Enhanced CCR9 expression levels in psoriatic skin are associated with poor clinical outcome to infliximab treatment

Infliximab is an anti‐tumor necrosis factor (TNF)‐α antibody drug that suppresses TNF‐α and its associated inflammatory responses. Although infliximab therapy generally results in a 75% or greater improvement in the Psoriasis Area and Severity Index from baseline in psoriasis patients, there is the heterogeneity of therapeutic efficacy in psoriasis patients among patients of a similar PASI baseline score. However, there are few published reports about the predictors of the clinical response among psoriasis patients who undergo biologic therapies. We thus evaluated the possible existence of biologic markers that would indicate poor prognosis of infliximab using skin biopsy specimens. This was because we assumed that the inhibitors for upregulated chemokine/chemokine receptors in non‐responders may have the ability to reduce the occurrence of psoriatic eruptions. PCR array analyses identified that the levels of various chemokines and chemokine receptors were increased in non‐responders in comparison to responders. Immunohistochemical analyses revealed that upregulation of the CCR9 protein levels was not associated with the pretherapeutic PASI score, but with poor response to infliximab. Our results indicated that the expression levels of CCR9 in lesional skin may be a useful biologic marker of the clinical efficacy of infliximab therapy in psoriasis patients.     

Safety profiles and efficacy of infliximab therapy in Japanese patients with plaque psoriasis with or without psoriatic arthritis,pustular psoriasis or psoriatic erythroderma: Results from the prospective post‐marketing surveillance

A large‐scale prospective post‐marketing surveillance was conducted to evaluate the safety and efficacy of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. This study was conducted in all psoriasis patients treated with infliximab after its Japanese regulatory approval. Infliximab was administrated at 5 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter. Patients were serially enrolled and observed for 6 months to evaluate the safety and efficacy. The safety and efficacy were evaluated in 764 and 746 patients, respectively. Incidences of any and serious adverse drug reactions were 22.51% and 6.94%, respectively, and those of any and serious infusion reactions were 6.15% and 1.31%, respectively, which were comparable with the results in the post‐marketing surveillance with 5000 rheumatoid arthritis patients in Japan. Major adverse drug reactions during the follow‐up period were infections (5.10%) including pneumonia, cellulitis and herpes zoster, however, no tuberculosis was observed. The safety profiles were equivalent, regardless of the psoriasis types. No new safety problems were identified. The response rates on global improvement and median improvement rate of Psoriasis Area and Severity Index in all patients were 88.0% and 85.0%, respectively. Of note, the efficacy was equivalent for each psoriasis type as well as for each body region. Infliximab was also effective in pustular psoriasis symptoms, joint symptoms and nail psoriasis, as well as improvement of quality of life. Infliximab was confirmed to be highly effective and well tolerated in treating refractory psoriasis, including pustular psoriasis and psoriatic erythroderma.     

Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma

The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.     

Anti‐hapten antibodies in response to skin sensitization

Whereas T lymphocyte (T cell) activation is the key event in the acquisition of skin sensitization and subsequent elicitation of allergic contact dermatitis, the humoral component of immune responses to organic contact allergens has received little consideration. There is evidence that, in experimental animals, topical exposure to potent contact allergens is associated with B cell activation and proliferation, and hapten‐specific antibody production. However, there is very limited evidence available for anti‐hapten antibody responses being induced following topical exposure of humans to contact allergens. Nevertheless, it is important to appreciate that there are almost no negative studies in which evidence for antibody production as the result of skin sensitization has been sought and not found. That is, there is absence of evidence rather than evidence of absence. Furthermore, exposure to chemical respiratory allergens, in which the skin has been implicated as a potential route of sensitization, results in anti‐hapten antibody responses. It is proposed that skin sensitization to contact allergens will normally be accompanied by antibody production. The phenomenon is worthy of investigation, as anti‐hapten antibodies could potentially influence and/or regulate the induction of skin sensitization. Moreover, such antibodies may provide an informative correlate of the extent to which sensitization has been acquired.     

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.     

Relationship between the efficacy of biologics and clinical plaque psoriasis subtypes in Japanese patients: A single‐center pilot study

Although biologics for plaque psoriasis brought epoch‐making efficacy, not all patients achieve treatment success with all reagents. The aim of this study was to clarify the correlation between clinical plaque psoriasis subtypes, age at onset, and the efficacy of biologics. Clinical records for patients with plaque psoriasis at Fukuoka University Hospital were reviewed retrospectively. The efficacy of biologics was compared using the survival of the first biologics administered in treatment‐naïve patients. The survival of infliximab, adalimumab, and ustekinumab were followed until December 2016. The patients were clinically classified into three subtypes: small, large, or gigantic plaques using the size of the plaques on the back; early onset psoriasis (EOP, onset <40 years); or late‐onset psoriasis (LOP, ≥40 years). Eighty‐seven patients were enrolled. The survival of biologics was significantly better in large plaques compared with small or gigantic plaques (P = 0.0007). In patients treated with tumor necrosis factor (TNF) inhibitors, large plaques had significantly better survival than did the other types (P = 0.0122), while ustekinumab showed good survival in all three subtypes. The survival of biologics was numerically better in EOP than in LOP, but this was not significant. The efficacy of TNF inhibitors was different among clinical subtypes. Psoriatic patients with small plaques may be less responsive to TNF inhibitors. Further studies are needed.     

