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  • Review Article
  • Published:

JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Nature Reviews Drug Discovery volume 16, pages 843–862 (2017)Cite this article

Subjects

A Corrigendum to this article was published on 28 December 2017

This article has been updated

Key Points

  • Despite their success, conventional and biologic disease-modifying antirheumatic drugs are not effective in all patients.

  • First-generation Janus kinase (JAK) inhibitors, or jakinibs, are effective for rheumatoid arthritis and in a number of other autoimmune conditions.

  • Next-generation selective jakinibs are being developed and are effective in rheumatoid arthritis, inflammatory bowel disease and other autoimmune conditions.

  • First-generation and second-generation jakinibs are currently being investigated for a number of new indications.

  • Many of the adverse effects of jakinibs can be linked to the action of the cytokines that are blocked.

  • Topical jakinibs represent an exciting new class of agents that may preserve therapeutic efficacy while eliminating adverse effects that result from systemic JAK inhibition.

Abstract

The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.

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Figure 1: Signalling by type I and type II cytokine receptors.
Figure 2: Effects of targeting different JAKs.
Figure 3: Chemical structure and attributes of various jakinibs.

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Change history

  • 28 December 2017

    In the version of this article that was originally published, there was an error in Figure 3 on page 847. In this figure, the structure attributed to the compound BMS-986165 is incorrect and the correct structure for this compound has not yet been disclosed. This error has now been corrected in the online version of the article, and the structure of SAR-20347 has been added instead. We apologize for any inconvenience that this error may have caused.

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Acknowledgements

The work of D.M.S., M.G. and J.O'S. is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health.

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Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Daniella M. Schwartz, Yuka Kanno, Alejandro Villarino & John J. O'Shea

  2. Clinical Trials and Outcomes Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Michael Ward

  3. Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Massimo Gadina

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Correspondence to John J. O'Shea.

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Competing interests

J.O'S. declares that he and the US Government receive royalties based on patents related to the targeting of Janus kinases. J.O'S., M.G. and the US Government have had longstanding Cooperative Research and Development Agreements with Pfizer, which produces tofacitinib, a Janus kinase inhibitor.

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Glossary

C-reactive protein

(CRP). A protein classified as an acute phase reactant and produced in the liver in response to inflammation.

Serum amyloid A

An acute phase reactant, produced predominantly in the liver and expressed at different levels in response to inflammatory stimuli.

Phosphoproteomic analysis

A proteome-wide analysis of phosphorylated proteins.

American College of Rheumatology 20%, 50% and 70% response criteria

(ACR20, 50, 70). Standard criteria used to measure the effectiveness of treatments for rheumatoid arthritis. These criteria measure percentage improvement in tender or swollen joint counts and three of the following measures: patient assessment; physician assessment; pain scale; disability/functional questionnaire and acute phase reactants

36-Item Short Form Survey

(SF-36). A set of generic, coherent and easily administered quality-of-life measures that rely on patient self-reporting and are now widely used by managed care organizations for routine monitoring and assessment of care outcomes in adult patients.

Biologics

Agents that target cytokines or cytokine receptors, usually monoclonal antibodies or chimeric receptors.

Baseline structural damage

Abnormal imaging findings on radiographic assessment, specifically joint space narrowing and erosion.

Complete response letter

A letter issued by the US Food and Drug Administration to communicate that it has completed its review of a drug application and decided not to approve it in its present form.

Transmural inflammation

Full-thickness inflammation across the entire bowel wall (as opposed to being limited to the mucosa and submucosa).

Skip lesions

Lesions that are discontinuous. In the context of this Review, the term refers to discontinuous lesions in the gastrointestinal tract.

Psoriasis Activity and Severity Index

A standardized score used to measure the severity and extent of skin involvement in psoriasis. A representative area of psoriasis is selected for each body region, and the intensity of redness, thickness and scaliness is assessed on a scale of 0 (none) to 4 (very severe).

BK viraemia

Disseminated viral infection with BK virus, a polyomavirus whose name is an abbreviation of the name of the index patient from whom this virus was isolated.

Post-transplant lymphoproliferative disease

(PTLD). A post-transplantation malignancy that can occur as a complication of solid organ or haematopoietic stem cell transplantation. Often associated with Epstein-Barr virus infection of B cells.

Sjogren's syndrome

A systemic autoimmune condition characterized by autoimmune exocrinopathy (salivary and lacrimal glands), as well as, in some cases, systemic inflammation (central nervous system, hepatic, skin, renal and others).

Myositis

Inflammation of the muscles. In the context of this Review, myositis refers to the two systemic autoimmune conditions polymyositis and dermatomyositis.

Eosinophilic oesophagitis

A disease characterized by eosinophilic inflammation of the oesophagus, also termed allergic oesophagitis.

Plasmablasts

Immature cells of plasma cell lineage, a type of B cell. Plasmablasts secrete more antibodies than B cells but fewer than mature plasma cells.

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Schwartz, D., Kanno, Y., Villarino, A. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 16, 843–862 (2017). https://doi.org/10.1038/nrd.2017.201

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