Perspectives: Immune-mediated Inflammatory Disease Therapeutics

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Over the past two decades, the treatment of immune-mediated inflammatory diseases (IMID) has moved from broad-spectrum immune modulators to agents that have exquisite specificity. Substantial toxicity is no longer the norm, and remission or low states of disease activity are typical outcomes.

Ellen M. Gravallese, MD, chief of the Division of Rheumatology, Inflammation and Immunity at Brigham and Women’s Hospital, and a colleague recently reviewed in Nature Reviews Immunology the past, present and future of IMID therapeutics. This “Perspectives” piece, written for the 20th anniversary issue of the journal, captures key lessons for clinicians and reflects on the next steps in the therapeutic journey.

Key Takeaways

  • A recent perspectives article describes the past, present and future of highly targeted therapies for immune-mediated inflammatory diseases (IMID)
  • Two key lessons for clinicians are that targeted therapy should be started early and aggressively in the disease process. However, even when disease appears well controlled, in most cases will recur with discontinuation of therapy
  • There is a movement toward testing interventions during a “pre-disease” state, particularly for patients at risk for rheumatoid arthritis and those with psoriasis, who are at risk for psoriatic arthritis
  • Modification of inflammation alters levels of metabolic vascular risk factors, and the use of immune targeted therapy to manage cardiovascular risk, is expanding rapidly
  • Goals for future IMID therapies are to achieve remission in greater numbers of patients, preserve tissue integrity, repair organ damage and perhaps even restore immune homeostasis

Importance of Controlling Inflammation and Immune Activation

  • The best disease outcomes occur when inflammation is completely controlled: Early and aggressive use of targeted therapies can prevent irreversible tissue damage
  • IMIDs should be defined on the basis of their absolute immunological activity state, such as: active with no therapy; in a residual activation state despite intervention; in remission, either drug-maintained or drug-free, rather than according to transient response to an intervention
  • Typically, targeted therapy does not fundamentally change the underlying immunologic process: If an IMID is controlled with early, aggressive achievement of immunologic remission, short-term discontinuation of therapy may be possible, but in most cases the disease has simply been suppressed and will recur
  • There is a movement toward testing interventions during a “pre-disease” state: This is particularly exciting in the area of psoriasis, where approximately 30% of patients progress to psoriatic arthritis and other spondylitis-related disease manifestations, and in rheumatoid arthritis, where family history and the presence of circulating autoantibodies are early warning signals

Insights from Adverse Effects

Many patients with IMIDs have cardiometabolic comorbidities, and modification of inflammation alters levels of circulating lipids and other metabolic vascular risk factors. For example:

  • IL-6 receptor inhibitors and JAK inhibitors elicit rapid increases in circulating low-density, high-density and very-low-density lipoprotein cholesterols, indicating fundamental roles for these immune pathways in regulating hepatic and peripheral cholesterol metabolism
  • TNF inhibitors alter insulin sensitivity in IMID patients
  • Imaging studies have demonstrated the impact of immune targeting on vascular inflammation in psoriasis, likely reflecting accelerated atherosclerosis in the context of systemic inflammation

A rapidly expanding field is the use of immune-targeted therapy to manage cardiovascular risk. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), reported in The New England Journal of Medicine, interleukin-1β inhibition in patients with a history of myocardial infarction and evidence of ongoing inflammation resulted in a significantly lower rate of recurrent cardiovascular events compared with placebo.

Future Approaches to Developing IMID Therapeutics

Designing future therapies for IMIDs is envisioned to involve a combination of routes for target discovery: kinome interrogation, novel cellular therapies, poly-omic disease deconstruction (epi/genomic, transcriptomic, proteomic and metabolomic methods) and advances in regenerative medicine.

Discovery programs will be enhanced by artificial intelligence–based methods, in silico medicinal chemistry, extensive in silico testing of new agents prior to clinical trials, and pre-disease intervention.

The goals are to achieve remission in greater numbers of patients, preserve tissue integrity, repair organ damage and restore immune homeostasis.