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Infections in the Era of Targeted Therapies: Mapping the Road Ahead.

ABSTRACT: Immunosuppressive treatment strategies for autoimmune diseases have changed drastically with the development of targeted therapies. While targeted therapies have changed the way we manage immune mediated diseases, their use has been attended by a variety of infectious complications-some expected, others unexpected. This perspective examines lessons learned from the use of different targeted therapies over the past several decades, and reviews existing strategies to minimize infectious risk. Several of these infectious complications were predictable in the light of preclinical models and early clinical trials (i.e., tuberculosis and TNF inhibitors; meningococcus; and eculizumab). While these scenarios can potentially help us in terms of enhancing our predictive powers (higher vigilance, earlier detection, and risk mitigation), targeted therapies have also revealed unpredictable toxicities (i.e., natalizumab and progressive multifocal leukoencephalopathy). Severe infectious complications, even if rare, can derail a promising therapeutic and highlight the need for increased awareness and meticulous adjudication. Tools are available to help mitigate infectious risks. The first step is to ensure that infection safety is adequately studied at every level of drug development prior to regulatory approval, with adequate post-marketing surveillance including registries that collect real-world adverse events in a collaborative effort. The second step is to identify high risk patients (using risk calculators such as the RABBIT risk score; big data analyses; artificial intelligence). Finally, the most underutilized interventions to prevent severe infections in patients receiving targeted therapies across the spectrum of immune mediated inflammatory diseases are vaccinations.

SUBMITTER: Calabrese LH

PROVIDER: S-EPMC7461856 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Infections in the Era of Targeted Therapies: Mapping the Road Ahead.

Calabrese Leonard H LH Calabrese Cassandra C Lenfant Tiphaine T Kirchner Elizabeth E Strand Vibeke V

Frontiers in medicine 20200818

Immunosuppressive treatment strategies for autoimmune diseases have changed drastically with the development of targeted therapies. While targeted therapies have changed the way we manage immune mediated diseases, their use has been attended by a variety of infectious complications-some expected, others unexpected. This perspective examines lessons learned from the use of different targeted therapies over the past several decades, and reviews existing strategies to minimize infectious risk. Seve ...[more]

PMID: 32974356

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Project description:Morphea is a rare autoimmune condition causing inflammation and sclerosis of the skin and underlying soft tissue. It is characterized by periods of activity (inflammation admixed with fibrosis), ultimately resulting in permanent damage (pigment change and tissue loss). Damage resulting from unchecked activity can lead to devastating, permanent cosmetic and functional sequelae including hair loss; cutaneous, soft tissue and bony atrophy; joint contractures; and growth restriction of the affected body site in children. This makes the early identification of activity and initiation of appropriate treatment crucial to limiting damage in morphea. To this end, recent investigative work has focused on validation of clinical, biomarker, imaging, and histologic outcomes aimed at accurately quantifying activity and damage. Despite promising results, further work is needed to better validate these measures before they can be used in the clinic and research settings. Although there has been recent approval of less toxic, targeted therapies for many inflammatory skin conditions, none have been systematically investigated in morphea. The mainstays of treatment for active morphea are corticosteroids and methotrexate. These are often limited by substantial toxicity. The paucity of new treatments for morphea is the result of a lack of studies examining its pathogenesis, with many reviews extrapolating from research in systemic sclerosis. Recent studies have demonstrated the role of dysregulated immune and fibrotic pathways in the pathogenesis of morphea, particularly interferon (IFN) gamma related pathways. Active morphea lesions have been found to display an inflammatory morphea signature with CXCR3 receptor ligands, as well as a distinct fibrotic signature reflecting fibroblast activation and collagen production. CXCL9 and 10 have been associated with increased measures of disease activity. While immune dysfunction is thought to play the primary role in morphea pathogenesis, there are other factors that may also contribute, including genetic predisposition, environmental factors, and vascular dysregulation. There remains an essential need for further research to elucidate the pathogenesis of morphea and the mode of action of dysregulated upstream and downstream immune and fibrotic pathways. These studies will allow for the discovery of novel biomarkers and targets for therapeutic development.

Dataset Information

Infections in the Era of Targeted Therapies: Mapping the Road Ahead.

Publications

Infections in the Era of Targeted Therapies: Mapping the Road Ahead.

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