Effects of Janus Kinase Inhibitors on Rheumatoid Arthritis Pain: Clinical Evidence and Mechanistic Pathways
Abstract
1. Introduction
2. Pathophysiology of Pain in RA and the JAK-STAT Pathway
- IL-6/JAK/STAT3 Axis: IL-6 is a key pro-inflammatory cytokine in RA. It activates JAK1, JAK2, and TYK2 kinases, which in turn phosphorylate the STAT3 protein. Elevated levels of phosphorylated STAT3 (pSTAT3) have been found in RA patients’ peripheral blood mononuclear cells (AP2) and are correlated with markers of inflammation such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Disease Activity Score (DAS28). This axis is not only a marker of disease activity but also a therapeutic target, with JAKi demonstrating the ability to modulate its effects [39].
- Predominant Role of JAK1: JAK1 is critically involved in signaling for several pro-inflammatory cytokines, including IL-6 and interferons. It contributes to synovial inflammation and bone remodeling, making JAK1-selective inhibitors an attractive treatment strategy in RA. Targeting JAK1 specifically may help reduce inflammation while minimizing side effects associated with broader JAK inhibition [40].
- Impaired JAK/STAT Activity in Some Patients: Despite elevated serum cytokine levels, certain RA patients exhibit reduced JAK/STAT pathway activation. This paradox may explain why some patients respond poorly to cytokine-targeted therapies. Evaluating STAT protein phosphorylation could help identify individuals at higher risk of treatment resistance [41].
- Role of SOCS Proteins: Suppressors of cytokine signaling (SOCS) proteins, such as SOCS2, function as natural inhibitors of the JAK-STAT pathway. In RA, reduced expression of SOCS2 may allow unchecked pathway activation, contributing to chronic inflammation and ongoing joint damage [42].
3. JAK Inhibitors and Pain: Mechanisms Beyond Inflammation
Comparison with TNF-α Inhibitors: Differences in Central vs. Peripheral Pain Modulation
4. Clinical Evidence: JAK Inhibitors for Pain Relief
4.1. Baricitinib
4.2. Tofacitinib
4.3. Upadacitinib
4.4. Filgotinib
| JAK Inhibitors | Authors: | Drugs Compared | Study | Concluded |
|---|---|---|---|---|
| Baricitinib | Genovese MC et al. (2016) [88] | baricitinib (2 or 4 mg daily) and placebo | RA-BEACON | baricitinib at 4 mg was associated with clinical improvement at 12 weeks |
| Fleischmann R et al. (2017) [86] | baricitinib, baricitinib + MTX, and MTX | RA-BEGIN | baricitinib alone or in combination with MTX demonstrated superior efficacy | |
| Schiff M et al. (2017) [89] | baricitinib as monotherapy or combined with MTX | baricitinib (alone or in combination), when used as initial therapy, showed improvement compared to MTX in most PRO measures | ||
| Fautrel B et al. (2019) [90] | baricitinib and adalimumab, placebo | RA-BEAM (exploratory analyses) | Baricitinib 4 mg provided enhanced improvement in pain and physical function | |
| Taylor PC et al. (2022) [87] | baricitinib, baricitinib + MTX, and MTX over 1 year | RA-BEGIN (post hoc analysis) | patients treated with baricitinib had significantly greater and more rapid pain relief, 9–10 additional weeks of limited to no pain, and clinically meaningful improvements in physical health | |
| Tofacitinib | Fleischmann R et al. (2012) [93] | tofacitinib monotherapy, Placebo | ORAL Solo | tofacitinib monotherapy was associated with reductions in RA symptoms and signs and improvement in physical function |
