What are the predictive factors of response to treatment with tocilizumab in routine clinical practice? The experience of the Czech national registry ATTRA

Česká verzia

Authors: K. Pavelka; K. Hejduk ; H. Mann
Authors place of work: Revmatologický ústav a Klinika revmatologie 1. LF UK
Published in the journal: Čes. Revmatol., 21, 2013, No. 3, p. 132-139.
Category: Original Papers

Summary

Tocilizumab is a monoclonal antibody against IL-6R, which is registered for the treatment of moderately- and highly active rheumatoid arthritis in the first and second line of biological treatment. Tocilizumab has been registered on the basis of a series of randomized phase III clinical trials. Other valuable data have been obtained from registries of biological treatment. In the present paper the issue of predictive factors of efficacy of tocilizumab is discussed as well.

Methods:
An observational study of the effectiveness of tocilizumab (TCZ) in routine clinical practice has been performed. Patients enrolled in the study met the criteria of the Czech Society for Rheumatology for the application of biological treatment and were filed into the national registry ATTRA. The study monitored the following parameters: demographic characteristics of a patient, previous and current treatment, the presence of RF and anti-CCP antibodies (ACPA), DAS 28, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), therapeutic response according to EULAR, achieving low disease activity (LDA) after 6 and 12 months (DAS 28 < 3.2) and achieving remission (DAS 28 < 2.6). Pre-treatment predictors of achievement of low disease activity at 6 and 12 months were evaluated.

Statistical analysis:
Univariate logistic regression evaluating the effect of all factors to achieve LDA was performed as the first step. The main factors were assessed by ROC analysis to identify the threshold value that divides the factor preferably in the sense of prediction of achieving LDA.

Results:
A total of 151 patients, whose test results were evaluated for safety, were enrolled into the registry. Data of 113 patients, who were newly started on TCZ at baseline, were used to assess the treatment efficacy. In the remaining 38 patients the efficacy was not evaluated because these were patients who continued therapy in the registry after the termination of clinical trials. Patients with advanced disease with a mean duration of 11 years and high disease activity (DAS 28 5.9, mean CRP 24.1 mg / l) were included in the analysis. The entire six-month monitoring was completed by 88% of patients treated concomitantly with disease-modifying antirheumatic drugs (DMARDs) and 85% of patients on monotherapy with TCZ. Therapeutic response according to EULAR at 6 months was reached by 88–89% of patients. After 12 months of treatment low disease activity was achieved by 67% of patients and 48% of patients were in remission. There were no differences found between the group treated with monotherapy or the group treated with combination of TCZ + DMARDs in achievement of LDA and remission. The only significant predictive indicator of achievement of low disease activity (LDA) after 12 months of treatment was the number of swollen joints. The incidence of adverse events was comparable between patients treated with monotherapy and combination of TCZ + DMARDs.

Conclusion:
The results of our study show good efficacy of TCZ in patients with rheumatoid arthritis in routine clinical practice. No significant difference was found between patients treated with monotherapy or with combination of TCZ+DMARDs in the efficacy or safety. The only predictive indicator of response to treatment with TCZ was the number of swollen joints.

Key words:
Rheumatoid arthritis, biological therapy, prediction of therapeutic response, tocilizumab

Zdroje

1. Redlich K, Smolen JS, et al. Inflammatory bone loss: pathogenetic and therapeutic intervention. Nat Rev Drug Discov 2012;11:234-250.

2. Smolen J, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double blind, placebo-controlled, randomised study. Lancet 2008;371:987-97.

3. Genovese M, McKay JD, Nasonov E, et al. Interleukin - 6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to DMARD. Arthritis Rheum 2008;58:2968-2980.

4. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti. tumour necrosis factor biologicals: results from a 24 week multicentre, randomised placebo controlled study. Ann Rheum Dis 2008;67(11):1516-23.

5. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis. Ann Rheum Dis 2010;69(1):88-96.

6. Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011;63(3):609-21.

7. Bykerk VP, Ostor AJ, Alvaro-Gracia J, Pavelka K, et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses do DMARDs / or TNF inhibitors: a large, open label, study close to clinical practise. Ann Rheum Dis 2012 in print.

8. Pavelka K, Vencovský J. Doporučení České revmatologické společnosti pro léčbu revmatoidní artritidy. Čes Revmatol 2012;20:182-112.

9. Vencovský J. Bezpečnost biologické léčby – Doporučení České revmatologické společnosti. Čes Revmatol 2009;17:146-160.

10. Nishimoto N, Miysaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol 2009;19:12-19.

11. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in MTX inadequate responders: 24 - week symptomatic and structural results of a 2 year randomized, controlled strategy trial in RA (ACT-RAY). Ann Rheum Dis 2013;72(1):43-50.

12. Gabay C, Emery P, Vollenhoven R, et al. Tocilizumab monotherapy is superior to adalimumab monotherapy in reducing disease activity in patients with RA: 24 week data from the phase IV. study ADACTA trial. Abstract. Ann Rheum Dis 2012;71(Suppl.3):152.

13. Conaghan PC. Predicting outcomes in rheumatoid arthritis. Clinical Rheumatol 2011;30(Suppl.1):41-47.

14. Marotte H, Miossec P. Biomarkers for prediction of TNF alpha blockers response in rheumatoid arthritis. Joint Bone Spine 2010;77:297-305.

15. Ortea I, Roschitzki B, Ovalles JG, et al. Discovery of serum proteomic biomarkers for prediction of response to infliximab (a monoclonal anti-TNF antibody) treatment in rheumatoid arthritis. An exploratory analysis. J Proteomics 2012;77:372-82.

16. Klaasen R, Cantaert T, Wijbrandts CA, et al. The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study. Rheumatology 2011;50:1487-1493.

17. Sokka T, Hetland ML, Mäkinen H, et al. Remission and Rheumatoid Arthritis. Data on Patients Receiving usual Care in Twenty-Four Countries. Arthritis Rheum 2008;9:2642-51.

18. Curtis J, Luijtens K, Kavanaugh A. Predicting future response to certolizumab pegol in rheumatoid arthritis patients: features at 12 weeks associated with low disease activity at 1 year. Arthritis Care Res 2012;64:658-67.