Age-Specific Patterns in Biologic and Targeted Synthetic DMARDs Discontinuation and Drug-Specific Risks
Keywords:
Rheumatoid arthritis, biologic DMARD, targeted synthetic DMARD, treatment failure
Abstract
This study aims to analyse and delineate the predictor factors linked to the likelihood of treatment failure, encompassing adverse drug reactions (ADRs) or inefficacy. The specific focus of this investigation is on elderly Malaysian rheumatoid arthritis (RA) patients undergoing therapy with biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). An observational, prospective longitudinal study on individuals with RA used Cox proportional hazards regression to compare treatment failure risk due to ADRs or lack of effectiveness across age groups. To ensure contributing factors related to treatment failure, adjustments were made for factors such as age, gender, disease duration, comorbidities, smoking, DAS28, and steroid use. In a cohort of 270 patients, 32.2% were classified as elderly. The elderly group exhibited higher RA disease activity, measured by DAS28 ESR, compared to the younger population (mean DAS28 ESR 6.748 versus 5.916, p<0.001). Regarding treatment, elderly individuals were more likely to receive biologic and targeted synthetic DMARDs as monotherapy rather than combination therapy (52.9% versus 47.1%, p = 486), with non-TNF inhibitors being more prevalent than TNF inhibitors (50.6% versus 37.9%, p = 0.040). Notably, the administration of targeted synthetic DMARDs in the elderly showed a significant negative association with treatment failure compared to TNF inhibitor therapy (adjusted HR: 0.12, 95% CI: 0.038, 1.265, p<0.001) after adjustment. Noteworthy predictors of failure in both biologic and targeted synthetic DMARD therapies, encompassing comorbidities, polypharmacy, smoking, corticosteroid use, and gender, were discerned. The utilisation of targeted synthetic DMARDs among elderly RA patients suggests a potentially more suitable and secure treatment option compared to biologic DMARDs. The identified predictors hold potential significance for guiding clinical decisions, particularly in the context of considering the discontinuation of biologic and targeted synthetic DMARDs in patients.
References
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Jinno, S., Onishi, A., Dubreuil, M., Hashimoto, M., Yamamoto, W., Murata, K.,…Ebina, K. (2021). Comparison of the drug retention and reasons for discontinuation of tumor necrosis factor inhibitors and interleukin-6 inhibitors in Japanese patients with elderly-onset rheumatoid arthritis—the ANSWER cohort study. Arthritis research & therapy, 23(1), 1-9. https://doi.org/https://doi.org/10.1186/s13075-021-02496-w
Kalden, J. R., & Schulze-Koops, H. (2017). Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nature Reviews Rheumatology, 13(12), 707-718. https://doi.org/https://doi.org/10.1038/nrrheum.2017.187
Kawashima, H., Kagami, S.-i., Kashiwakuma, D., Takahashi, K., Yokota, M., Furuta, S., & Iwamoto, I. (2017). Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis. Rheumatology international, 37, 369-376. https://doi.org/https://doi.org/10.1007/s00296-016-3631-z
Krams, T., Ruyssen-Witrand, A., Nigon, D., Degboe, Y., Tobon, G., Fautrel, B.,…Constantin, A. (2016). Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: the ESPOIR cohort. Joint Bone Spine, 83(5), 511-515. https://doi.org/https://doi.org/10.1016/j.jbspin.2015.09.010
Lauper, K., Nordström, D. C., Pavelka, K., Hernández, M. V., Kvien, T. K., Kristianslund, E. K.,…Codreanu, C. (2018). Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration. Annals of the rheumatic diseases, 77(9), 1276-1282. https://doi.org/https://doi.org/10.1136/annrheumdis-2017-212845
Michaud, K., & Wolfe, F. (2007). Comorbidities in rheumatoid arthritis. Best practice & research Clinical rheumatology, 21(5), 885-906. https://doi.org/https://doi.org/10.1016/j.berh.2007.06.002
Mueller, R. B., Kaegi, T., Finckh, A., Haile, S. R., Schulze-Koops, H., & von Kempis, J. (2014). Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort. Rheumatology, 53(4), 671-677. https://doi.org/https://doi.org/10.1093/rheumatology/ket399
Nakao, Y., Asanuma, Y. F., Wada, T. T., Matsuda, M., Yazawa, H., Yoshida, Y.,…Mimura, T. (2021). Efficacy, safety, and adherence of tocilizumab therapy in elderly patients with rheumatoid arthritis: A real-world observational study. European Journal of Inflammation, 19, 20587392211045790.
