Evaluation of the effectiveness of Tofacitinib in rheumatoid arthritis in real clinical practice: The relationship between pain relief in the first 4 weeks and disease activity after 3–6 months

The JAK inhibitor tofacitinib (TOFA) blocks the intracellular signaling pathway that activates the synthesis of cytokines and mediators involved in the development of pain and central sensitization (CS), which determines the rapid analgesic effect. However, it is not clear how pain reduction is associated with achieving low activity in rheumatoid arthritis (RA).

The aim of the study was to assess the relationship between the early clinical response to tofacitinib and a decrease in rheumatoid arthritis activity after 3 and 6 months.

Material and methods. The study group consisted of 88 RA patients (age – 53±11.5 years; 79.3% of women) who received basic anti-inflammatory drugs (59.5% – methotrexate, 19.8% – leflunomide) and who were prescribed TOFA in a dose 10 mg/day. Seropositivity for rheumatoid factor was 89.8%; the value of the DAS28 index is 5.2±1.2. The severity of pain was assessed using the Brief Pain Inventory questionnaire, the neuropathic component of pain (NCP) – using the PainDETECT questionnaire, signs of CS – using the Central Sensitization Inventory (CSI) questionnaire in the early stages after the administration of TOFA, RA activity – using the DAS28-CRP index after 3 and 6 months.

Results. The mean severity of pain at baseline was 5.3±2.0 on the visual analogue scale (VAS); 51.1% of patients had signs of CS (CSI>40), 15.9% had NCP (PainDETECT>18). 7 days after the start of therapy, there was a significant decrease in pain – to 4.1±1.8 according to VAS (p<0.05) and CS – 40.4±13.5 to 36.5±12.5 according to CSI (p=0.01). After 28 days, the effect was even more significant: the level of pain according to the VAS was 2.8±1.6 (p=0.000), the NCP decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CS – up to 31.6±13.9 (p=0.000). The value of the DAS28-CRP index after 3 and 6 months was 3.7±1.3 and 3.6±1.2, respectively. The number of patients with pain relief ≥50% after 28 days was 59.9%, low RA activity after 3 months. (DAS28-CRP≤3.2) was acieved in 64.4% of patients. There was a clear correlation between the number of patients with a pain reduction of ≥50% at 28 days and the number of patients who achieved low RA activity at 3 and 6 months. (rS=0.548, p=0.000 and rS=0.790, p=0.000). 6 patients dropped out of the study due to inefficiency or social reasons. No serious adverse reactions were noted.

Conclusions. The use of the JAK inhibitor TOFA allows achieving a quick analgesic effect and reducing the signs of CS. An early clinical response to TOFA (pain relief) predicts a decrease in RA activity after 3 and 6 months of therapy.

1. Nasonov EL, Avdeeva AS, Lila AM. Efficacy and safety of tofacitinib for immune-mediated inflammatory rheumatic diseases (Part I). Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2020;58(1):62-79 (In Russ.). doi: 10.14412/1995-4484-2020-62-79

2. Wang F, Sun L, Wang S, Davis JM 3rd, Matteson EL, Murad MH, et al. Efficacy and safety of tofacitinib, baricitinib, and upadacitinib for rheumatoid arthritis: A systematic review and meta-analysis. Mayo Clin Proc. 2020;95(7):1404-1419. doi: 10.1016/j.mayocp.2020.01.039

3. Strand V, Kaine J, Alten R, Wallenstein G, Diehl A, Shi H, et al. Associations between Patient Global Assessment scores and pain, physical function, and fatigue in rheumatoid arthritis: A post hoc analysis of data from phase 3 trials of tofacitinib. Arthritis Res Ther. 2020;22(1):243. doi: 10.1186/s13075-020-02324-7

4. Hiligsmann M, Rademacher S, Kaal KJ, Bansback N, Harrison M. The use of routinely collected patient-reported outcome measures in rheumatoid arthritis. Semin Arthritis Rheum. 2018;48(3):357-366. doi: 10.1016/j.semarthrit.2018.03.006

5. Ogdie A, de Vlam K, McInnes IB, Mease PJ, Baer P, Lukic T, et al. Efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. RMD Open. 2020;6(1):e001042. doi: 10.1136/rmdopen-2019-001042

6. Crispino N, Ciccia F. JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2021;39(3):668-675.

7. Seifert O, Baerwald C. Interaction of pain and chronic inflammation. Z Rheumatol. 2021;80(3):205-213. doi: 10.1007/s00393-020-00951-8

8. Adami G, Gerratana E, Atzeni F, Benini C, Vantaggiato E, Rotta D, et al. Is central sensitization an important determinant of functional disability in patients with chronic inflammatory arthritides? Ther Adv Musculoskelet Dis. 2021;13:1759720X21993252. doi: 10.1177/1759720X21993252

9. Karateev AE, Filatova ES, Pogozheva EYu, Amirjanova VN, Nasonov EL, Lila AM, et al. A very early clinical response to treatment with the Janus kinase inhibitor tofacitinib in patients with active rheumatoid arthritis: the dynamics of pain and central sensitization elements. Modern Rheumatology Journal. 2020;14(2):69-75 (In Russ.). doi: 10.14412/1996-7012-2020-2-69-75

10. Zhilyaev EV, Lukina GV, Koltsova EN, Shmidt EI, Lytkina KA. Clinical significance of the direct analgesic effect of targeted medications in patients with rheumatoid arthritis. Russian Medical Review. 2020;4(8):483-486 (In Russ.). doi: 10.32364/2587-6821-2020-4-8-483-486

11. Karateev DE, Luchikhina EL. The role of targeted synthetic drugs in the treatment of rheumatic diseases: focus on tofacitinib. Meditsinskiy sovet = Medical Council. 2020;(2):83-94 (In Russ.). doi: 10.21518/2079-701X-2020-2-83-94

12. Harrington R, Al Nokhatha SA, Conway R. JAK inhibitors in rheumatoid arthritis: An evidence-based review on the emerging clinical data. J Inflamm Res. 2020;13:519-531. doi: 10.2147/JIR.S219586

13. Fautrel B, Kirkham B, Pope JE, Takeuchi T, Gaich C, Quebe A, et al. Effect of baricitinib and adalimumab in reducing pain and improving function in patients with rheumatoid arthritis in low disease activity: Exploratory analyses from RA-BEAM. J Clin Med. 2019;8(9):1394. doi: 10.3390/jcm8091394

14. Corominas H, Alegre C, Narváez J, Fernández-Cid CM, Torrente- Segarra V, Gómez MR, et al. Correlation of fatigue with other disease related and psychosocial factors in patients with rheumatoid arthritis treated with tocilizumab: ACT-AXIS study. Medicine (Baltimore). 2019;98(26):e15947. doi: 10.1097/MD.0000000000015947

15. Strand V, Kremer JM, Gruben D, Krishnaswami S, Zwillich SH, Wallenstein GV. Tofacitinib in combination with conventional disease- modifying antirheumatic drugs in patients with active rheumatoid arthritis: Patient-reported outcomes from a phase III randomized controlled trial. Arthritis Care Res (Hoboken). 2017;69(4):592-598. doi: 10.1002/acr.23004