Skip to main content

Advertisement

SpringerLink
Log in

First multi-center retrospective study assessed the compliance with and persistence of biological therapies in Bulgarian population with rheumatoid arthritis

  • Observational Research
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis is an inflammatory joint disease that causes progressive joint damage, leading to severe disability. Early diagnosis, optimal therapy, and strict adherence to the prescribed medication are key factors that allow for the cessation of the disease progression and the preserving of the patient’s quality of life. The objective of this study was to estimate the compliance to and persistence of biologic disease-modifying anti-rheumatic drugs (bDMARDs) among the Bulgarian population with RA. This retrospective observational cohort study included 179 patients, who were tracked over a 36-month period. During baseline and subsequent follow-up visits (at months 6, 12, 24, and 36), we monitored the disease activity, side effects, medication tolerability and effectiveness, compliance, and persistence to the prescribed biologic agent. The compliance with bDMARDs among Bulgarian patients with RA was 85.5% in the first year, 76.0% in the second year, and 63.7% in the third year. The Infliximab cohort showed the lowest compliance rate (50%), with the other subgroups bDMARDs having similar results (64–70%) during the period of observation. The median therapy duration across all patient cohorts is 61.9 months (IQR 55.7–67.6). Our study did not establish any significant impact of gender, age and disease duration, concomitant treatment with methotrexate, type of biologic agent and previous exposure to biological agents on the treatment adherence. The compliance with and persistence of the prescribed bDMARD among the Bulgarian population with RA is unsatisfactory. Therapy interruption and nonadherence to recommended therapy are associated with disease progression and patient disability. The consequences include not only financial burdens but also psychosocial and physical impacts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets generated and/or analyzed during the current study are not public available, but are available from the correcsponding author on reasonable request.

References

  1. Popova V, Vazhev Z, Geneva-Popova M, Batalov A (2019) Comparison of RANKL expression, inflammatory markers, and cardiovascular risk in patients with acute coronary syndrome with and without rheumatoid arthritis. Rheumatol Int 39:1723–1732. https://doi.org/10.1007/s00296-019-04367-9

    Article  CAS  PubMed  Google Scholar 

  2. Kirilova E, Kirilov N, Vladeva S (2019) AB0838 comparison of the characteristics of the osteoporotic patients with and without rheumatoid arthritis through radiofrequency echographic multi spectrometry. Ann Rheum Dis 78:1888–1889. https://doi.org/10.1136/annrheumdis-2019-eular.2203

    Article  Google Scholar 

  3. Mayou R (1977) Compliance with Therapeutic Regimens Edited by Sackett DL and Haynes BR Baltimore and London: Johns Hopkins University Press (1976) Pp xiv 287, Index 5 pp. Br J Psychiatry 131: 214–214. https://doi.org/10.1192/S0007125000016251

  4. World Health Organization. Adherence to long-term therapies: evidence for action. 2003. www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Accessed 20.08.2023

  5. Haynes RB, McDonald H, Garg AX, Montague P (2002) Interventions for helping patients to follow prescriptions for medications. Cochrane Database Syst Rev 2:000011. https://doi.org/10.1002/14651858.CD000011

    Article  Google Scholar 

  6. Garcês S, Demengeot J (2018) The immunogenicity of biologic therapies. Curr Probl Dermatol 53:37–48. https://doi.org/10.1159/000478077

    Article  PubMed  Google Scholar 

  7. Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, van Vollenhoven RF, de Wit M, Aletaha D, Aringer M, Askling J, Balsa A, Boers M, den Broeder AA, Buch MH, Buttgereit F, Caporali R, Cardiel MH, van der Heijde D (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79:685–699. https://doi.org/10.1136/annrheumdis-2019-216655

    Article  CAS  PubMed  Google Scholar 

  8. Harrold LR, Andrade SE (2009) Medication adherence of patients with selected rheumatic conditions: a systematic review of the literature. Semin Arthritis Rheum 38:396–402. https://doi.org/10.1016/j.semarthrit.2008.01.011

    Article  PubMed  Google Scholar 

  9. Koncz T, Pentek M, Brodszky V, Ersek K, Orlewska E, Gulacsi L (2010) Adherence to biologic DMARD therapies in rheumatoid arthritis. Expert Opin Biol Ther 10:1367–1378. https://doi.org/10.1517/14712598.2010.510508

