Abstract
Objective: To evaluate the real-world effectiveness and safety of adalimumab for the treatment of ankylosing spondylitis (AS) in Japan.
Methods: All AS patients initiated on adalimumab from 27 October 2010 to 28 May 2015, were enrolled. Patient characteristics at baseline, changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, and adverse drug reactions (ADRs) for 24 weeks from the first adalimumab treatment were evaluated.
Results: Of 403 enrolled patients, 396 and 374 comprised the safety and effectiveness analysis sets, respectively. In the safety analysis set, 266/396 (67.2%) were males, with a mean ± standard deviation (SD) age of 46.3 ± 15.6 years and mean ± SD disease duration of 9.8 ± 9.8 years. Of 236 patients examined for human leukocyte antigen (HLA)-B27, 131 (55.5%) were HLA-B27–positive. In the effectiveness analysis set, the mean ± SD BASDAI score was 4.9 ± 2.3 at baseline (n = 292). Overall, 216 patients had BASDAI data pre- and post-baseline. At 24 weeks, 143 patients had BASDAI scores, and the mean ± SD decrease was −2.0 ± 2.6 (p < .0001). Fifteen serious ADRs occurred in 15 (3.79%) patients; 30 (7.58%) ADRs of infections were reported, of which, five (1.26%) were serious.
Conclusion: Safety and effectiveness of adalimumab in this postmarketing observational study were similar to that in previous clinical trials.
Introduction
Ankylosing spondylitis (AS) is a chronic, progressive, seronegative, inflammatory spondyloarthropathy mainly affecting the spine, sacroiliac joints, and major joints of the extremities. It occurs primarily in young individuals (aged <30 years) [Citation1] and commonly presents as inflammatory pain arising in the lower back associated with stiffness, limitation of spinal mobility, and inhibited chest expansion. Extra-articular manifestations of AS include anterior uveitis, aortic valve insufficiency, restrictive lung disease, ulcerative colitis, and Crohn disease [Citation2]. While the prevalence of AS is estimated between 0.1% and 1.4% globally [Citation3], the estimated prevalence is much lower in Japan (0.0065%, using data from 1985 to 1996) [Citation4]; ∼4500 individuals in Japan are estimated to have AS [Citation5].
Several factors may contribute to the low estimated prevalence in Japan. For example, the presence of human leukocyte antigen-B27 (HLA-B27) is strongly associated with AS and accounts for approximately one-third of the overall genetic susceptibility to spondyloarthropathies (SpAs) [Citation6]. However, this association varies greatly among racial and ethnic groups. HLA-B27 is present in ∼8% of individuals of Western European extraction and in more than 90% of patients with primary AS [Citation7]. In contrast, the frequency of HLA-B27 is low (∼0.4%) in the general Japanese population [Citation8].
Biologics such as tumor necrosis factor inhibitors (TNFis; infliximab and adalimumab) are approved for the treatment of AS, with substantial evidence supporting their efficacy and safety [Citation9–11].
In a phase 3, open-label trial for adalimumab conducted in Japan, 73.2% of patients with AS who had an inadequate response or were intolerant to treatment with ≥1 nonsteroidal anti-inflammatory drug (NSAID) achieved an Assessment in Ankylosing Spondylitis (ASAS) 20 response after 12 weeks of treatment with adalimumab [Citation12]. Overall, responses to treatment in AS patients in Japan were similar to those observed in the Western countries despite differences in many background factors; however, only 41 Japanese patients were assessed in the trial. Therefore, we conducted this all-case postmarketing observational study (PMOS) to evaluate the real-world effectiveness and safety of adalimumab in Japanese patients with AS who initiated adalimumab after the indication was expanded to include AS with insufficient response to prior treatments.
Materials and methods
Study design and patients
This single-arm, multicenter PMOS was conducted at 195 centers between 27 October 2010 and 15 April 2016, in Japan. In this all-case PMOS, all AS patients who initiated adalimumab from 27 October 2010 to 28 May 2015, in Japan were enrolled. The diagnosis of AS was based on clinical assessment by each physician. Adalimumab treatment was initiated at 40 mg subcutaneously (SQ) once every 2 weeks; however, the dose could be increased to 80 mg SQ every other week in patients with insufficient response. The follow-up period was 24 weeks. This study was conducted in accordance with the Good Vigilance Practice/Good Post-Marketing Study Practice.
