Dataset Information

Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review.

ABSTRACT:

Background

Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the SPINK5 gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes.

Objective

to provide an overview of systemic treatment options and their outcomes in adults and children with NS.

Methods

Embase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach.

Results

36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low.

Conclusion

NS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).

SUBMITTER: Nouwen AEM

PROVIDER: S-EPMC9022473 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceNetherton syndrome (NS) is a rare, severe genetic disorder of cornification with high morbidity. Treatment for NS has been notoriously difficult. Recent studies showed an upregulated helper T cell (TH) 17/interleukin 23 (IL-23) pathway in NS, suggesting the possibility of treatment strategies that target IL-17.ObjectiveTo evaluate the clinical response of NS to treatment with the IL-17 antagonist secukinumab.Design, setting, and participantsThis case series study reports the experience of compassionate use therapy with secukinumab in 4 patients with severe NS, including 2 children, from December 1, 2018, to December 1, 2019, with 3 patients still undergoing treatment at the time of final analysis. Data were analyzed from December 1, 2018, to December 1, 2019.Main outcomes and measuresExpression of IL-17 in the skin was evaluated by immunohistochemical analysis, and serum cytokine concentrations were measured using a commercially available assay. Treatment response was assessed using the Ichthyosis Area and Severity Index (IASI) total score, including measures of erythema and scaling, the Dermatology Life Quality Index (DLQI), and the 5-D itch scale.ResultsIn all 4 patients (age range, 9-27 years; 3 male and 1 female), immunostaining with an IL-17A antibody showed an increased number of positive cells in lesional skin. Cytokine assessment in serum samples revealed increased levels of CCL20. Treatment duration with secukinumab was 3 to 12 months at the time of this report. After 3 months of therapy, IASI scores were reduced by 44% to 88%, DLQI scores were reduced by 40% to 76%, and 5-D itch scale scores were reduced by 27% to 62%. This outcome was sustained at the 6-month follow-up. Two patients with an erythrodermic phenotype showed marked improvement of all parameters. A refractory palmoplantar eczematous eruption occurred in 2 patients, and a candidal nail infection developed in 2 patients. No severe adverse events were reported.Conclusions and relevanceThis initial case series reporting the use of anti-IL-17 therapy in NS demonstrated marked cutaneous improvement, particularly in 2 pediatric patients with erythrodermic phenotypes. Further studies are needed to evaluate the long-term benefit of this potential treatment modality.

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