Perioperative management of tumor necrosis factor‐alpha blocker‐treated psoriatic patients: Case reports and review

Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque‐type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)‐α blocker therapy. Three GPP cases experienced uneventful post‐surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF‐α blockers in all cases were determined following the Japanese guideline.     

Effectiveness of and factors associated with clinical response to methotrexate under daily life conditions in Asian patients with psoriasis: A retrospective cohort study

Given the relative scarcity of data concerning the efficacy of methotrexate under daily life conditions in psoriasis, this study aimed to investigate the effectiveness of methotrexate in Asian psoriatic patients and to identify factors associated with clinical response. This observational retrospective cohort study included adult psoriatic patients who had been treated with or were going to start methotrexate. Psoriasis Area and Severity Index (PASI) scores at baseline and at 3, 6 and 12 months were recorded. At 3 months, patients achieving 50% or more reduction from baseline PASI score were defined as responders. One hundred, 74 and 61 patients were followed for 3, 6 and 12 months, respectively. Mean follow‐up time was 15.3 ± 10.2 months. A reduction in PASI score of at least 75% was achieved in 26%, 32.5% and 45.2% at 3, 6 and 12 months, respectively. At 12 and 24 months, Kaplan–Meier analysis showed 68.7% and 52.1% probability of drug survival, respectively. Male sex, body mass index (BMI) of less than 25 kg/m² and absence of abdominal obesity were factors associated with response to treatment in univariate analysis. Male sex was the only significant factor in multivariate analysis. The effectiveness of methotrexate in clinical practise seemed to be lower than in clinical trials, but effectiveness increased with longer duration of treatment. Problems associated with methotrexate use in clinical practise may be due to medication adherence rather than lack of medication effectiveness. Female sex, abdominal obesity and BMI of 25 kg/m² or more might decrease response to methotrexate.     

Incidence of tuberculosis infection in psoriatic patients on anti‐TNF therapy: report of a case series with 144 patients

Background Worldwide clinical trials and post‐marketing surveillance data have demonstrated an increased incidence of tuberculosis (TB) disease associated with antitumour necrosis factor (anti‐TNF) agents. The majority of these cases are presumed to result from a reactivation of latent disease, while the rate of new infections is unknown. A study was performed to evaluate the incidence of latent tuberculosis infection (LTBI) in psoriatic patients screened for biological therapy in a high‐incidence area, such as Madrid, Spain. Patients and methods One hundred and forty‐four patients with moderate‐to‐severe psoriasis treated with anti‐TNF agents were recruited. All of them were screened for active TB or LTBI before therapy. The screening included a detailed medical study, physical examination, chest X‐ray, tuberculin skin test (TST) with purified protein derivative and re‐TST. Results A total of 42 (29%) patients were diagnosed with LTBI based on a positive TST or re‐TST, and/or signs of past TB in the chest X‐ray. All of them received chemoprophylaxis with isoniazide. One patient developed a primary active lymphnode TB. Conclusion This is the first study to underscore the incidence of LTBI in patients with psoriasis treated with anti‐TNF therapy in the Spanish population. We support that the use of TST is still reliable and an effective diagnostic method for the detection of LTBI in anti‐TNF therapy.     

Neutrophil/platelet to lymphocyte ratio in monitoring of response to TNF‐α inhibitors in psoriatic patients

Neutrophil or platelet to lymphocyte ratio (NLR and PLR) has been proposed to be used as prognostic purposes in a variety of diseases. The aim of this study was to evaluate the usefulness of these ratios in monitoring of response to TNF‐α‐inhibitors in psoriatic patients. Eighty psoriatic patients were included and treated with TNF‐α‐inhibitors for 12 months based on drug protocol. Hematologic indices, including NLR and PLR values were assessed before and after treatment. Data on psoriasis area and severity index (PASI), smoking behavior, alcohol intake habit, nail abnormality, body mass index (BMI), joint involvement, and disease duration were also recorded. PASI scores were improved significantly after one‐year treatment (P = .000). Furthermore, this type of treatment significantly reduced the NLR and PLR (P = .000). These changes were in accordance with PASI scores. Patients with BMI greater than 24.9 had higher, but non‐significant NLR and PLR than normal or lean individuals. Cigarette smokers and alcohol consumers had lower NLR and PLR values than other individuals (P < .05). There was no significant association between NLR and PLR and joint or nail involvement. Although NLR and PLR will not be helpful in primary diagnosis of inflammatory diseases, they could be accounted as monitoring tools in management of psoriasis or globally indicators of inflammation.     