Nishina, N., Kaneko, Y., Kameda, H., Kuwana, M., & Takeuchi, T. (2013). Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. Clinical rheumatology, 32, 1661-1666. https://doi.org/https://doi.org/10.1007/s10067-013-2309-0
Okazaki, M., Kobayashi, H., Shimizu, H., Ishii, Y., Yajima, T., & Kanbori, M. (2018). Safety, effectiveness, and treatment persistence of golimumab in elderly patients with rheumatoid arthritis in real-world clinical practice in Japan. Rheumatology and therapy, 5, 135-148. https://doi.org/https://doi.org/10.1007/s40744-018-0101-y
Pascual-Salcedo, D., Plasencia, C., Ramiro, S., Nuno, L., Bonilla, G., Nagore, D.,…Martín-Mola, E. (2011). Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology, 50(8), 1445-1452. https://doi.org/https://doi.org/10.1093/rheumatology/ker124
Pope, J., Bessette, L., Jones, N., Fallon, L., Woolcott, J., Gruben, D.,…Haraoui, B. (2020). Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years. Rheumatology, 59(3), 568-574. https://doi.org/https://doi.org/10.1093/rheumatology/kez324
Radovits, B. J., Kievit, W., Fransen, J., van de Laar, M. A., Jansen, T. L., van Riel, P. L., & Laan, R. F. (2009). Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis. Annals of the rheumatic diseases, 68(9), 1470-1473. https://doi.org/https://doi.org/10.1136/ard.2008.094730
Siegrist, C.-A., & Aspinall, R. (2009). B-cell responses to vaccination at the extremes of age. Nature Reviews Immunology, 9(3), 185-194. https://doi.org/https://doi.org/10.1038/nri2508
Tanaka, Y., Harigai, M., Takeuchi, T., Yamanaka, H., Ishiguro, N., Yamamoto, K.,…Ishii, Y. (2016). Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial. Modern Rheumatology, 26(4), 481-490. https://doi.org/https://doi.org/10.3109/14397595.2015.1109762
Wolfe, F., & Michaud, K. (2010). The Hawthorne effect, sponsored trials, and the overestimation of treatment effectiveness. The Journal of rheumatology, 37(11), 2216-2220. https://doi.org/https://doi.org/10.3899/jrheum.100497
Yathish, G., Balakrishnan, C., Mangat, G., & Parikshit, S. (2015). Immunomodulators in managing geriatric rheumatoid arthritis. Internet Journal of Rheumatology and Clinical Immunology, 3(S1). https://doi.org/https://doi.org/10.15305/ijrci/v3iS1/156
Bartelds, G. M., Wijbrandts, C. A., Nurmohamed, M. T., Stapel, S., Lems, W. F., Aarden, L.,…Wolbink, G. J. (2007). Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Annals of the rheumatic diseases, 66(7), 921-926. https://doi.org/https://doi.org/10.1136/ard.2006.065615
Bathon, J. M., Fleischmann, R. M., Van der Heijde, D., Tesser, J. R., Peloso, P. M., Chon, Y., & White, B. (2006). Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. The Journal of rheumatology, 33(2), 234-243.
Boots, A. M., Maier, A. B., Stinissen, P., Masson, P., Lories, R. J., & De Keyser, F. (2013). The influence of ageing on the development and management of rheumatoid arthritis. Nature Reviews Rheumatology, 9(10), 604-613. https://doi.org/https://doi.org/10.1038/nrrheum.2013.92
Busquets, N., Tomero, E., Descalzo, M. Á., Ponce, A., Ortiz-Santamaría, V., Surís, X.,…Gómez-Reino, J. J. (2011). Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry. Rheumatology, 50(11), 1999-2004.
