TNF‐α and IL‐10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population

Backround Pemphigus vulgaris is a rare chronic autoimmune disease of skin and mucous membranes, with several cytokines participating in its development. The role of their gene polymorphisms in susceptibility to the disease is, however, not fully understood. Objective The aim of our case‐control study was to investigate whether some of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes (IL‐1α, IL‐1β, IL‐1RI, IL‐1Ra, IL‐4Rα, IL‐12, IFN‐γ, TGF‐β1, TNF‐α, IL‐2, IL‐4, IL‐6 and IL‐10) are associated with pemphigus vulgaris in the Slovak population. Methods DNA samples were obtained from 34 pemphigus vulgaris patients and 140 healthy controls of Slovak origin. Cytokine gene SNPs were determined using the polymerase chain reaction with sequence‐specific primers (PCR‐SSP) method. Results We found a weak association between pemphigus vulgaris and polymorphic variants in TNF‐α and IL‐10 genes only, with haplotypes TNF‐α–308G/–238G and IL‐10 –1082A/–819C/–592C being significantly overrepresented in pemphigus vulgaris patients (TNF‐α GG: 94.12% vs. 82.86%, P = 0.0216; IL‐10 ACC: 44.12% vs. 30.00%, P = 0.0309). Conclusions Our preliminary results suggest that certain TNF‐α and IL‐10 gene polymorphisms might contribute to genetic susceptibility to pemphigus vulgaris; however, their overall impact on disease development will be rather limited.     

Mechanism of pathogenesis of imiquimod‐induced skin inflammation in the mouse: A role for interferon‐alpha in dendritic cell activation by imiquimod

Topical application of imiquimod (IMQ), a Toll‐like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ‐induced psoriasis‐like skin inflammation, T‐helper (Th)17 cells and interleukin (IL)‐17/IL‐22‐producing γδ‐T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis‐like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ‐induced psoriasis‐like skin inflammation in mice. We first confirmed that, together with an increase in IL‐17 and IL‐22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro‐inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7^?/? mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)‐α, IL‐23, IL‐6 and tumor necrosis factor (TNF)‐α. Furthermore, when we analyzed in vitro‐generated bone marrow‐derived DCs with features similar to TNF‐α and inducible nitric oxide synthase (iNOS)‐producing DCs, IL‐23, IL‐6, IL‐1β, TNF‐α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co‐stimulation with IMQ and IFN‐α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN‐α was suggested to be caused by upregulation of TLR7 expression by IFN‐α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis‐like skin inflammation are induced by IMQ and IFN‐α in a mouse model.     

Tumour necrosis factor‐α inhibition can stabilize disease in progressive vitiligo

Tumour necrosis factor (TNF)‐α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro‐ and anti‐inflammatory properties and examine the effects of blocking its actions with TNF‐α antagonist therapeutics in reports available in the literature. We found that TNF‐α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF‐α inhibition has proven useful for patients with progressive vitiligo, where TNF‐α inhibition is able to quash cytotoxic T‐cell‐mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.     

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.     

The levels of adiponectin and leptin and their relation to other markers of cardiovascular risk in patients with psoriasis

Background A link between psoriasis and risk for cardiovascular disease (CVD) is supposed. Adipokines (adiponectin and leptin) playing roles in inflammation as well as lipid metabolism could have impact on CVD. Objectives We investigated links between adiponectin and leptin levels and several inflammation‐ and oxidative stress‐related CVD risk makers in patients with psoriasis. Methods Sixty patients with plaque‐type psoriasis with normal total cholesterol levels belonging to three body mass index (BMI) categories: BMI < 24.9, BMI 25.0–29.9 and BMI ≥ 30.0 kg/m² were studied. Fasting blood samples were analysed for adiponectin, leptin, high‐sensitive C‐reactive protein (hsCRP), interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α), oxidized low density lipoprotein (oxLDL), oxidized LDL/β₂‐glycoprotein complexes (oxLDL‐β₂‐GPI) and standard blood lipid panel. Results In patients, adiponectin was negatively (P < 0.005), and leptin, oxLDL and oxLDL‐β₂‐GPI levels were positively correlated to BMI (P < 0.005, P < 0.05, and P < 0.01, respectively). Patients had higher hsCRP and IL‐6 levels as compared with the endemic reference values. High adiponectin was strongly associated with higher TNF‐α and high density lipoprotein cholesterol (P = 0.001), and lower triglycerides (TG) (P = 0.01) as well as oxLDL‐β₂‐GPI levels (P < 0.05). After multivariate adjustment, the association for TNF‐α and TG remained significant (P < 0.01 for both). Multiple regression analysis also revealed that leptin concentration was significantly associated with hsCRP, oxLDL and TG levels. Conclusion The data suggest that in addition to the strong effect of inflammation and LDL oxidation, adipokine level may be one of the mechanisms behind the close association between psoriasis and CVD. Given the significant relations of several markers with BMI, health consequences of excessive weight should be better communicated to patients with psoriasis.     