Evaluation of risk factors for body weight increment in psoriatic patients on infliximab: a multicentre,cross‐sectional study

Background A significant weight gain has been reported in patients with psoriasis treated with anti‐tumour necrosis factor‐alpha agents. Among these patients, there are contradictory results about risk factors for weight gain. Objective Assessing risk factors for weight increment in psoriatic patients on infliximab (IFX). Methods This study was a 4‐month, non‐interventional, cross‐sectional, multicentre study on adults with psoriasis performed in 19 French dermatological centres. All the patients who received IFX for at least 1 year were prospectively included, with retrospective analysis of data. Impact of sex, age, severity of the disease, cardiovascular and metabolic comorbidities, and previous and simultaneous systemic treatments on weight changes, was analysed. Weight gain was defined as an increment of more than 2% of baseline weight. Results Overall, 191 psoriatic patients (males: 68.6%; mean age: 46.9 years) were included. Mean weight gain was 1.6 kg (2.1%) after 1 year of IFX. Half (48.2%) suffered from a weight gain, and 9.9% from a weight increment of 10% or more. Baseline weight and Body Mass Index, and cardiovascular and metabolic comorbidities did not influence weight. Men (P = 0.007) and patients with severe psoriasis (BSA, P = 0.005) had a tendency to put on weight. Patients with a hospital dietary follow‐up (P = 0.01; OR = 0.36 [0.16–0.79]) and patients on methotrexate (P = 0.03; OR = 0.41 [0.18–0.93]) during IFX treatment are thinner, in a multivariate analysis. Conclusion Severe weight increment is frequent on IFX treatment, mainly in men, and patients with severe psoriasis. Dietary follow‐up or simultaneous use of methotrexate could limit this weight increment.     

Familial Blau syndrome without uveitis caused by a novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene with good response to infliximab

The proband in this study was a 4‐year‐old Mexican girl with Blau syndrome. She and her affected family members had skin rash and arthritis but no uveitis. Exome sequencing and DNA direct sequencing from blood samples revealed a novel nucleotide‐binding oligomerization domain‐containing protein 2 gene mutation in the affected family members. This study is the first report of a Mexican family with Blau syndrome showing good infliximab treatment response. The novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene (c.1808A>G) enriches the mutation spectrum in Blau syndrome. This family represents one of the few cases of autosomal Blau syndrome with no uveitis; because of phenotype variability, it is important to recognize Blau syndrome's clinical spectrum and recommend genetic consultation.     

A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity

BACKGROUND: Infliximab, an antitumour necrosis factor-alpha chimeric monoclonal antibody, is effective for the treatment of severe psoriasis. While the induction of antinuclear antibodies (ANA) and antidouble-stranded-DNA antibodies (anti-dsDNA-ab) is frequently observed in patients with rheumatoid arthritis and Crohn disease receiving infliximab, the incidence of induced biological and clinical autoimmunity remains unknown in the context of psoriasis. OBJECTIVES: To investigate biological and clinical signs of autoimmunity in 28 patients receiving infliximab for severe, recalcitrant forms of psoriasis, and the clinical response to treatment. METHODS: Twenty-eight patients, 15 men and 13 women (median age 39.4 years) with psoriasis refractory to three or more systemic treatments were included. Twenty presented with plaque-type psoriasis [median Psoriasis Area and Severity Index (PASI) score 25.9; range 7.2-48], five with psoriatic erythroderma (median PASI score 54; range 48-72) and three with generalized pustular psoriasis (GPP). Psoriatic arthritis was present in 13 patients (46.4%). Infliximab 5 mg kg(-1) was given at week (W) 0, W2, W6 and every 8 weeks thereafter. Clinical data were assessed at baseline and before each infusion. Detection of ANA and of IgM and IgG anti-dsDNA-ab were performed at baseline and at W22 by immunofluorescence and enzyme-linked immunosorbent assay, respectively. RESULTS: The mean number of infliximab infusions was 5.5 (range 2-15). Among patients with plaque-type and erythrodermic psoriasis, 17 of 25 (68%) and three of five reached a PASI improvement of 75% or more, respectively, while rapid improvement of clinical and biological signs was observed in all three patients with GPP. The prevalence of positive detection of ANA raised from 12% at baseline to 72% at W22 (P = 0.0001), an increase which was also observed for IgM anti-dsDNA-ab (68% vs. 0%, P < 0.0001), while no significant change was observed for the IgG isotype (16% vs. 0%, P = 0.125). Three patients developed nonerosive polyarthritis, without any other criteria for systemic lupus. CONCLUSIONS: The incidence of biological autoimmunity is high in patients with refractory psoriasis receiving infliximab. The concomitant onset of polyarthritis in three cases raises the need to investigate the incidence of autoimmune manifestations in psoriatic patients receiving infliximab in further large-scale studies.