Charlesworth, C. J., Smit, E., Lee, D. S., Alramadhan, F., & Odden, M. C. (2015). Polypharmacy among adults aged 65 years and older in the United States: 1988–2010. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 70(8), 989-995. https://doi.org/https://doi.org/10.1093/gerona/glv013
Choy, E. H., Bernasconi, C., Aassi, M., Molina, J. F., & Epis, O. M. (2017). Treatment of Rheumatoid Arthritis With Anti–Tumor Necrosis Factor or Tocilizumab Therapy as First Biologic Agent in a Global Comparative Observational Study. Arthritis care & research, 69(10), 1484-1494. https://doi.org/https://doi.org/10.1002/acr.23303
England, B. R., Sayles, H., Mikuls, T. R., Johnson, D. S., & Michaud, K. (2015). Validation of the rheumatic disease comorbidity index. Arthritis care & research, 67(6), 865-872. https://doi.org/https://doi.org/10.1002/acr.22456
Filippini, M., Bazzani, C., Favalli, E. G., Marchesoni, A., Atzeni, F., Sarzi-Puttini, P.,…Gorla, R. (2010). Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid arthritis: an observational study. Clinical reviews in allergy & immunology, 38, 90-96. https://doi.org/https://doi.org/10.1007/s12016-009-8142-1
Genevay, S., Finckh, A., Ciurea, A., Chamot, A. M., Kyburz, D., Gabay, C., & Arthritis, P. o. t. S. C. Q. M. P. f. R. (2007). Tolerance and effectiveness of anti–tumor necrosis factor α therapies in elderly patients with rheumatoid arthritis: A population‐based cohort study. Arthritis care & research, 57(4), 679-685. https://doi.org/https://doi.org/10.1002/art.22688
Gomez, E. L., Gun, S. C., Somanath, S. D., Chinna, K., & Radhakrishnan, A. K. (2013). Ethnic differences in the prognostic utility of rheumatoid factor isotypes and anticyclic citrullinated peptides in rheumatoid arthritis patients: a cross-sectional study. Modern Rheumatology, 23(4), 716-721. https://doi.org/https://doi.org/10.1007/s10165-012-0718-6
Goronzy, J. J., Shao, L., & Weyand, C. M. (2010). Immune aging and rheumatoid arthritis. Rheumatic Disease Clinics, 36(2), 297-310. https://doi.org/https://doi.org/10.1016/j.rdc.2010.03.001
Hajjar, E. R., Cafiero, A. C., & Hanlon, J. T. (2007). Polypharmacy in elderly patients. The American journal of geriatric pharmacotherapy, 5(4), 345-351. https://doi.org/https://doi.org/10.1016/j.amjopharm.2007.12.002
Hetland, M. L., Christensen, I. J., Tarp, U., Dreyer, L., Hansen, A., Hansen, I. T.,…Poulsen, U. E. (2010). Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 62(1), 22-32. https://doi.org/https://doi.org/10.1002/art.27227
Hsieh, S.-C. (2018). Real-world use of tofacitinib compared with tumor necrosis factor inhibitors in a cohort of 211 patients with rheumatoid arthritis: data from a drug-based registry study in Taiwan. 2018 ACR/ARHP Annual Meeting,
Hyrich, K., Watson, K., Silman, A., Symmons, D. P., & Register, B. B. (2006). Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology, 45(12), 1558-1565. https://doi.org/https://doi.org/10.1093/rheumatology/kel149
Iannone, F., Ferraccioli, G., Sinigaglia, L., Favalli, E., Sarzi-Puttini, P., Atzeni, F.,…Farina, I. (2018). Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics’ register GISEA. Clinical rheumatology, 37, 315-321. https://doi.org/https://doi.org/10.1007/s10067-017-3846-8
Jani, M., Barton, A., Warren, R. B., Griffiths, C. E., & Chinoy, H. (2014). The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology, 53(2), 213-222. https://doi.org/https://doi.org/10.1093/rheumatology/ket260
Jinno, S., Onishi, A., Dubreuil, M., Hashimoto, M., Yamamoto, W., Murata, K.,…Ebina, K. (2021). Comparison of the drug retention and reasons for discontinuation of tumor necrosis factor inhibitors and interleukin-6 inhibitors in Japanese patients with elderly-onset rheumatoid arthritis—the ANSWER cohort study. Arthritis research & therapy, 23(1), 1-9. https://doi.org/https://doi.org/10.1186/s13075-021-02496-w
Kalden, J. R., & Schulze-Koops, H. (2017). Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nature Reviews Rheumatology, 13(12), 707-718. https://doi.org/https://doi.org/10.1038/nrrheum.2017.187