Assessments
Patient demographics and baseline characteristics, including HLA-B27 status, concomitant medications, comorbid conditions, and extra-articular manifestations, were recorded in the case report form. Overall improvement (remarkably improved, improved, or not improved) was evaluated by physician judgment at weeks 12 and 24 or at discontinuation. Overall Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, from its symptom component (fatigue, spinal pain, joint pain, localized tenderness, and morning stiffness), were evaluated at baseline, week 12, and week 24. Change in BASDAI score from baseline and change in BASDAI score of ≥50% (BASDAI50 response) from baseline to week 12 and week 24 were evaluated. Extra-articular manifestations of AS were deemed ‘improved,’ ‘worsened,’ ‘remained undeterminable,’ or ‘no change in disease status’ at week 12 and week 24, again based on physician judgment.
Adverse drug reactions (ADRs), along with severity, were recorded throughout the study and were coded according to the Medical Dictionary for Regulatory Activities (version 20.1) system organ class and preferred term. The following were pre-specified as ADRs of special interest: infectious disease, tuberculosis, malignant tumor, injection site reaction, autoimmune disorder, pancytopenia, demyelinating disease, congestive heart failure, and interstitial pneumonia. After collecting the case report forms at 24 weeks, information on imaging findings for sacroiliac joints and vertebral segments and occurrence of malignant tumors was collected for 2 years from the start of treatment administration as a follow-up survey.
Statistical analysis
The target sample size was 100; however, 403 patients were enrolled. Unlike in a clinical trial, the sample size was not determined strictly by protocol because this real-world PMOS was conducted to evaluate the effectiveness and safety of adalimumab in daily clinical practice. The safety analysis set comprised all patients treated with adalimumab and with ≥1 safety record, and the effectiveness analysis set – a subset of the safety analysis set – comprised patients who used adalimumab to treat AS and had available overall improvement data. BASDAI was evaluated among patients with available data from both baseline and week 12 or week 24. Change in BASDAI score from baseline was calculated for each evaluation period, and a paired t-test was performed. Achievement of BASDAI50 response was determined for each evaluation period, and the Clopper-Pearson confidence interval (CI) was calculated.
Results
Patient disposition and baseline characteristics
A total of 403 patients were prospectively enrolled in the study; there were 396 and 374 patients in the safety and effectiveness analysis sets, respectively (). In the safety analysis set, most patients were male (n = 266, 67.2%), with a mean (standard deviation [SD]) age of 46.3 (15.6) years, body weight of 63.2 (13.4) kg, and disease duration of 9.8 (9.8) years (). Further, most of the patients (90.7%) were outpatients. Among 292 patients with BASDAI score at baseline, the mean (SD) BASDAI score was 4.9 (2.3), and about one-half of the patients (48.2%) had a BASDAI score ≥4. Among 236 patients with known HLA-B27 status, 131 (55.5%) were HLA-B27–positive. Comorbid conditions, including extra-articular manifestations of AS, were present in many patients (n = 231, 58.3%), and most were taking concomitant medications (n = 369, 93.2%) ().
Figure 1. Patient disposition.
Table 1. Baseline characteristics.
Effectiveness
A total of 216 patients had BASDAI data at both pre- and post-baseline. The mean (SD) BASDAI score at baseline was 4.9 (2.3). At weeks 12 and 24, 181 and 143 patients had BASDAI scores and the mean (SD) scores were 2.9 (2.3) and 2.9 (2.4), respectively (). Patients treated with adalimumab experienced significant reductions in BASDAI scores between baseline and week 12 (mean [SD], −1.9 [2.2]) and week 24 (−2.0 [2.6]; p < .0001). Overall, BASDAI50 response was achieved in 77/181 (42.5%; 95% CI, 35.2–50.1) and 70/143 (49.0%; 95% CI, 40.5–57.4) patients at week 12 and week 24, respectively.
Figure 2. BASDAI scores over 24 weeks (effectiveness analysis set, n = 374). BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; SD: standard deviation.
For overall improvement by physician’s assessment at last evaluation (week 24 or at discontinuation) in the effectiveness analysis set, 333 (89.0%) patients were considered ‘remarkably improved’ or ‘improved’ and 41 (11.0%) were deemed ‘not improved,’ respectively ().
Table 2. Overall improvement by physician’s assessment (effectiveness analysis set, n = 374).
Outcome of extra-articular manifestations of AS at week 24 or at the time of discontinuation of adalimumab
Among patients with extra-articular manifestations of AS at baseline, some experienced amelioration of symptoms with adalimumab. Of 41 patients with uveitis, 12 improved, 20 had no change in disease status, one worsened, six remained undeterminable, and two had missing data. Of six patients with inflammatory bowel disease (IBD), one improved, two had no change in disease status, one worsened, and two remained undeterminable. Similarly, of five patients with psoriasis, four improved and one had no change in disease status.