Carotid intima‐media thickness and serum proinflammatory cytokine levels in rosacea patients without cardiovascular risk factors

There is a growing body of evidence linking rosacea to various systemic disorders, even though data regarding the association between rosacea and cardiovascular diseases are presently controversial. We sought to investigate the potential association of rosacea with subclinical atherosclerosis and serum proinflammatory/proatherogenic markers. This study included 44 patients with rosacea and 44 age‐matched and sex‐matched healthy control subjects. Patients with traditional cardiovascular risk factors or a history of cardiovascular events were excluded. Demographic, clinical, and laboratory data, including serum interleukin‐1 beta (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and high‐sensitivity C‐reactive protein (hs‐CRP) levels were assessed. Carotid intima‐media thickness (CIMT) and carotid plaques were measured by carotid ultrasonography. Serum IL‐1β (P < .001), IL‐6 (P < .001), TNF‐α (P < .001), and hs‐CRP (P < .001) levels were significantly higher in the patient group compared with the control group. Mean CIMT values did not differ significantly between the patient group and control group (P > .05). Patients with moderate to severe rosacea had a significantly greater CIMT than those with mild rosacea (P = .047). Rosacea patients with eye involvement had a significantly greater CIMT than those without eye involvement (P = .008). There was no significant correlation between CIMT values and inflammation parameters. As conclusion, in the absence of other traditional cardiovascular risk factors, rosacea does not seem to affect mean CIMT value. However, specific subgroups such as patients with moderate to severe disease or with eye involvement are associated with increased subclinical atherosclerosis and may require additional attention for cardiovascular disease prevention.     

Anti–tumour necrosis factor-α therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study

Background Chronic plaque psoriasis is associated with overweight or obesity. Anti–tumour necrosis factor‐α (anti‐TNF‐α) treatments are now frequently used in psoriasis management. TNF‐α is deeply involved in body weight homeostasis, which may be affected by TNF‐α–targeted therapy. Objective To investigate whether anti‐TNF‐α treatments is associated with changes in body weight in patients with chronic plaque psoriasis. Methods We performed a retrospective controlled analysis comparing the variations in body weight and body mass index (BMI) in three closed cohorts of psoriatic patients during a 6‐month treatment with etanercept (N = 58), infliximab (N = 40) or methotrexate (N = 43). Results We observed a body weight increment of 1.5 ± 2.7 kg (mean ± SD; P = 0.0002) and 2.5 ± 3.3 kg (P = 0.004) in patients treated with etanercept and infliximab, respectively. In contrast, a non‐significant change (0.6 ± 1.4 kg; P = 0.4) was measured in patients treated with methotrexate. The BMI increased with 0.5 ± 0.5 (P = 0.01) and 0.8 ± 1 (P = 0.003) points in patients treated with etanercept and infliximab, respectively, whereas it did not change (< 0.2 ± 0.5; P = 0.06) in patients treated with methotrexate. About one fourth of patients experienced a 4‐ to 10‐kg weight gain. Differences in body weight variations among patients treated with anti‐TNF‐α therapies and methotrexate were statistically significant (P = 0.0005). We could not identify clinical parameters predicting this phenomenon. Conclusions Patients with psoriasis treated with long‐term anti‐TNF‐α therapies may manifest a body weight gain. This effect should be taken into account in the global approach to patients with psoriasis.     

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.     

TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behçet's disease

Background Genetic factors that predispose individuals to Behçet's disease (BD) are considered to play an important role in development of the disease. The tumour necrosis factor (TNF)‐α gene, which is closely linked to the HLA‐B51 gene, is involved in susceptibility for BD. Recently, a polymorphism at position ?1031 within the TNF‐α promoter region was demonstrated to be responsible for susceptibility to BD in a British population. However, the functional effects of this polymorphism have not yet been determined. Objectives To investigate the possible relation of the TNF‐α–1031 T/C polymorphism with susceptibility to BD in a Turkish population and to determine the functional importance of this polymorphism. Methods Ninety‐nine unrelated patients (47 women, 52 men; mean ± SD age, 34·10 ± 10·53 years) with BD and 103 ethnically matched healthy controls (52 males, 51 females; mean ± SD age, 40·25 ± 14·15) were enrolled in the study. For genotyping, polymerase chain reaction – restriction fragment length polymorphism (PCR‐RFLP) analysis was employed. The functional importance of TNF‐α–1031 T/C polymorphism was determined with an enzyme‐linked immunospot (ELISPOT) assay. For this purpose, mononuclear cells obtained from BD patients and controls were analysed for TNF‐α and interferon (IFN)‐γ production. Results A significant difference was observed between BD patients and controls with respect to the allele frequency of TNF‐α–1031C [P = 0·018, OR = 1·83, 95% confidence interval (CI) = 1·07–3·13]. When the allele frequencies were analysed according to the clinical features, the T allele in patients with positive skin pathergy test (SPT) was significantly increased when compared with those of patients without these findings (P = 0·004, OR = 2·75, 95% CI = 1·3–5·86). To demonstrate the frequency of TNF‐α and IFN‐γ producing cells, mononuclear cells from four representative individuals of each genotype were used and the spontaneous and stimulated TNF‐α and IFN‐γ values (spot numbers) were analysed. Compared with the control groups, a significant increase was observed in the number of cells producing TNF‐α obtained from BD patients (P < 0·001). Moreover, the stimulation index for TNF‐α [bacterial lipopolysaccharide (LPS) stimulated/unstimulated] was higher for the CC genotype (9 ± 9·5) with respect to the other genotypes (TT; 1·3 ± 0·3 and TC; 1·2 ± 0·2). While the difference in the spontaneous IFN‐γ values between groups were not statistically significant, the stimulated IFN‐γ values were found to be significantly increased in the BD group when compared with the healthy control group (P = 0·004). Conclusions Our results showed that, in the Turkish population the TNF‐α–1031C allele is associated with susceptibility to BD. On the other hand, carrying the T allele may render patients more prone to developing a positive skin pathergy test. In addition, ELISPOT assays revealed that BD patients exhibited a significantly higher number of mononuclear cells producing TNF‐α, and cells obtained from patients with a CC genotype had a stronger response to LPS stimulation. The strong IFN‐γ response upon LPS stimulation in BD patients supports the previous findings that BD is a Th1 driven disease. These findings suggest that the TNF‐α–1031 polymorphism may have a functional effect and could explain the reason for high levels of TNF‐α production observed in BD patients.     

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.     

Does MBL2 codon 54 polymorphism play a role in the pathogenesis of psoriasis?

Background Psoriasis is a T cell‐mediated immune disease in which various cytokines, primarily tumor necrosis factor‐α (TNF‐α), are complexly involved. Mannose‐binding lectin (MBL) gene polymorphisms decrease MBL serum levels, thereby increasing the synthesis of proinflammatory cytokines such as TNF‐α. Objectives This trial was designed to evaluate the role of the MBL2 codon 54 polymorphism in the pathogenesis of psoriasis. Methods Fifty patients diagnosed with psoriasis vulgaris and 53 healthy subjects were included in the trial. The polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) method was applied to determine the MBL2 codon 54 polymorphism. Genotypes were determined according to the bands formed in agarose electrophoresis gels. For the statistical analysis, the level of significance was set at P < 0.05. Results A total of 33 (66.0%) of the 50 psoriasis patients were detected to have A/A genotype and 17 (34.0%) had B/B genotype. Of the control subjects, 44 (83.0%) had A/A genotype and nine (17.0%) had B/B genotype. There was a statistically significant difference between the groups (P = 0.047). The analysis of allele frequencies revealed A allele prevalences to be 79 (79.0%) and 95 (89.6%), and B allele prevalences to be 21 (21.0%) and 11 (10.4%), in the patient and control groups, respectively. A statistically significant difference between allele frequencies was detected (P = 0.031). Conclusions This study suggests that the MBL2 codon 54 polymorphism may have an association with psoriasis in the Turkish population.     