Kawashima, H., Kagami, S.-i., Kashiwakuma, D., Takahashi, K., Yokota, M., Furuta, S., & Iwamoto, I. (2017). Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis. Rheumatology international, 37, 369-376. https://doi.org/https://doi.org/10.1007/s00296-016-3631-z
Krams, T., Ruyssen-Witrand, A., Nigon, D., Degboe, Y., Tobon, G., Fautrel, B.,…Constantin, A. (2016). Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: the ESPOIR cohort. Joint Bone Spine, 83(5), 511-515. https://doi.org/https://doi.org/10.1016/j.jbspin.2015.09.010
Lauper, K., Nordström, D. C., Pavelka, K., Hernández, M. V., Kvien, T. K., Kristianslund, E. K.,…Codreanu, C. (2018). Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration. Annals of the rheumatic diseases, 77(9), 1276-1282. https://doi.org/https://doi.org/10.1136/annrheumdis-2017-212845
Michaud, K., & Wolfe, F. (2007). Comorbidities in rheumatoid arthritis. Best practice & research Clinical rheumatology, 21(5), 885-906. https://doi.org/https://doi.org/10.1016/j.berh.2007.06.002
Mueller, R. B., Kaegi, T., Finckh, A., Haile, S. R., Schulze-Koops, H., & von Kempis, J. (2014). Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort. Rheumatology, 53(4), 671-677. https://doi.org/https://doi.org/10.1093/rheumatology/ket399
Nakao, Y., Asanuma, Y. F., Wada, T. T., Matsuda, M., Yazawa, H., Yoshida, Y.,…Mimura, T. (2021). Efficacy, safety, and adherence of tocilizumab therapy in elderly patients with rheumatoid arthritis: A real-world observational study. European Journal of Inflammation, 19, 20587392211045790.
Nishina, N., Kaneko, Y., Kameda, H., Kuwana, M., & Takeuchi, T. (2013). Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. Clinical rheumatology, 32, 1661-1666. https://doi.org/https://doi.org/10.1007/s10067-013-2309-0
Okazaki, M., Kobayashi, H., Shimizu, H., Ishii, Y., Yajima, T., & Kanbori, M. (2018). Safety, effectiveness, and treatment persistence of golimumab in elderly patients with rheumatoid arthritis in real-world clinical practice in Japan. Rheumatology and therapy, 5, 135-148. https://doi.org/https://doi.org/10.1007/s40744-018-0101-y
Pascual-Salcedo, D., Plasencia, C., Ramiro, S., Nuno, L., Bonilla, G., Nagore, D.,…Martín-Mola, E. (2011). Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology, 50(8), 1445-1452. https://doi.org/https://doi.org/10.1093/rheumatology/ker124
Pope, J., Bessette, L., Jones, N., Fallon, L., Woolcott, J., Gruben, D.,…Haraoui, B. (2020). Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years. Rheumatology, 59(3), 568-574. https://doi.org/https://doi.org/10.1093/rheumatology/kez324
Radovits, B. J., Kievit, W., Fransen, J., van de Laar, M. A., Jansen, T. L., van Riel, P. L., & Laan, R. F. (2009). Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis. Annals of the rheumatic diseases, 68(9), 1470-1473. https://doi.org/https://doi.org/10.1136/ard.2008.094730
Siegrist, C.-A., & Aspinall, R. (2009). B-cell responses to vaccination at the extremes of age. Nature Reviews Immunology, 9(3), 185-194. https://doi.org/https://doi.org/10.1038/nri2508
Tanaka, Y., Harigai, M., Takeuchi, T., Yamanaka, H., Ishiguro, N., Yamamoto, K.,…Ishii, Y. (2016). Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial. Modern Rheumatology, 26(4), 481-490. https://doi.org/https://doi.org/10.3109/14397595.2015.1109762
Wolfe, F., & Michaud, K. (2010). The Hawthorne effect, sponsored trials, and the overestimation of treatment effectiveness. The Journal of rheumatology, 37(11), 2216-2220. https://doi.org/https://doi.org/10.3899/jrheum.100497
Yathish, G., Balakrishnan, C., Mangat, G., & Parikshit, S. (2015). Immunomodulators in managing geriatric rheumatoid arthritis. Internet Journal of Rheumatology and Clinical Immunology, 3(S1). https://doi.org/https://doi.org/10.15305/ijrci/v3iS1/156
Published
2024-10-09
How to Cite
Shamsi Poor Gheshmi, N., Hayat Khan, A., Syed Sulaiman, S. A., Rahmawati, F., & Ling, L. C. (2024). Age-Specific Patterns in Biologic and Targeted Synthetic DMARDs Discontinuation and Drug-Specific Risks . Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.14611
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Research Article
