Rheumatology
Rheumatol Int DOI 10.1007/s00296-015-3243-z
INTERNATIONAL
LETTER TO THE EDITOR - OBSERVATIONAL RESEARCH
Reduced dose of tocilizumab for the maintenance of remission in patients with rheumatoid arthritis: a clinical experience Oscar Epis1 · Cinzia Casu1 · Laura Belloli1 · Emanuela Schito1 · Davide Filippini1 · Marina Muscarà1 · Eleonora Bruschi1
Received: 17 February 2015 / Accepted: 3 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Tocilizumab (TCZ) is a humanized monoclonal interleukin-6 (IL-6) receptor antibody which has demonstrated clinical efficacy in the treatment of patients with moderate–severe rheumatoid arthritis (RA) who experienced inadequate response to methotrexate and one or more antiTNFα agent [1, 2]. The efficacy of TCZ in the treatment of RA is supported by a bulk of evidence which includes randomized clinical trials and observational, ‘field-practice’ studies [2]. TCZ can be administered intravenously at the standard dose of 8 mg/kg either in combination with other disease-modifying antirheumatic drugs (DMARDs) or as a monotherapy [2]. The favorable efficacy and tolerability profile of TCZ is sustained over a long term (up to 9 years) [2]. Although the above-mentioned evidence supports the use of TCZ in clinical practice, additional data are required to fully explore the optimal individualization of this treatment for each single patient [3]. For instance, it has been recently suggested that some of patients on TCZ achieve low disease activity with a lower than registered starting dose, i.e., 4 mg/kg [4]. In a retrospective study by van Herwaarden et al. [4] on 22 RA patients treated with TCZ 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity, 55 % of patients remain in disease remission at 6 months since the reduction in dose; however, a slight increase in the disease activity score 28 (DAS28) was observed at the end of the observation period. Interestingly, all patients with worsened
* Oscar Epis [email protected] 1
Rheumatology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy
disease activity after dose reduction regained low disease activity after returning to the standard dose. The study by van Herwaarden et al. paved the way for further investigation on the effectiveness of reduced-dose TCZ in clinical practice. At our center, we conducted a small pilot, descriptive-only observation in ten RA patients who were under therapy with standard-dose TCZ from at least 12 months and in clinical remission from at least 6 months. After informed consent, TCZ therapy was reduced to 4 mg/kg. Each month, at the infusion visit, patients were monitored using approved clinical scales (VAS, HAQ, CDAI, and SDAI) and by ultrasound (US) examination, which is increasingly used in the determination of disease progression [5]. One patient developed a neoplasia and was then excluded from the analysis. Two patients experienced reactivation of disease, 2 and 4 months since the initiation of reduced-dose TCZ, respectively; standard-dose TCZ therapy was then reinstituted, and clinical remission was observed at the following visit in both patients. We report here the data reported at 12 months after the initiation of reduced-dose TCZ, in the remaining seven patients. Overall, at the end of the observation period, all patients showed stable disease remission, although a minor worsening in all scales was observed (mean DAS28-VES: 1.7 ± 1.1 at baseline vs. 2.4 ± 1.2 at 12 months; DAS28-PCR: 1.5 ± 0.8 vs. 2.2 ± 0.5; HAQ: 0.1 ± 0.4 vs. 0.2 ± 0.4; CDAI: 3.1 ± 2.9 vs. 4.7 ± 2.8; SDAI: 3.2 ± 2.9 vs. 4.8 ± 2.8). Disease remission was also confirmed at US (number of joints with articular effusion: 4.0 ± 2.5 vs. 5.7 ± 4.1; number of joints with synovial hypertrophy: 4.7 ± 2.8 vs. 6.6 ± 4.4; number of positive joints at Power Doppler: 0.7 ± 1.0 vs. 0.6 ± 0.8). Although the preliminary and descriptive-only nature of our pilot analysis does not allow to retrieve any definite conclusion, our findings lend further support to the
13
potential use of TCZ at a reduced dose of 4 mg/kg to maintain clinical and echographic remission in RA patients. In the case of clinical flare, reestablishing the standard dose could allow to restore disease remission. Conflict of interest The authors declare no conflicts of interest.