| Burmester GR et al. (2013) [92] | tofacitinib (5 mg or 10 mg BID) combined with MTX | ORAL STEP | tofacitinib with MTX had rapid and clinically meaningful improvements in RA symptoms, signs, and physical function over 6 months | |
| Lee EB et al. (2014) [91] | tofacitinib, baricitinib, upadacitinib, filgotinib monotherapy, and MTX | ORAL Start | Treatment with tofacitinib, baricitinib, upadacitinib, filgotinib achieved a significantly higher remission rate than MTX | |
| Upadacitinib | Genovese MC et al. (2018) [81] | upadacitinib compared with a placebo | SELECT-BEYOND | upadacitinib led to rapid and significant improvements compared with a placebo over 12 weeks |
| Van Vollenhoven R et al. (2020) [94] | upadacitinib as monotherapy, methotrexat | SELECT-EARLY | patients receiving upadacitinib experienced significant clinical improvements and PROs compared to patients receiving MTX | |
| Filgotinib | Genovese MC et al. (2019) [84] | filgotinib compared to placebo | FINCH 2 | patients with active RA who had an inadequate response or intolerance to one or more bDMARDs, filgotinib achieved greater clinical response at week 12 |
| Aletaha D et al. (2021) [95] | filgotinib versus MTX, filgotinib plus MTX | FINCH 3 (post hoc analysis) | showed greater pain and physical function improvement | |
| Atsumi T et al. (2023) [71] | filgotinib, filgotinib plus MTX or MTX | FINCH 3 (Long-term safety) | efficacy was maintained through week 52 and longer | |
| Network meta-analysis | Sung YK et al. (2021) [83] | tofacitinib, baricitinib, upadacitinib, and filgotinib versus methotrexate | network meta-analysis | tofacitinib, baricitinib, upadacitinib, and filgotinib were effective pharmacotherapy options for DMARDs-naive RA patients |
| Lee YH et al. (2023) [85] | tofacitinib, baricitinib, upadacitinib, filgotinib monotherapy, and MTX | network meta-analysis | upadacitinib seems to be one of the most effective interventions for achieving remission | |
| Cai W et al. (2024) [72] | five approved JAK inhibitors as monotherapy and combination therapy | network meta-analysis | all JAK inhibitors were more effective than placebo |
5. Head-to-Head Comparisons and Indirect Evidence
6. JAK Inhibitors vs. Other RA Treatments for Pain
6.1. Comparing JAK Inhibitors with csDMARDs
6.2. Biologic DMARDs and Their Limitations in Pain Control
6.3. Clinical Trials Comparing JAK Inhibitors to TNF-α Inhibitors
6.4. Comparative Pain Outcomes with JAK Inhibitors Versus Abatacept
6.5. Network Meta-Analyses: Synthesizing Indirect Evidence
6.6. Real-World Evidence Supporting Rapid and Sustained Pain Relief
6.7. Special Populations: Comorbid Fibromyalgia and Non-Inflammatory Pain
6.8. Safety-Tolerability Balance in the Context of Pain Management
7. Unmet Needs and Future Directions
7.1. Why Some Patients Fail to Achieve Pain Relief Despite JAK Inhibition
7.2. Predictive Biomarkers for Pain Relief Response
7.3. Emerging JAK Inhibitors and Novel Therapeutic Targets in RA Pain
7.4. Personalized Pain Management Approaches in RA
7.5. Future Directions
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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| JAKi | Selectivity | Recommended Dose | FDA Approved | EMA Approved |
|---|---|---|---|---|
| tofacitinib | JAK 1 and JAK 3 (strong) JAK 2 (minor) TYK 2 (minor) | 2 × 5 mg | 11/2012 | 3/2017 |
| baricitinib | JAK 1 and JAK 2 (strong) TYK 2 (moderate) JAK 3 (minor) | 2 mg 4 mg | 5/2018 | 12/2016 |
| upadacitinib | JAK 1 (strong) | 15 mg | 8/2019 | 12/2019 |
| filgotinib | JAK 1 (strong) | 100 mg 200 mg | - | 9/2020 |
