of life questionnaire. Conclusions Despite the lack of a control group, our results demonstrate a beneficial effect of adalimumab on psoriatic nail disease.     

Alopecia areata im Tiermodell – Neue Einblicke in Pathogenese und Therapie einer T‐Zell‐vermittelten Autoimmunerkrankung

Alopecia areata is a common disease, but for ethical reasons it seems difficult to perform large‐scale studies to elucidate the pathogenesis and to develop new therapeutic approaches in man. It is therefore helpful to develop appropriate animal models. The Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well‐established animal models for alopecia areata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease. In C3H/HeJ mice alopecia areata can be experimentally induced by grafting lesional skin from an affected mouse to a histocompatible recipient which offers the possibility to study the influence of various factors on the development of the disease. Studies on the C3H/HeJ mouse and the DEBR have corroborated the concept that alopecia areata is a T‐cell mediated autoimmune disease and various steps and aspects of the pathogenesis have been elucidated. Based on this knowledge new therapeutic options may be developed such as inhibition of lymphocyte‐homing by an anti‐CD44v10 antibody, or inhibition of costimulation by monoclonal antibodies. Therapeutic studies in the C3H/HeJ mouse and the DEBR suggest that alopecia areata can be treated by topical tacrolimus but treatment in humans may only be successful after development of an improved vehicle that facilitates penetration of tacrolimus down to the hair bulb. Current investigations in mice are designed to elucidate the mechanisms how contact sensitizers act in the treatment of alopecia areata, and this will hopefully lead to the development of more specific approaches based on the beneficial effect of contact sensitizers.     

Human skin melanocyte migration towards stromal cell‐derived factor‐1α demonstrated by optical real‐time cell mobility assay: modulation of their chemotactic ability by α‐melanocyte‐stimulating hormone

To identify potential regulators of normal human melanocyte behaviour, we have developed an in vitro human melanocyte migration assay, using the optically accessible, real‐time cell motility assay device TAXIScan. Coating of the glass surface with an extracellular matrix that served as scaffolding molecule was essential to demonstrate efficient melanocyte migration. Among several chemokines tested, stromal cell‐derived factor (SDF)‐1α/CXCL12 was the most effective driver of human normal skin melanocytes. Incubation of melanocytes with α‐melanocyte‐stimulating hormone (MSH) before the assay specifically enhanced CXCR4 expression and consequently chemotaxis towards SDF‐1α/CXCL12. These results suggest that α‐MSH acts on melanocytes to produce melanin as well as stimulates the cells to migrate to the site where they work through CXCR4 up‐regulation, which is a new dynamic mode of action of α‐MSH on melanocyte physiology.