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We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP,...
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP, there was a very small difference between week 12 and week 16, consistent with the natural variability observed in the measurements over time in this study. Furthermore, as ASDAS inactive disease is a very stringent outcome measure, which is challenging to achieve and maintain, some variability in the observed responses was to be expected. Of note, 15 patients had inactive disease at week 12, compared with nine patients at week 16. Finally, at week 16, all patients entered the open-label phase of the study, with those receiving placebo switching to tofacitinib 5 mg BID in a blinded manner until the final database release. It is not uncommon to see a perceived ‘dip’ in efficacy at the last visit of the blinded phase in a randomized study, ahead of the open-label extension phase. While the exact cause of this phenomenon is not known, it may be related to patients’ belief that they could have been receiving placebo when they are informed that the blinded phase is over and that they will be entering the open-label phase.
Patients in the study could indeed continue stable background non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids or conventional synthetic disease-modifying drugs (csDMARDs), methotrexate or sulfasalazine. As noted by Wei JC-C, et al., tofacitinib in combination with methotrexate has been shown to be efficacious and well-tolerated in previous phase II and phase III studies of patients with rheumatoid arthritis.2-4 However, methotrexate and systemic corticosteroids have not demonstrated efficacy in the axial skeleton.5 6 We therefore do not believe that methotrexate provides any additional benefits for axial symptoms in ankylosing spondylitis. Notably, in the current study, the proportion of patients using NSAIDs was balanced across treatment groups (both approximately 80%; Table 1), and while csDMARD use was not as balanced (22% of patients receiving tofacitinib 5 mg BID vs 32% of patients receiving placebo), we believe that this should not have had an effect on the results specific to signs and symptoms of axial disease. Furthermore, if there was an effect of csDMARDs, with the imbalance mentioned above, it would have gone against tofacitinib.
We agree with Wei JC-C, et al., that the ASAS Health Index (ASAS-HI) assesses the overall picture of a broad range of health aspects,7 and is therefore a reliable and comprehensive measure to include in clinical trial protocols.8 In the current study, we measured the Ankylosing Spondylitis Quality of Life score, a widely accepted measure,9 which was pre-specified in the clinical trial protocol and is used as standard in the regulatory setting (and is mandated by the Food and Drug Administration). As this study is complete and data collection has ended, we are unable to include the ASAS-HI at this stage, but we will be sensitive to survey fatigue in future clinical trials and continue to advocate for specific endpoints such as the ASAS-HI to be included.
We believe that we have addressed the queries and concerns of Wei JC-C, et al. as far as possible within the scope of this correspondence.
Medical writing support, under the guidance of the authors, was provided by
Kimberley Haines, MSc, CMC Connect, McCann Health Medical Communications, and was funded by Pfizer Inc, New York, NY, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015;163:461–464).
1. Wei JC-C, Ker A, Yang C-R, et al. Correspondence to “Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study” by “Deodhar et al.”. Ann Rheum Dis 2021. https://ard.bmj.com/content/80/8/1004.responses#correspondence-to-%E2%80....
2. Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011;63(8):1150–58. doi: 10.1002/acr.20494
3. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013;381(9865):451–60. doi: 10.1016/S0140-6736(12)61424-X
4. Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013;159(4):253–61. doi: 10.7326/0003-4819-159-4-201308200-00006
5. Haibel H, Brandt HC, Song IH, et al. No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis 2007;66(3):419–21. doi: 10.1136/ard.2006.054098
6. Haibel H, Fendler C, Listing J, et al. Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial. Ann Rheum Dis 2014;73(1):243–46. doi: 10.1136/annrheumdis-2012-203055
7. Assessment of SpondyloArthritis International Society. Description of ASAS Health Index 2021 [Available from: https://www.asas-group.org/instruments/asas-health-index/#:~:text=The%20....
Accessed 24 August 2021.
8. Kiltz U, van der Heijde D, Boonen A, et al. Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis 2018;77(9):1311–17. doi: 10.1136/annrheumdis-2017-212076
9. Doward LC, Spoorenberg A, Cook SA, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003;62(1):20–26.
We read with great interest the article of Deodhar et al assessing the efficacy of tofacitinib in adult patients with active ankylosing spondylitis. The study is interesting and the results are provocative, yet some concerns still remain to be discussed.
Firstly, we have noticed an unexplained pattern in the results of the primary and a few secondary endpoints of the tofacitinib group. In Figure 2A, the ASAS20 response rate increases in the first few weeks but declines at week 16, and then it continues to rise steadily. Also, in Figure 2B, Figure 3, and online supplemental figures, similar counter-trends at week 16 can be found in ASAS40 response rate, ΔASDAS, ΔhsCRP, ASAS 5/6 response, ASDAS LDA, and ASDAS inactive disease. We would like to know the reasons why the results are presented in the current way instead of showing a steady upward trend, and we hope to receive a more detailed explanation of your data.
Secondly, the drugs combination and drug-drug interaction should be brought into discussion. The enrolled patients in this study were receiving continuous background therapies such as NSAID, methotrexate (MTX), sulfasalazine, and oral corticosteroids respectively. Yet, a previous study has shown that rheumatoid arthritis patients treated with tofacitinib with a combination of MTX achieved better improvements in the clinical outcomes. Therefore, the subgroup analyses are strongly suggested to analyze the combined medication effects to ensure the a...
Secondly, the drugs combination and drug-drug interaction should be brought into discussion. The enrolled patients in this study were receiving continuous background therapies such as NSAID, methotrexate (MTX), sulfasalazine, and oral corticosteroids respectively. Yet, a previous study has shown that rheumatoid arthritis patients treated with tofacitinib with a combination of MTX achieved better improvements in the clinical outcomes. Therefore, the subgroup analyses are strongly suggested to analyze the combined medication effects to ensure the accuracy of the study.
Finally, upon evaluating the health status of AS patients, we further suggest including the ASAS Health Index (ASAS HI). It is based on the Comprehensive ICF core set which serves as the model of disease. While other current criteria and indexes focus predominantly on specific aspects of health, ASAS HI adequately assesses the overall picture of a broad range of aspects. A previous study in patients with axial and peripheral spondyloarthritis within 23 countries and 18 translations also proved ASAS HI to be valid, reliable, and responsive on a global level. By including ASAS HI, we believe the assessments in this trial would be more inclusive and comprehensive.
For the abovementioned reasons, we are convinced that more pieces of information should be elucidated and included in order to strengthen the future clinical application of this study.
1. Deodhar, A., et al., Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Annals of the Rheumatic Diseases, 2021. 80(8): p. 1004.
2. Tanaka, Y., et al., Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken), 2011. 63(8): p. 1150-8.
3. Boonen, A., et al., ASAS/WHO ICF Core Sets for ankylosing spondylitis (AS): how to classify the impact of AS on functioning and health. Ann Rheum Dis, 2010. 69(1): p. 102-7.
4. Kiltz, U., et al., Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis, 2018. 77(9): p. 1311-1317.