Efficacy of olokizumab in treating comorbid depression in patients with rheumatoid arthritis: results of a single-center randomized controlled trial

Background. Interleukin (IL) 6 plays an important role in the pathogenesis of comorbid rheumatoid arthritis (RA) depression. IL-6 inhibitors used to treat patients with RA may also have an antidepressant effect.
The objective of this study is to evaluate the effectiveness of 24-week interleukin 6 inhibitor therapy with olokizumab (OKZ) in combination with or without psychopharmacotherapy (PPT) in patients with moderate to high rheumatoid arthritis activity.
Material and methods. A total of 125 patients with RA were included, 102 (81.6%) of them being women. The average age of the patients was 48.5±12.6 years; the majority of the patients (86.4%) had high RA activity and had shown ineffectiveness with stable 12-week therapy using conventional synthetic disease modifying antirheumatic drugs (csDMARDs). Additionally, 34 (27.2%) patients had shown inefficiency with one or more biological DMARDs. According to the International Classification of Diseases, 10th revision (ICD-10), a psychiatrist diagnosed varying severity of depression (chronic or recurrent) in all patients during a semi-structured interview. At week 0, all patients were randomized using sequential numbers in a 2:2:1 ratio into one of three groups: in the group 1, patients received csDMARDs+OKZ 64 mg subcutaneously once every 4 weeks (q4w) (n=49); in the group 2, patients received csDMARDs+OKZ 64 mg subcutaneously q4w along with psychopharmacotherapy (PPT) (n=51); in the group 3, patients received csDMARDs+PPT (n=25). The study duration was 24 weeks. The severity of depression was assessed using the PHQ-9 (Patient Health Questionnaire 9) and MADRS (Montgomery – Åsberg Depression Rating Scale) scales; while anxiety was assessed using the HAM-A (Hamilton Anxiety Rating Scale) scale. Projective experimental psychological techniques were also used.
Results. After 12 and 24 weeks of therapy, a significant decrease in the severity of depression and anxiety was observed in all groups of patients. However the differences between the final and initial values of the scales filled in by a psychiatrist were statistically significantly greater (p<0.001) in the groups of patients receiving PPT: in the group 2 (ΔMADRS24–0=–20.2±6.57; ΔHAM-A24–0=–13.2±5.68) and group 3 (ΔMADRS24–0=–17.8±4.73; ΔHAM-A24–0=–13.4±4.41), compared with the group 1 (ΔMADRS24–0=–5.42±7.14; ΔHAM-A24–0=–4.58±6.80). There were no significant differences between the groups according to the PHQ-9 depression questionnaire (respectively, in group 1, ΔPHQ-924–0=–4.89±4.87; in group 2, ΔPHQ-924–0=–6.73±4.97; in group 3, ΔPHQ-924–0=–7.26±5.58), despite a greater decrease in the severity of depression observed in the groups with PPT. According to a semi-structured interview with a psychiatrist and in accordance with the criteria of ICD-10 the proportion of patients without depression 24 weeks after the start of therapy was significantly higher in the groups receiving PPT: 84.3% in group 2, 100% in group 3, and 16.3% in group 1.
Conclusion. In patients with moderate/high RA activity and comorbid depression, OKZ without PPT can lead to a decrease in the severity of depression or, less often, to a complete regression of depressive symptoms, mainly in patients with minor depression. OKZ therapy without PPT also reduces the severity of anxiety, but does not eliminate it completely. The combination of OKZ and PPT is optimal for achieving complete regression of depression and anxiety in this category of RA patients.

1. Liao KP, Karlson EW. Classification and epidemiology of rheumatoid arthritis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (eds). Rheumatology. Elsevier Mosby:Maryland Heights;2015:691-697.

2. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023-2038. doi: 10.1016/S0140-6736(16)30173-8

3. Lwin MN, Serhal L, Holroyd C, Edwards CJ. Rheumatoid arthritis: The impact of mental health on disease: A narrative review. Rheumatol Ther. 2020;7(3):457-471. doi: 10.1007/s40744-020-00217-4

4. Vitturi BK, Nascimento BAC, Alves BR, de Campos FSC, Torigoe DY. Cognitive impairment in patients with rheumatoid arthritis. J Clin Neurosci. 2019;69:81-87. doi: 10.1016/j.jocn.2019.08.027

5. Abramkin AA, Lisitsyna TA, Veltishchev DY, Seravina OF, Kovalevskaya OB, et al. Depression and severity of articular destruction in patients with rheumatoid arthritis. Terapevticheskii arkhiv. 2020;92(5):22-32 (In Russ.). doi: 10.26442/00403660.2020.05.000624

6. Baghdadi LR. Tocilizumab reduces depression risk in rheumatoid arthritis patients: A systematic review and meta-analysis. Psychol Res Behav Manag. 2024;17:3419-3441. doi: 10.2147/PRBM.S482409

7. Ionescu CE, Popescu CC, Agache M, Dinache G, Codreanu C. Depression in rheumatoid arthritis: A narrative review – diagnostic challenges, pathogenic mechanisms and effects. Medicina. 2022;58:1637. doi: 10.3390/medicina58111637

8. Schäfer M, Albrecht K, Kekow J, Rockwitz K, Liebhaber A, Zink A, et al. Factors associated with treatment satisfaction in patients with rheumatoid arthritis: Data from the biological register RABBIT. RMD Open. 2020;6(3):e001290. doi: 10.1136/rmdopen-2020 001290

9. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696-1709. doi: 10.1038/mp.2016.3

10. Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: Important facts. Psychol Med. 2017;47(13):2229-2237. doi: 10.1017/S0033291717000745

11. Ting EY, Yang AC, Tsai SJ. Role of interleukin-6 in depressive disorder. Int J Mol Sci. 2020;21(6):2194. doi: 10.3390/ijms21062194

12. Lisitsyna TA, Veltishchev DYu, Lila AM, Nasonov EL. Interleukin 6 as a pathogenic factor mediating clinical manifestations and a therapeutic target for rheumatic diseases and depressive disorders. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2019;57(3):318-327 (In Russ.). doi: 10.14412/1995-4484-2019-318-327

13. Drevets WC, Wittenberg GM, Bullmore ET, Manji HK. Immune targets for therapeutic development in depression: Towards precision medicine. Nat Rev Drug Discov. 2022;21(3):224-244. doi: 10.1038/s41573-021-00368-1

14. Citera G, Jain R, Irazoque F, Madariaga H, Gruben D, Wang L, et al. Tofacitinib efficacy in patients with rheumatoid arthritis and probable depression/anxiety: Post hoc analysis of phase 3 and 3b/4 randomized controlled trials. Rheumatol Ther. 2024;11(1):35-50. doi: 10.1007/s40744-023-00612-7

15. Nasonov E, Fatenejad S, Feist E, Ivanova M, Korneva E, Krechikova DG, et al. Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: Efficacy and safety results of a randomised controlled phase III study. Ann Rheum Dis. 2022;81(4):469-479. doi: 10.1136/annrheumdis-2021-219876

16. Feist E, Fatenejad S, Grishin S, Korneva E, Luggen ME, Nasonov E, et al. Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: Efficacy and safety results of a randomised controlled phase III study. Ann Rheum Dis. 2022;81(12):1661-1668. doi: 10.1136/ard-2022-222630

17. Smolen JS, Feist E, Fatenejad S, Grishin SA, Korneva EV, Nasonov EL, et al.; CREDO2 Group. Olokizumab versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2022;387(8):715-726. doi: 10.1056/NEJMoa2201302

18. Feist E, Fleischmann RM, Fatenejad S, Bukhanova D, Grishin S, Kuzkina S, et al. Olokizumab plus methotrexate: Safety and efficacy over 106 weeks of treatment. Ann Rheum Dis. 2024;83(11):1454- 1464. doi: 10.1136/ard-2023-225473

19. Lisitsyna TA, Abramkin AA, Veltishchev DYu, Seravina OF, Kovalevskaya OB, Borisova AB, et al. Efficacy of olokizumab against comorbid depressive disorder in patients with rheumatoid arthritis: Preliminary results of the study. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2023;61(2):188-198 (In Russ.). doi: 10.47360/1995-4484-2023-188-198