    Article  CAS  PubMed  Google Scholar 

  10. Salt E, Frazier SK (2010) Adherence to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a narrative review of the literature. Orthop Nurs 29:260–275. https://doi.org/10.1097/NOR.0b013e3181e5c2c9

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK (2008) Medication compliance and persistence: terminology and definitions. Value Health 11:44–47. https://doi.org/10.1111/j.1524-4733.2007.00213.x

    Article  PubMed  Google Scholar 

  12. Neycheva S, Naseva E, Batalov Z et al (2023) Adherence to biological therapies in patients with rheumatoid arthritis: a retrospective cohort study. Rheumatol Int 43:1287–1296. https://doi.org/10.1007/s00296-023-05327-0

    Article  CAS  PubMed  Google Scholar 

  13. Kay J, Upchurch KS (2012) ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology 51:5–9. https://doi.org/10.1093/rheumatology/kes279

    Article  Google Scholar 

  14. Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J, Ramiro S, Winthrop K, de Wit M, Aletaha D, Betteridge N, Bijlsma JW, Boers M, Buttgereit F, Combe B, Cutolo M, van der Heijde D (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509. https://doi.org/10.1136/annrheumdis-2013-204573

    Article  CAS  PubMed  Google Scholar 

  15. World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194. https://doi.org/10.1001/jama.2013.281053

    Article  CAS  Google Scholar 

  16. World Health Organization (2013) Ethical issues in patient safety research: interpreting existing guidance. IOP Publishing World Health Organization. https://apps.who.int/iris/handle/10665/85371. Accessed 04 Apr 2023

  17. Harley CR, Frytak JR, Tandon N (2003) Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate. Am J Manag Care 9:136–143

    Google Scholar 

  18. Murage M, Tongbram V, Feldman S, Malatestinic W, Larmore C, Muram T, Araujo A (2018) Medication adherence and persistence in patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis: a systematic literature review. Patient Preference Adher 12:1483–1503. https://doi.org/10.2147/ppa.s167508

    Article  Google Scholar 

  19. Rubbert-Roth A, Szabó MZ, Kedves M et al (2019) Failure of anti-TNF treatment in patients with rheumatoid arthritis: the pros and cons of the early use of alternative biological agents. Autoimmun Rev. https://doi.org/10.1016/j.autrev.2019.102398

    Article  PubMed  Google Scholar 

  20. Jørgensen TS, Kristensen LE, Christensen R, Bliddal H, Lorenzen T, Hansen MS, Lund Hetland M (2015) Effectiveness and drug adherence of biologic monotherapy in routine care of patients with rheumatoid arthritis: a cohort study of patients registered in the Danish biologics registry. Rheumatology. https://doi.org/10.1093/rheumatology/kev216

    Article  PubMed  Google Scholar 

  21. Leffers HC, Ostergaard M, Glintborg B et al (2011) Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry. Ann Rheum Dis 70:1216–1222. https://doi.org/10.1136/ard.2010.140129

    Article  CAS  PubMed  Google Scholar 

  22. Li P, Blum MA, Von Feldt J, Hennessy S, Doshi JA (2010) Adherence, discontinuation, and switching of biologic therapies in medicaid enrollees with rheumatoid arthritis. Value in Health 13:805–812. https://doi.org/10.1111/j.1524-4733.2010.00764.x

    Article  CAS  PubMed  Google Scholar 

  23. Aaltonen K, Joensuu J, Pirilä L, Kauppi M, Uutela T, Varjolahti-Lehtinen T, Sokka T (2016) Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis in Finland. Scand J Rheumatol 46:359–363. https://doi.org/10.1080/03009742.2016.1234641

    Article  CAS  PubMed  Google Scholar 

  24. Chu L-H, Kawatkar AA, Gabriel SE (2015) Medication adherence and attrition to biologic treatment in rheumatoid arthritis patients. Clin Ther 37:660–666. https://doi.org/10.1016/j.clinthera.2014.10.022

    Article  PubMed  Google Scholar 

  25. Marras C, Monteagudo I, Salvador G, de Toro FJ, Escudero A, Alegre-Sancho JJ, Raya E, Ortiz A, Carmona L, Mestre Y, CeaCalvo L, Calvo-Alen J (2017) Identification of patients at risk of non-adherence to oral antirheumatic drugs in rheumatoid arthritis using the Compliance Questionnaire in Rheumatology: an ARCO sub-study. Rheumatol Int 37:1195–1202. https://doi.org/10.1007/s00296-017-3737-y

