Janus kinase-targeting therapies in rheumatology: A mechanisms-based approach
Open accessAbstract
The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK-STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In atopic dermatitis, barrier dysfunction and type 2 immune responses reciprocally reinforce each other in a self-amplifying loop that underlies disease initiation and chronicity.
“Collectively, these mechanisms establish a self-amplifying loop in which barrier dysfunction and type 2 immune responses reciprocally reinforce each other, underlying both disease initiation and chronicity in atopic dermatitis [9,10].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [10]
The “JAK inhibition in other diseases” section discusses treatments for atopic dermatitis, including a drug targeting IL-4 and IL-13, but does not describe a reciprocal relationship with barrier dysfunction. A search for the proposed barrier–type 2 immune feedback loop and its role in disease initiation or chronicity found no passage addressing it; the barrier discussion in “JAK inhibition in spondyloarthritis” concerns a different disease. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIL-4 and IL-13 directly sensitize sensory neurons and enhance pruritogenic signaling.
“Additionally, neuroimmune interactions also contribute, as IL-4 and IL-13 directly sensitize sensory neurons and enhance pruritogenic signaling.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [10]
The ‘JAK inhibition in other diseases’ section mentions IL-4 and IL-13 as targets of an atopic dermatitis treatment, but does not discuss sensory neurons or itch signaling. Searches for sensory-neuron sensitization and pruritus found no passage in our copy addressing the claimed mechanism; page numbers were not provided. (LLM, conf=0.74)
Experimental — accuracy not yet measuredEosinophils, activated downstream of IL-5 and type 2 cytokines, contribute to tissue remodeling and inflammation.
“Eosinophils, activated downstream of IL-5 and type 2 cytokines, further contribute to tissue remodeling and inflammation.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [10]
The “What are JAK inhibitors?” section lists IL-5 among factors that signal through JAKs, but does not link it to eosinophil activation. Searches for eosinophils and tissue remodelling found no passage in our copy addressing eosinophils’ contribution to inflammation or remodelling; page numbers were unavailable. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIL-4, IL-13, and IL-31, produced upon antigen re-exposure, maintain inflammation even in clinically normal skin.
“IL-4, IL-13, and IL-31, produced upon antigen re-exposure, maintain inflammation even in clinically normal skin.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [10]
The ‘JAK inhibition in other diseases’ section mentions IL-4 and IL-13 as targets of a treatment for atopic dermatitis, but does not address their production upon antigen re-exposure or inflammation in clinically normal skin. Searches for IL-31, antigen re-exposure, and unaffected skin found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredChronic atopic dermatitis is thought to be sustained by skin-resident memory T cells, which rapidly produce type 2 cytokines and contribute to recurrent inflammation.
“Chronic disease is thought to be sustained by skin-resident memory T cells, which rapidly produce type 2 cytokines and contribute to recurrent inflammation.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [10]
The ‘JAK inhibition in other diseases’ section discusses treatments for atopic dermatitis, but not what sustains its chronic or recurrent inflammation. Searches for skin-resident memory T cells and type 2 cytokines found no passage linking them to recurrent atopic dermatitis. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 102 · Cited by 501
Research works printed but not linked: 3
- [60]Hahn, B. H. Systemic lupus erythematosus. In Harrison’s Principles of Internal Medicine, 20th edn (ed. Jameson, J. R. et al.) pp 2515–2526 (McGraw-Hill, 2018). This is a comprehensive and highly educative textbook on SLE.
- [104]Pfizer. Pfizer shares co-primary endpoint results from post-marketing required safety study of Xeljanz® (tofacitinib) in subjects with rheumatoid arthritis (RA) https://www.pfizer.com/news/press-release/press-release-detail/pfizer-shares-co-primary-endpoint-results-post-marketing (2021).
- [107]Pfizer. U.S. FDA approves Pfizer’s Xeljanz® (tofacitinib) for the treatment of active polyarticular course juvenile idiopathic arthritis, https://investors.pfizer.com/investor-news/press-release-details/2020/U.S.-FDA-Approves-Pfizers-XELJANZ-tofacitinib-for-the-Treatment-of-Active-Polyarticular-Course-Juvenile-Idiopathic-Arthritis/default.aspx (2020).
- Authors
- Tanaka, Y., Luo, Y., O’Shea, J. J., & Nakayamada, S.
- Affiliations
- University of Occupational and Environmental Health Japan (JP)
- National Institutes of Health (US)
- Corresponding author
- Tanaka, Yoshiya
- Venue
- Nature Reviews Rheumatology
- Published
- 2022-01-05
- Volume
- 18
- Issue
- 3
- Pages
- 133-145
- ISSN
- 1759-4790 (ISSN-L)
- 1759-4804
- PMC
- PMC8730299
- OpenAlex
- W4205276722
- Cited by
- 501
- References
- 102
- Citations by year
- 2026: 83 · 2025: 120 · 2024: 124 · 2023: 129 · 2022: 45
- FWCI
- 12.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Rheumatology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- JAK inhibitors, JAK/STAT signaling, rheumatoid arthritis, autoimmune disease, spondyloarthritis, inflammatory bowel disease, alopecia areata, systemic lupus erythematosus, atopic dermatitis, cytokine storm, COVID-19 pandemic, cytokine receptors, steroid-sparing therapy, small-molecule targeted therapy
- MeSH terms
- COVID-19, SARS-CoV-2, Humans, Rheumatology, STAT Transcription Factors, Janus Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
