Biomarkers of tolerance in immune-mediated inflammatory diseases: a new era in clinical management?

Summary

Modern therapeutic agents and treatment regimens have made sustained remission an attainable target for many patients across a spectrum of immune-mediated inflammatory diseases, albeit at the risk of adverse events and the expense of drug prescription and safety monitoring. Clinicians and patients are thus increasingly faced with a novel treatment dilemma: whether and how best to stop immunomodulatory treatment in patients who achieve remission. In this final paper in a Series on therapeutic tolerance induction, we summarise our current knowledge of biomarkers of immune homeostasis in immune-mediated inflammatory diseases and their application to the prediction and attainment of sustained drug-free remission. We summarise evidence from prospective studies of immunomodulatory drug cessation across a range of immune-mediated inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, and inflammatory bowel disease. We also consider current evidence for clinical, serological, proteomic, metabolomic, cellular, and microbiomic biomarkers of immune homeostasis. Finally, we discuss the steps necessary for clinical translation of these biomarkers, as well as the potential transformative effect of these biomarkers on management of patients with immune-mediated inflammatory diseases if clinical translation is successfully achieved.

Introduction

The past two decades have witnessed a remarkable revolution in the management of immune-mediated inflammatory diseases. Whereas progressive end organ damage, disability, and mortality were previously viewed as inevitable consequences of unrelenting chronic inflammation, sustained remission is now attainable in substantial proportions of patients across a range of different diseases. These impressive advances have been achieved largely through a combination of early diagnosis combined with treat-to-target strategies utilising an increasingly broad armamentarium of immunomodulatory agents—a therapeutic blueprint that has been successfully replicated across a wide spectrum of immune-mediated inflammatory diseases.1, 2, 3, 4, 5 A prime example is in rheumatoid arthritis, for which management has shifted from a historical approach of symptom palliation with non-steroidal anti-inflammatory drugs and glucocorticoids to rapid and tight control of disease activity, with 50–60% of patients now attaining clinical remission (as defined by the 28-joint Disease Activity Score [DAS28]) in modern cohort studies.6, 7

Nevertheless, the increasing use of potent immunomodulatory agents in the treatment of immune-mediated inflammatory diseases poses challenges in terms of the risk of medication-related adverse events,⁸ the resources required for regular safety monitoring,⁹ and the substantial prescription costs of newer biological and targeted therapies. These drawbacks provide impetus for the development of novel strategies of treatment de-escalation and cessation, with consequent benefits for both patients and health-care systems. Central to this step-down therapeutic approach is an ability to define and quantify the mechanisms underlying the restoration of immune homeostasis in order to identify those patients most likely to benefit.

In this Series paper, we summarise developments over the past decade in the search for biomarkers of immune homeostasis in human immune-mediated inflammatory diseases, from early work exploring immune tolerance biomarkers in solid organ transplantation to more recent clinical trials of drug cessation in the setting of remission in patients with immune-mediated inflammatory diseases. Finally, we discuss the key steps required to translate such biomarkers to the clinic, and the potentially transformative effect on disease management pathways if this translation is successfully achieved.