    Article  PubMed  Google Scholar 

  26. Tkacz J, Ellis L, Bolge SC, Meyer R, Brady BL, Ruetsch C (2014) Utilization and adherence patterns of subcutaneously administered anti-tumor necrosis factor treatment among rheumatoid arthritis patients. Clin Ther 36:737–747. https://doi.org/10.1016/j.clinthera.2014.02.019

    Article  CAS  PubMed  Google Scholar 

  27. Müller R, Kallikorm R, Põlluste K, Lember M (2011) Compliance with treatment of rheumatoid arthritis. Rheumatol Int 32:3131–3135. https://doi.org/10.1007/s00296-011-2162-x

    Article  PubMed  Google Scholar 

  28. Souto A, Maneiro JR, Gómez-Reino JJ (2016) Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology 55:523–534. https://doi.org/10.1093/rheumatology/kev37

    Article  CAS  PubMed  Google Scholar 

  29. Fautrel B, Belhassen M, Hudry C et al (2020) Predictive factors of tumour necrosis inhibitor treatment persistence for rheumatoid arthritis: An observational study in 8052 patients. Joint Bone Spine 87:137–139. https://doi.org/10.1016/j.jbspin.2019.10.004

    Article  PubMed  Google Scholar 

  30. Du Pan SM, Scherer A, Gabay C, Finckh A (2012) Differential drug retention between anti-TNF agents and alternative biological agents after inadequate response to an anti-TNF agent in rheumatoid arthritis patients. Ann Rheum Dis 71:997–999. https://doi.org/10.1136/annrheumdis-2011-200882

    Article  CAS  PubMed  Google Scholar 

  31. Forsblad-dElia H, Bengtsson K, Kristensen LE, Jacobsson LT (2015) Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoid arthritis: results from the Swedish biologics register. Rheumatology 54:1186–1193. https://doi.org/10.1093/rheumatology/keu455

    Article  CAS  PubMed  Google Scholar 

  32. Borah BJ, Huang X, Zarotsky V, Globe D (2009) Trends in RA patients’ adherence to subcutaneous anti-TNF therapies and costs. Curr Med Res Opin 25:1365–1377. https://doi.org/10.1185/03007990902896386

    Article  PubMed  Google Scholar 

  33. Tuncay R, Eksioglu E, Cakir B, Gurcay E, Cakci A (2007) Factors affecting drug treatment compliance in patients with rheumatoid arthritis. Rheumatol Int 27:743–746. https://doi.org/10.1007/s00296-006-0299-9

    Article  PubMed  Google Scholar 

  34. Gadallah MA, Boulos DNK, Dewedar S, Gebrel A, Morisky DE (2015) Assessment of Rheumatoid Arthritis Patients’ Adherence to Treatment. Am J Med Sci 349:151–156. https://doi.org/10.1097/maj.0000000000000376

    Article  PubMed  Google Scholar 

  35. Joplin S, van der Zwan R, Joshua F, Wong PK (2015) Medication adherence in patients with rheumatoid arthritis: the effect of patient education, health literacy, and musculoskeletal ultrasound. Biomed Res Int 2015:150658. https://doi.org/10.1155/2015/150658

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gallo G, Brock F, Kerkmann U, Kola B, Huizinga TWJ (2016) Efficacy of etanercept in combination with methotrexate in moderate-to severe rheumatoid arthritis is not dependent on methotrexate dosage. RMD Open 2:e000186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Grijalva CG, Chung CP, Arbogast PG, Stein CM, Mitchel EF Jr, Griffin MR (2007) Assessment of adherence to and persistence on disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis. Med care 45(102):S66–S76. https://doi.org/10.1097/MLR.0b013e318041384c

    Article  PubMed  Google Scholar 

  38. Strand V, Miller P, Williams SA, Saunders K, Grant S, Kremer J (2017) Discontinuation of biologic therapy in rheumatoid arthritis: analysis from the corrona RA Registry. Rheumatol Ther 4:489–502. https://doi.org/10.1007/s40744-017-0078-y

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lauper K, Mongin D, Alpizar-Rodriguez D et al (2019) Drug retention of biological DMARD in rheumatoid arthritis patients: the role of baseline characteristics and disease evolution. Rheumatology (Oxford) 58:2221–2229. https://doi.org/10.1093/rheumatology/kez221