References 1. Patel AM, Moreland LW (2010) Interleukin-6 inhibition for treatment of rheumatoid arthritis: a review of tocilizumab therapy. Drug Des Dev Ther 4:263–278
13
Rheumatol Int 2. Dhillon S (2014) Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. BioDrugs 28:75–106 3. Tanaka T, Hishitani Y, Ogata A (2014) Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors. Biologics 8:141–153 4. van Herwaarden N, Herfkens-Hol S, van der Maas A, van den Bemt BJ, van Vollenhoven RF, Bijlsma JW, den Broeder AA (2014) Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity. Clin Exp Rheumatol 32:390–394 5. Epis O, Giacomelli L, Bruschi E (2013) Imaging in rheumatology: ultrasafe + ultrasure = ultrasound. Rheumatol Int 33:1901–1903
Rheumatol Int DOI 10.1007/s00296-015-3243-z
INTERNATIONAL
LETTER TO THE EDITOR - OBSERVATIONAL RESEARCH
Reduced dose of tocilizumab for the maintenance of remission in patients with rheumatoid arthritis: a clinical experience Oscar Epis1 · Cinzia Casu1 · Laura Belloli1 · Emanuela Schito1 · Davide Filippini1 · Marina Muscarà1 · Eleonora Bruschi1
Received: 17 February 2015 / Accepted: 3 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Tocilizumab (TCZ) is a humanized monoclonal interleukin-6 (IL-6) receptor antibody which has demonstrated clinical efficacy in the treatment of patients with moderate–severe rheumatoid arthritis (RA) who experienced inadequate response to methotrexate and one or more antiTNFα agent [1, 2]. The efficacy of TCZ in the treatment of RA is supported by a bulk of evidence which includes randomized clinical trials and observational, ‘field-practice’ studies [2]. TCZ can be administered intravenously at the standard dose of 8 mg/kg either in combination with other disease-modifying antirheumatic drugs (DMARDs) or as a monotherapy [2]. The favorable efficacy and tolerability profile of TCZ is sustained over a long term (up to 9 years) [2]. Although the above-mentioned evidence supports the use of TCZ in clinical practice, additional data are required to fully explore the optimal individualization of this treatment for each single patient [3]. For instance, it has been recently suggested that some of patients on TCZ achieve low disease activity with a lower than registered starting dose, i.e., 4 mg/kg [4]. In a retrospective study by van Herwaarden et al. [4] on 22 RA patients treated with TCZ 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity, 55 % of patients remain in disease remission at 6 months since the reduction in dose; however, a slight increase in the disease activity score 28 (DAS28) was observed at the end of the observation period. Interestingly, all patients with worsened
* Oscar Epis [email protected] 1
Rheumatology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy
disease activity after dose reduction regained low disease activity after returning to the standard dose. The study by van Herwaarden et al. paved the way for further investigation on the effectiveness of reduced-dose TCZ in clinical practice. At our center, we conducted a small pilot, descriptive-only observation in ten RA patients who were under therapy with standard-dose TCZ from at least 12 months and in clinical remission from at least 6 months. After informed consent, TCZ therapy was reduced to 4 mg/kg. Each month, at the infusion visit, patients were monitored using approved clinical scales (VAS, HAQ, CDAI, and SDAI) and by ultrasound (US) examination, which is increasingly used in the determination of disease progression [5]. One patient developed a neoplasia and was then excluded from the analysis. Two patients experienced reactivation of disease, 2 and 4 months since the initiation of reduced-dose TCZ, respectively; standard-dose TCZ therapy was then reinstituted, and clinical remission was observed at the following visit in both patients. We report here the data reported at 12 months after the initiation of reduced-dose TCZ, in the remaining seven patients. Overall, at the end of the observation period, all patients showed stable disease remission, although a minor worsening in all scales was observed (mean DAS28-VES: 1.7 ± 1.1 at baseline vs. 2.4 ± 1.2 at 12 months; DAS28-PCR: 1.5 ± 0.8 vs. 2.2 ± 0.5; HAQ: 0.1 ± 0.4 vs. 0.2 ± 0.4; CDAI: 3.1 ± 2.9 vs. 4.7 ± 2.8; SDAI: 3.2 ± 2.9 vs. 4.8 ± 2.8). Disease remission was also confirmed at US (number of joints with articular effusion: 4.0 ± 2.5 vs. 5.7 ± 4.1; number of joints with synovial hypertrophy: 4.7 ± 2.8 vs. 6.6 ± 4.4; number of positive joints at Power Doppler: 0.7 ± 1.0 vs. 0.6 ± 0.8). Although the preliminary and descriptive-only nature of our pilot analysis does not allow to retrieve any definite conclusion, our findings lend further support to the
13
potential use of TCZ at a reduced dose of 4 mg/kg to maintain clinical and echographic remission in RA patients. In the case of clinical flare, reestablishing the standard dose could allow to restore disease remission. Conflict of interest The authors declare no conflicts of interest.
References 1. Patel AM, Moreland LW (2010) Interleukin-6 inhibition for treatment of rheumatoid arthritis: a review of tocilizumab therapy. Drug Des Dev Ther 4:263–278
13
Rheumatol Int 2. Dhillon S (2014) Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. BioDrugs 28:75–106 3. Tanaka T, Hishitani Y, Ogata A (2014) Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors. Biologics 8:141–153 4. van Herwaarden N, Herfkens-Hol S, van der Maas A, van den Bemt BJ, van Vollenhoven RF, Bijlsma JW, den Broeder AA (2014) Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity. Clin Exp Rheumatol 32:390–394 5. Epis O, Giacomelli L, Bruschi E (2013) Imaging in rheumatology: ultrasafe + ultrasure = ultrasound. Rheumatol Int 33:1901–1903
