Patients with atopic dermatitis with filaggrin loss-of-function mutations show good but lower responses to immunosuppressive treatment

Filaggrin (FLG) mutations are a strong risk factor to develop atopic dermatitis (AD). However, the relationship between FLG mutations and treatment outcome in AD has not been thoroughly studied. To investigate whether FLG mutations influence immunosuppressive treatment outcome in AD, we studied the effect of FLG mutations in patients with severe AD participating in a single blinded randomized controlled trial (RCT) with methotrexate (MTX) or azathioprine (AZA) during a 24 weeks treatment regimen.((1)) Two years after randomization buccal mucosa swabs were collected from 36 of the 42 RCT patients (86%) to determine the FLG genotype status (R501X, 2282del4, R2447X, S3247X and 3321delA mutations). This article is protected by copyright. All rights reserve

Nailfold capillary scleroderma pattern may be associated with disease damage in childhood-onset systemic lupus erythematosus:important lessons from longitudinal follow-up

OBJECTIVES: To observe if capillary patterns in childhood-onset SLE (cSLE) change over time and find associations between a capillary scleroderma pattern with disease activity, damage or scleroderma-like features. METHODS: Clinical and (yearly) capillaroscopy data from a longitudinal cohort of patients with cSLE (minimum of four Systemic Lupus International Collaborating Clinics (SLICC) criteria, onset <18 years) were analysed. Disease activity was measured by Systemic Lupus Erythematosus Activity Index (SLEDAI) and disease damage by SLICC Damage Index. A scleroderma pattern was defined according to the ‘fast track algorithm’ from the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. An abnormal capillary pattern, not matching a scleroderma pattern, was defined as ‘microangiopathy’. RESULTS: Our cohort consisted of 53 patients with cSLE with a median disease onset of 14 years (IQR 12.5–15.5 years), median SLEDAI score at diagnosis was 11 (IQR 8–16), median SLEDAI at follow-up was 2 (IQR 1–6). A scleroderma pattern (ever) was seen in 18.9%, while only 13.2% of patients had a normal capillary pattern. Thirty-three patients had follow-up capillaroscopy of which 21.2% showed changes in type of capillary pattern over time. Type of capillary pattern was not associated with disease activity. Raynaud’s phenomenon (ever) was equally distributed among patients with different capillaroscopy patterns (p=0.26). Anti-ribonucleoprotein antibodies (ever) were significantly more detected (Χ(2), p=0.016) in the scleroderma pattern subgroup (n=7 of 10, 70%). Already 5 years after disease onset, more than 50% of patients with a scleroderma pattern had SLE-related disease damage (HR 4.5, 95% CI 1.1 to 18.8, p=0.034), but they did not develop clinical features of systemic sclerosis at follow-up. Number of detected fingers with a scleroderma pattern was similar between cSLE, juvenile systemic sclerosis and juvenile undifferentiated connective tissue disease. CONCLUSION: This longitudinal study shows that the majority of capillary patterns in cSLE are abnormal and they can change over time. Irrespective of disease activity, a capillary scleroderma pattern in cSLE may be associated with higher risk of SLE-related disease damage

TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.

BACKGROUND: A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. OBJECTIVES: To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. METHODS: We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. CONCLUSIONS: This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations

Can serum biomarkers predict the outcome of systemic immunosuppressive therapy in adult atopic dermatitis patients?

Background: Atopic dermatitis (AD or eczema) is a most common chronic skin disease. Designing personalised treatment strategies for AD based on patient stratification is of high clinical relevance, given a considerable variation in the clinical phenotype and responses to treatments among patients. It has been hypothesised that the measurement of biomarkers could help predict therapeutic responses for individual patients. Objective: We aim to assess whether serum biomarkers can predict the outcome of systemic immunosuppressive therapy in adult AD patients. Methods: We developed a statistical machine learning model using the data of an already published longitudinal study of 42 patients who received azathioprine or methotrexate for over 24 weeks. The data contained 26 serum cytokines and chemokines measured before the therapy. The model described the dynamic evolution of the latent disease severity and measurement errors to predict AD severity scores (Eczema Area and Severity Index, (o)SCORing of AD and Patient Oriented Eczema Measure) two-weeks ahead. We conducted feature selection to identify the most important biomarkers for the prediction of AD severity scores. Results: We validated our model in a forward chaining setting and confirmed that it outperformed standard time-series forecasting models. Adding biomarkers did not improve predictive performance. Conclusions: In this study, biomarkers had a negligible and non-significant effect for predicting the future AD severity scores and the outcome of the systemic therapy

Effect of immunosuppressive treatment on biomarkers in adult atopic dermatitis patients