Tumor necrosis factor –238A is associated with pediatric‐onset generalized pustular psoriasis in Han patients in Eastern China

The correlation between polymorphisms at the tumor necrosis factor (TNF) gene and generalized pustular psoriasis (GPP) has rarely been reported. The goal of this study is to investigate whether TNF polymorphisms (?238 A/G, ?308 A/G, ?857C/T) are associated with susceptibility to GPP in a Han population from Eastern China and to perform subgroup analysis to explore the influence of age onset. Polymorphisms were assessed by polymerase chain reaction amplification and resequencing in 91 GPP patients and 102 healthy controls. The frequencies of the TNF ?238A allele and GA+AA genotypes were significantly higher in GPP patients than in those of healthy controls. The subgroup analysis revealed that these significant associations were still present between ?238A variants and pediatric‐onset GPP patients who developed GPP at less than 18 years old (PGPP), but not for patients with adult‐onset GPP who developed GPP at 18 years old or more. There were no significant differences in genotype or allele frequencies of TNF ?308 A/G and ?857C/T polymorphisms between GPP and controls. In conclusion, individuals carrying TNF ?238A may be more susceptible to PGPP.     

Impact of Toll‐like receptor‐4 and tumour necrosis factor gene polymorphisms in patients with hidradenitis suppurativa

Background Recent evidence has suggested that deranged immune responses play a role in the pathogenesis of hidradenitis suppurativa (HS). Objectives To investigate the role of single nucleotide polymorphisms (SNPs) of the tumour necrosis factor (TNF) and Toll‐like receptor 4 (TLR4) genes in the physical course of HS; these genes encode for proteins implicated in the immune response of the host. Methods DNA was isolated from 190 patients with HS and 84 healthy controls. SNPs at the promoter regions ?376G/A, ?238G/A and ?308G/A of the TNF gene and the Asp299Gly and Thr399Ile SNPs of the TLR4 gene were determined by polymerase chain reaction (PCR) and digestion of the PCR product by restriction enzymes; after electrophoresis on 2·0% agarose gel, products were visualized on under ultraviolet radiation. Results The presence of the ?238 TNF gene polymorphism was associated with a predisposition to HS (P = 0·027). Susceptibility to the disease was strongly correlated with the presence of AGG/GGA/AGA/GAA TNF haplotypes in 32 (17%) patients compared with two (2%) controls (P < 0·001, odds ratio 8·30, 95% confidence interval 1·94–35·52). The frequency of HS exacerbations and disease severity were greater in patients carrying any of the GAG/AGG/GGA/AGA/GAA haplotypes of the TNF gene. Thirty‐two patients were given TNF antagonists. Nineteen of these patients were carriers of the GGG haplotype of the TNF gene, whereas 13 were carriers of other haplotypes; favourable responses as evidenced by the Sartorius score were registered in 15 (79%) and five (38%, P = 0·025), respectively. Carriage of the TLR4 gene alleles was not associated with any disease parameter. Conclusions A significant role of SNPs at the promoter region of the TNF gene is indicated for susceptibility to HS and for response to TNF antagonists.     

Beta defensin‐1 gene (DEFB1) polymorphisms are not associated with atopic dermatitis in children and adolescents from northeast Brazil (Recife,Pernambuco)