20. Anderson JK, Zimmerman L, Caplan L, Michaud K. Measures of rheumatoid arthritis disease activity: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Activity Score with 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data (RAPID), Rheumatoid Arthritis Disease Activity Index (RADAI) and Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based Disease Activity Score with ESR (PDAS1) and Patient-Based Disease Activity Score without ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S14-S36. doi: 10.1002/acr.20621

21. Levis B, Sun Y, He C, Wu Y, Krishnan A, Bhandari PM, et al. Accuracy of the PHQ-2 alone and in combination with the PHQ-9 for screening to detect major depression: Systematic review and meta-analysis. JAMA. 2020;323(22):2290-2300. doi: 10.1001/jama.2020.6504

22. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389. doi: 10.1192/bjp.134.4.382

23. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-55. doi: 10.1111/j.2044-8341.1959.tb00467.x

24. Dragunskaya LS. The study of signs of depressive states by the “Pictogram” method. Experimental studies in pathopsychology. Moscow:1976 (In Russ.)

25. Loginova SV, Rubinstein SA. On the application of the “pictograms” method for the experimental study of mental patients’ thinking. Moscow:1972 (In Russ.).

26. Zeigarnik BV. Thinking disorders in mentally ill (experimental psychological study). Moscow:1958 (In Russ.).

27. Zeigarnik BV. Pathology of thinking. Moscow:Publishing House of Moscow State University;1962 (In Russ.).

28. Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: Dimensions and practical applications. Health Qual Life Outcomes. 2003;9:20.

29. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727- 1736. doi: 10.1007/s11136-011-9903-x

30. World Health Organization. ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva:World Health Organization;1993.

31. American Psychiatric Association. Diagnostic and statistical manual of mental disorders; 5th ed. Arlington:American Psychiatric Association;2013.

32. Epis OM, Giacomelli L, Deidda S, Bruschi E. Tight control applied to the biological therapy of rheumatoid arthritis. Autoimmun Rev. 2013;12(8):839-841. doi: 10.1016/j.autrev.2012.11.010

33. Taylor PC, Feist E, Pope JE, Nash P, Sibilia J, Caporali R, et al. What have we learnt from the inhibition of IL-6 in RA and what are the clinical opportunities for patient outcomes? Ther Adv Musculoskelet Dis. 2024;(16):1759720X241283340. doi: 10.1177/1759720X241283340

34. Wittenberg GM, Stylianou A, Zhang Y, Sun Y, Gupta A, Jagannatha PS, et al. Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol Psychiatry. 2020;25(6):1275-1285. doi: 10.1038/s41380-019-0471-8

35. Starkova AS, Amirdzhanova VN, Panasyuk EYu, Nasonov EL. Functional ability and quality of life in patients with rheumatoid arthritis receiving tocilizumab therapy. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2013;51(6):680-685 (In Russ.). doi: 10.14412/1995-4484-2013-680-5

36. Gerasimova EV, Popkova TV, Gerasimova DA, Kondratyuk PA. Quality of life and functional assessment insufficiency, anxiety and depression screening in patients with rheumatoid arthritis on the background during five years of tocilizumab therapy. Current Problems of Health Care and Medical Statistics. 2023;4:47-62 (In Russ.). doi: 10.24412/2312-2935-2023-4-47-62

37. Behrens F, Burmester GR, Feuchtenberger M, Kellner H, Kuehne C, Liebhaber A, et al. Characterisation of depressive symptoms in rheumatoid arthritis patients treated with tocilizumab during routine daily care. Clin Exp Rheumatol. 2022;40(3):551-559. doi: 10.55563/clinexprheumatol/yu55rd

38. Tiosano S, Yavne Y, Watad A, Langevitz P, Lidar M, Feld J, et al. The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis. Eur J Clin Invest. 2020;50(9):e13268. doi: 10.1111/eci.13268

39. Salvadore G, Nash A, Bleys C. A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. Neuropsychopharmacology. 2018;43:292.

40. Girgis RR, Ciarleglio A, Choo T, Haynes G, Bathon JM, Cremers S, et al. A randomized, double-blind, placebo-controlled clinical trial of tocilizumab, an interleukin-6 receptor antibody, for residual symptoms in schizophrenia. Neuropsychopharmacology. 2018;43(6):1317-1323. doi: 10.1038/npp.2017.258