    Article  PubMed  Google Scholar 

  40. Du Pan SM, Scherer A, Gabay C, Finckh A (2017) Differential drug retention between anti-TNF agents and alternative biological agents after inadequate response to an anti-TNF agent in rheumatoid arthritis patients. Ann Rheum Dis 71:997–999. https://doi.org/10.1136/annrheumdis-2011-200882

    Article  CAS  Google Scholar 

  41. Leon L, Rodriguez-Rodriguez L, Rosales Z et al (2016) Long-term drug survival of biological agents in patients with rheumatoid arthritis in clinical practice. Scand J Rheumatol 45:456–460. https://doi.org/10.3109/03009742.2016.1141979

    Article  CAS  PubMed  Google Scholar 

  42. Lee J, Mason R, Martin L, Barnabe C (2014) Biologic therapy response and drug survival for females compared to males with rheumatoid arthritis: a cohort study. Rheumatol Int 34:1449–1453. https://doi.org/10.1007/s00296-014-2999-x

    Article  PubMed  Google Scholar 

  43. Kristensen LE, Saxne T, Nilsson JA, Geborek P (2006) Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden. Arthritis Res Ther 8:R174. https://doi.org/10.1186/ar208438

    Article  PubMed  PubMed Central  Google Scholar 

  44. Skácelová M, Nekvindová L, Mann H et al (2022) The beneficial effect of csDMARDs co-medication on drug persistence of first-line TNF inhibitor in rheumatoid arthritis patients: data from Czech ATTRA registry. Rheumatol Int 42:803–814. https://doi.org/10.1007/s00296-021-05072-239

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhang J, Xie F, Delzell E, Yun H, Lewis JD, Haynes K, Curtis JR (2015) Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients. Arthritis Care Res 67:624–632. https://doi.org/10.1002/acr.22510

    Article  CAS  Google Scholar 

  46. Markenson J, Gibofsky A, Palmer W, Keystone E, Schiff M, Feng J, Baumgartner S (2011) Persistence with anti-tumor necrosis factor therapies in patients with rheumatoid arthritis: observations from the RADIUS Registry. J Rheumatol 38:1273–1281. https://doi.org/10.3899/jrheum.101142

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors extend their gratitude to Dr. B. Oparanov, Head of the Department of Rheumatology, Military Medical Academy-MHAT, Sofia, Bulgaria for contributing to the data collection, providing and caring for the study patients, as well as his support. Additionally, the authors appreciate the critical comments and proofreading provided by Prof. Z. Kolarov, MD, St. Ivan Rilski UMHAT, Clinic of Rheumatology, Sofia, Bulgaria.

Funding

A therapeutic approach with bDMARD in adults is funded by the Bulgarian National Health Insurance Organization. All authors declare no competing financial or non-financial interests.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Military Medical Academy, MHAT - Sofia, 3 Sveti Georgi Sofiyski str., 1606, Sofia, Bulgaria

    Stefka Neycheva

  2. Faculty of Public Health “Prof. Tsekomir Vodenicharov, MD, DSc”, Medical University of Sofia, 8 Byalo More str., 1527, Sofia, Bulgaria

    Emilia Naseva

  3. Clinic of Rheumatology, UMHAT “Kaspela”, Medical University of Plovdiv, 64 Sofia str., 4000, Plovdiv, Bulgaria

    Zguro Batalov, Rositsa Karalilova & Anastas Batalov

Authors
  1. Stefka Neycheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emilia Naseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zguro Batalov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rositsa Karalilova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anastas Batalov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AB, SN, RK, and ZB developed the conception and design of the study, provided and cared for the study patients, contributed to the acquisition, analysis and interpretation of the data. EN designed and carried out the data analysis, and contributed to the interpretation of the data. SN, EN, RK, AB, and ZB co-wrote the paper. All authors reviewed the paper critically for important intellectual content; are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors take full responsibility for the integrity and accuracy of all aspects of the work. The authors maintained full control of the content of the manuscript. All authors had full access to all the data in this study. Authors have confidence in the integrity of the contributions of their co-authors approved the version to be published.

Corresponding author

Correspondence to Stefka Neycheva.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest with respect to the authorship and/or publication of this paper.

Ethical standards

This paper does not include any studies conducted on human participants by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neycheva, S., Naseva, E., Batalov, Z. et al. First multi-center retrospective study assessed the compliance with and persistence of biological therapies in Bulgarian population with rheumatoid arthritis. Rheumatol Int 43, 2233–2243 (2023). https://doi.org/10.1007/s00296-023-05458-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-023-05458-4

Keywords

Search

Navigation