Background Atopic dermatitis (AD) is a common inflammatory skin disease resulting from the interplay between environmental, immunological and genetic factors. In our study, we investigated the role of three single nucleotide polymorphisms (SNPs) at 5′‐UTR of DEFB1 gene, encoding for the human beta defensin‐1, on the susceptibility to develop AD in a group of Brazilian children and adolescents. Methods Three SNPs, ?20 G/A (rs11362), ?44 C/G (rs1800972), and ?52 G/A (rs1799946) at 5′‐UTR of DEFB1 gene were genotyped in two groups of children and adolescents, one affected by AD (96 subjects), the other healthy (191 individuals), from northeast Brazil. Results ?44 C/G frequencies were comparable between the two groups. The ?20 GG genotype was more frequent in AD subjects than in healthy controls; the ?52 GG, conversely, was more frequent in healthy controls than in AD. However, both these differences did not reach statistical significance. Also, association between SNPs and AD severity has been shown. The analysis of DEFB1 haplotypes did not highlight any association of the three SNPs with AD development or disease severity. Conclusions Our results seem to exclude a role for the ?44 C/G DEFB1 SNPs on the pathogenesis and severity of AD, while for the ?20 C/G and ?52 G/A, even if not statistically significant, we evidenced a slight trend for susceptibility (?20 GG) and protection (?52 GG) for the development of AD. However, as controversial findings have been reported in the literature, the role of DEFB1 in the development of AD and in the severity of the phenotype deserves further investigation.     

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.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.     

Borreliosis mimicking lupus‐like syndrome during infliximab treatment

Tumour necrosis factor (TNF)‐α antagonists are very effective treatments for immune‐mediated inflammatory disorders. Adverse events include severe infections and episodes of lupus‐like syndrome, multiple sclerosis‐like demyelination and other neuropathies. The pathomechanisms of these autoimmune‐like syndromes after TNF‐α blockade are still unknown. We report a patient with psoriasis who developed a lupus‐like syndrome during infliximab treatment, which was finally diagnosed as an exaggerated systemic infection with Borrelia burgdorferi. This case suggests that autoimmune‐like syndromes may actually represent pre‐existing or newly acquired nonseptic bacterial or viral infections, which have escaped immune surveillance during TNF‐α blockade. Each autoimmune‐like syndrome during TNF‐α blockade should therefore be carefully examined for potential causative infection.     

Cytokine gene polymorphisms in bullous pemphigoid in a Chinese population

Background Bullous pemphigoid (BP) is an autoimmune bullous disease mostly associated with autoantibodies to the hemidesmosomal BP autoantigens BP180 and BP230. High levels of interleukin (IL)‐1β, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, IL‐13, tumour necrosis factor (TNF)‐α and interferon (IFN)‐γ have been detected in skin lesions or sera of patients with BP. Cytokine gene polymorphisms may affect cytokine production and contribute to susceptibility to autoimmune diseases. Until now, no cytokine gene polymorphism study has been conducted on patients with BP. Objectives We aimed to determine whether the genetic polymorphisms of the cytokine genes might influence the development of BP. Methods DNA samples were obtained from 96 BP patients and 174 control subjects. Using direct sequencing and microsatellite genotyping, we examined 23 polymorphisms in 11 cytokine genes including the IL‐1α, IL‐1β, IL‐1 receptor antagonist, IL‐4, IL‐6, IL‐8, IL‐10, IL‐13, IL‐4 receptor, TNF‐α and IFN‐γ genes. Results Although the BP patients were more likely to carry the ?511T and ?31C alleles of the IL‐1β gene (P = 0·04), the significance disappeared after correction for multiple testing (P_c). There was complete linkage disequilibrium between the ?511T and ?31C alleles of the IL‐1β gene. In female patients with BP, the associations with IL‐1β (?511T) and (?31C) alleles were much stronger (68% vs. 40·6%, odds ratio = 3·11, P_c = 0·006). No significantly different allelic and genotypic distributions of other cytokine gene polymorphisms could be found between the patients with BP and controls. Moreover, no association with the extent of disease involvement (localized or generalized) was observed. Conclusions The IL‐1β (?511) and (?31) polymorphisms were significantly associated with BP in women. The other genetic polymorphisms of cytokine genes that we analysed do not appear to be associated with BP susceptibility in our Chinese population.     

TNF‐α: a treatment target or cause of sarcoidosis?

Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF‐α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF‐α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF‐α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF‐α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF‐α in granuloma formation, the therapeutic role of TNF‐α inhibition and immunologic abnormalities following treatment with these TNF‐α inhibitors including drug‐specific alterations involving interferon‐γ, lymphotoxin‐α, TNF receptor 2 (TNFR2) and T‐regulatory cells.