| Mechanism | Activated Pathway | Cells/Tissues Involved | Pathophysiological Outcome | Clinical Phenotype/ Relevance | Therapeutic Implication |
|---|---|---|---|---|---|
| IL-6/JAK/STAT3 Axis | IL-6 → JAK1/JAK2/TYK2 → STAT3 | Synovial cells, T cells | Inflammation, osteoclast activation, angiogenesis | Inflammatory pain, active disease phase | Key therapeutic target, biomarker of disease activity |
| Predominant Role of JAK1 | IL-6, IFN → JAK1 → STAT1/3 | Synovial fibroblasts, osteoclasts | Synovial inflammation, bone remodeling | Erosive disease, disease progression | Selective JAK1 inhibition as a targeted strategy |
| Impaired JAK/STAT Activity | Cytokines ↑, but ↓ STAT phosphorylation | PBMCs, T cells | Discordant inflammation-signaling response | Poor therapeutic response, disease heterogeneity | Basis for personalized therapeutic approaches |
| Role of SOCS Proteins | SOCS2 ↓ → loss of JAK/STAT regulation | T cells, macrophages | Loss of negative feedback, chronic inflammation | Persistent disease, chronic pain | Potential target for SOCS modulation therapies |
| Authors | JAK Inhibitors | Type of Study/Methods | Mechanism Affecting Pain Pathway |
|---|---|---|---|
| Makabe et al. [50] | baricitinib | CAIA mice model |
|
| Vazquez et al. [52] | baricitinib | C57BL/6J mice and Wistar rats, primary cultures of DRG neurons |
|
| Simon et al. [53] | baricitinib | CAIA mice model, DRG neurons culture |
|
| Matsushita et al. [55] | baricitinib | CIA mice model |
|
| Navarini et al. [64] | upadacitinib | Microglia culture |
|
| Li et al. [65] | abrocitinib | TBI mice model, BV2 microglial cell culture |
|
| Tsuda et al. [57] | AG490 | Neuropathic pain model—male Wistar rats |
|
| Tian et al. [59] | AG490 | Electrophysiological recordings- Sprague Dawley rats and C57BL/6J mice |
|
| Emerging JAKi | Approved | Indication | Selectivity |
|---|---|---|---|
| Peficitinib | Japan, 2019 | RA | JAK 3 (strong) JAK 1 and JAK 2 (minor) TYK 2 (minor) |
| Decernotinib | - | RA | JAK 3 (strong) |
| Itacitinib | - | RA | JAK 1 (strong) |
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Belančić, A.; Sener, S.; Sener, Y.Z.; Fajkić, A.; Vučković, M.; Markotić, A.; Benić, M.S.; Potočnjak, I.; Pavlović, M.R.; Radić, J.; et al. Effects of Janus Kinase Inhibitors on Rheumatoid Arthritis Pain: Clinical Evidence and Mechanistic Pathways. Biomedicines 2025, 13, 2429. https://doi.org/10.3390/biomedicines13102429
Belančić A, Sener S, Sener YZ, Fajkić A, Vučković M, Markotić A, Benić MS, Potočnjak I, Pavlović MR, Radić J, et al. Effects of Janus Kinase Inhibitors on Rheumatoid Arthritis Pain: Clinical Evidence and Mechanistic Pathways. Biomedicines. 2025; 13(10):2429. https://doi.org/10.3390/biomedicines13102429
Chicago/Turabian StyleBelančić, Andrej, Seher Sener, Yusuf Ziya Sener, Almir Fajkić, Marijana Vučković, Antonio Markotić, Mirjana Stanić Benić, Ines Potočnjak, Marija Rogoznica Pavlović, Josipa Radić, and et al. 2025. "Effects of Janus Kinase Inhibitors on Rheumatoid Arthritis Pain: Clinical Evidence and Mechanistic Pathways" Biomedicines 13, no. 10: 2429. https://doi.org/10.3390/biomedicines13102429
APA StyleBelančić, A., Sener, S., Sener, Y. Z., Fajkić, A., Vučković, M., Markotić, A., Benić, M. S., Potočnjak, I., Pavlović, M. R., Radić, J., & Radić, M. (2025). Effects of Janus Kinase Inhibitors on Rheumatoid Arthritis Pain: Clinical Evidence and Mechanistic Pathways. Biomedicines, 13(10), 2429. https://doi.org/10.3390/biomedicines13102429

