Adverse Drug Reaction Mechanisms and Management

Adverse drug reactions (ADRs) encompass a spectrum of harmful or unintended responses to medicinal agents, broadly classified into predictable, dose-dependent events and unpredictable, idiosyncratic responses. The latter arise from complex interactions between drug metabolites and the immune system, often involving hapten formation, direct pharmacological interactions with immune receptors and perturbation of cytokine networks. Genetic predispositions, notably variations in human leukocyte antigen (HLA) alleles and drug-metabolising enzymes, underlie many severe cutaneous and systemic syndromes. Mechanistic studies have revealed that reactive metabolites generated by cytochrome P450 enzymes can modify self-proteins, triggering T cell-mediated hypersensitivity. Immune effectors—including CD4+ and CD8+ T cells, natural killer cells and release of interferons and interleukins—drive tissue injury in syndromes such as Stevens–Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS). Management begins with early recognition, prompt withdrawal of the causative agent and supportive care tailored to organ involvement. Risk stratification tools such as SCORTEN inform prognosis in severe cutaneous reactions, while evolving therapeutics target specific pathogenic pathways. Pharmacogenomic screening and decision-support algorithms are increasingly deployed to predict susceptibility and prevent high-risk prescriptions. Advances in spatial proteomics, immunogenomics and biomarker discovery are paving the way for precision strategies that balance efficacy and safety on a global scale.

Research from Nature Portfolio

Deep visual proteomics has been applied to archival skin biopsies from patients with toxic epidermal necrolysis, mapping over 5,000 proteins at single-cell resolution and revealing a dominant type I and type II interferon signature alongside hyperactivated STAT1 in keratinocytes and infiltrating immune cells. Functional studies demonstrated that pan-JAK inhibitors, including tofacitinib and baricitinib, as well as JAK1-selective agents, attenuated keratinocyte cytotoxicity in vitro and markedly improved clinical and histological outcomes in murine models. Early compassionate-use data in patients supported rapid re-epithelialisation and recovery, establishing the JAK/STAT axis and interferon signalling as pivotal drivers of severe cutaneous ADRs and validating targeted JAK inhibition as a promising therapeutic avenue.

Adverse Drug Reaction Mechanisms and Management publication trend

The graph below shows the total number of articles in adverse drug reaction mechanisms and management across all publications each year (not limited to Nature Index journals).

Technical terms

Idiosyncratic reaction: An unpredictable, non–dose-related adverse response arising from individual genetic or immunological factors rather than the known pharmacology of a drug.

HLA allele: A variant form of a human leukocyte antigen gene that influences antigen presentation and can determine susceptibility to immune-mediated drug hypersensitivity.

JAK/STAT pathway: A signal transduction cascade in which Janus kinases (JAKs) phosphorylate signal transducers and activators of transcription (STATs), regulating expression of interferon-responsive and inflammatory genes.

DRESS syndrome: A severe hypersensitivity reaction characterised by drug-induced rash, fever, eosinophilia and multi-organ involvement, often accompanied by viral reactivation.

SCORTEN: A clinical severity-of-illness score used to predict mortality in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis based on seven independent risk factors.

References

1. Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature (2024).
2. Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population. Biomarker Research (2024).
3. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System. International Journal of Molecular Sciences (2017).