Background: Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD). Objective: Primary aim: To identify biomarkers reflecting therapeutic response in patients with AD treated systemically. Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non-FLG mutations carriers. Methods: Thirty-eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation-inducing ligand, B-cell activating factor of the TNF family, thymus and activation-regulated chemokine (chemokine (C-C motif) ligand 17) (TARC (CCl-17)), interleukin-1 receptor antagonist (IL-1RA), interleukin-1 bèta, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-18, IL-31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C-X-C motif) ligand 9), interferon gamma-induced protein 10 (C-X-C motif chemokine Ligand 10), monocyte chemoattractant protein-1 (chemokine (C-C Motif) ligand 2), macrophage inflammatory protein-1 beta (chemokine (C-C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C-C motif) ligand 5), Cutaneous T-cell-attracting chemokine (chemokine (C-C motif) ligand 27) (CTACK (CCL-27)), thymic stromal lymphopoietin, IL-5, interleukin-1 alpha and granulocyte-colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status. Results: Thymus and activation-regulated chemokine, CTACK, IL-13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non-responders, and FLG and non-FLG mutants showed similar biomarker profiles. Conclusion: Thymus and activation-regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL-13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non-responders, or FLG genotype status

Effectiveness of dupilumab treatment in 95 patients with atopic dermatitis: daily practice data

Background: Dupilumab is the first biologic registered for the treatment of moderate-to-severe atopic dermatitis (AD), and efficacy was shown in phase III clinical trials (primary outcome at week 16 was reached in 38% of patients). Currently, there are limited daily practice data available for dupilumab, especially when it is combined with systemic immunosuppressants. Objectives: To evaluate dupilumab treatment in daily practice in patients with AD. Methods: In this observational cohort study, we prospectively included all adult patients with AD who had been treated with dupilumab in two university hospitals in the Netherlands. Concomitant systemic immunosuppressive treatment was monitored. Physician-reported outcome measures and patient-reported outcome measures (PROMs) after ≥ 12 weeks of follow-up were analysed. We used a linear mixed-effects model to determine changes in scores during follow-up. Results: Ninety-five patients were included. Of these, 62 patients were using systemic immunosuppressants at baseline; the use of systemic immunosuppressants was continued during dupilumab treatment in 43 patients. From baseline to 16 weeks of treatment, the estimated mean Eczema Area and Severity Index score (0–72) decreased from 18·6 [95% confidence interval (CI) 16·0–21·4)] to 7·3 (95% CI 5·4–10·0), and the estimated mean PROMs showed a decrease of 41–66%. Investigator's Global Assessment 0 or 1 (clear/almost clear) was reached in 38% of the patients. Five patients discontinued dupilumab treatment due to side-effects or ineffectiveness. Eye symptoms and orofacial (nonocular) herpes simplex virus (HSV) reactivation were reported in 62% and 8% of the patients, respectively. Conclusions: Dupilumab treatment in daily practice shows a clinically relevant improvement of physician-reported outcome measures and PROMs, which is in line with efficacy data from clinical trials. Besides frequently reported eye symptoms and orofacial (nonocular) HSV reactivation, there were no apparent safety concerns. What's already known about this topic?. Dupilumab has been shown to be an efficacious treatment for atopic dermatitis in several clinical trials. However, it is known that there may be considerable differences in patient characteristics and treatment responses between clinical trials and daily practice. What does this study add?. This study presents the first experience with dupilumab treatment in 95 patients with atopic dermatitis in daily practice in two Dutch university hospitals. Less stringent inclusion and exclusion criteria and follow-up schedules, in contrast to those used in clinical trials, might better represent daily practice. Dupilumab treatment shows a clinically relevant improvement of physician- and patient-reported outcome measures; besides patient-reported eye symptoms (in 59 of 95 patients; 62%) and an apparent increase in orofacial (nonocular) herpes simplex virus reactivation (eight of 95 patients; 8%), there were no other safety concerns during follow-up up to 16 weeks of dupilumab treatment

The European treatment of severe atopic eczema in children taskforce (TREAT) survey

BackgroundThere is a paucity of evidence for the use of systemic agents in children with atopic eczema refractory to conventional therapy, resulting in considerable variation in patient management. ObjectivesThe European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey was established to collect data on current prescribing practice, to identify factors influencing the use of specific systemic agents, and to inform the design of a clinically relevant intervention study. MethodsConsultant physician members of the paediatric dermatology societies and interest groups of eight European countries were invited to participate in a web-based survey. The multiple-response format questionnaire collated data on clinical practice in general, as well as detailed information on the use of systemic agents in refractory paediatric atopic eczema. ResultsIn total, 343/765 members (44.8%) responded to the invitational emails; 89.2% were dermatologists and 71% initiate systemic immunosuppression for children with severe atopic eczema. The first-line drugs of choice were ciclosporin (43.0%), oral corticosteroids (30.7%) and azathioprine (21.7%). Ciclosporin was also the most commonly used second-line medication (33.6%), with methotrexate ranked as most popular third choice (26.2%). Around half of the respondents (53.7%) replied that they routinely test and treat reservoirs of cutaneous infection prior to starting systemic treatment. Across the eight countries, penicillins were the first-line antibiotic of choice (78.3%). ConclusionsIn the absence of a clear evidence base, the European TREAT survey confirms the wide variation in prescribing practice of systemic immunosuppression in refractory paediatric atopic eczema. The results will be used to inform the design of a randomized controlled trial relevant to patient management across Europe