Changes in imaging findings for sacroiliac joints and vertebral segments
Of the 351 patients whose follow-up case report forms were collected during the 2-year follow-up period, those with information on structural change since initiation of adalimumab included 177 for sacroiliac joints and 187 for vertebral segments. Among these, 157 (88.7%) and 168 (89.8%) patients were evaluated as having no change and few patients (10 [5.6%]) and 3 [1.6%]) were evaluated as improved in sacroiliac joints and vertebral segments, respectively ().
Table 3. Changes in imaging findings for sacroiliac joints and vertebral segments.
Safety
A total of 144 ADRs were reported in 101 patients among 396 patients in the safety analysis set, and a total of 15 serious ADRs were reported in 15 patients. Serious ADRs included two cases of bronchitis and one each of impetigo, infection, tonsillitis, dermatofibrosarcoma protuberans, anaphylactic shock, upper respiratory tract inflammation, ulcerative colitis, gastric ulcer perforation, hemorrhoids, paralytic ileus, acute pancreatitis, abnormal hepatic function, and lupus-like syndrome. shows the summary of ADRs that were previously defined as priority investigation. During the follow-up period (up to 2 years from the first administration of adalimumab), two new malignant tumors were reported in 392 patients. No new safety signals were observed.
Table 4. Adverse drug reactions of special interest.
Discussion
The results of this largest 24-week PMOS in 403 patients with AS in Japan show that the TNFi adalimumab is safe and effective in the treatment of AS in everyday clinical practice. There was a significant reduction in BASDAI scores at weeks 12 and 24. A good clinical response (BASDAI50) was achieved in 42.5% and 49.0% of patients at week 12 and week 24, respectively. Patients with extra-articular manifestations of AS at baseline also experienced some amelioration of symptoms. Further, adalimumab was generally well tolerated, with no unexpected ADRs.
So far, only two phase 3 clinical trials have evaluated the effectiveness and safety of biological products for the treatment of AS in Japan, albeit in only a small number of patients. The phase 3 study of adalimumab in 41 patients with active AS (who met ≥2 of the following three conditions: BASDAI score on a visual analog scale [VAS] ≥ 4 cm, total back pain on a VAS ≥40 mm, or duration of morning stiffness ≥1 h) showed a BASDAI50 response rate of 65.9% at 12 weeks that was maintained through week 60. The mean (95% CI) reduction (BASDAI [0–10 cm VAS]) in clinical signs and symptoms from baseline to week 12 was 3.4 (4.2, 2.7) [Citation12]. In our study, the BASDAI50 response rate was lower (42.5%) with a mean (SD) reduction from baseline in BASDAI scores of 1.9 (2.2) at week 12. However, the average BASDAI score in this study improved from 4.9 before treatment to 2.9 after 12 weeks of treatment, and per clinicians’ assessment, ∼90% of patients were evaluated as improved. As this was a real-world study, these differences are attributable to the study design, baseline patient characteristics, and lower disease severity. In the phase 3 study, 78% of patients were male, the average age was 37.2 years, and the mean disease duration was 4.1 years, whereas, in this PMOS, 67.2% were male, the average age was 46.3 years, and the mean disease duration was 9.8 years, with older age and longer duration of disease. The baseline average (SD) BASDAI score was 4.9 (2.3), which was milder than the average BASDAI score of 6.2 (1.5) in the phase 3 trial. The second phase 3 study from Japan evaluated infliximab in 33 patients with active AS who were using or were intolerant to NSAIDs and reported a BASDAI50 response rate of approximately 55% at 12 weeks [Citation13]. Furthermore, the BASDAI50 response at 12 weeks, in this study, was comparable to that of the international phase 3 study from US and Europe (45.2% [94/208]) [Citation11].
This is the first report from Japan showing the changes in bone lesions of Japanese patients with AS during TNFαi treatment. The changes in imaging findings of sacroiliac joints and vertebral bodies before and after adalimumab administration demonstrated stable disease at 2 years of follow-up in 88.7% of sacroiliac joints and 89.8% of vertebral segments evaluated.
Although treatment of AS with a TNFi improves symptoms and lessens disease activity, previous studies have demonstrated that the progression of structural spine damage cannot be prevented in early years [Citation14,Citation15]. Recently, however, long-term observation of structural changes in bone showed suppression of spinal structural changes. Also, as expected, it has been suggested that the treatment effect is caused by suppression of disease activity by TNFis [Citation16–19]. Because this study did not use the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) for evaluation, it cannot be compared with global studies; however, in the 2-year follow-up survey, the proportion of patients judged to have undergone structural change was <10%, and longer-term use of adalimumab may further slow the progression of structural change.
This study also reported the rates of concurrent extra-articular symptoms of AS, including uveitis (10.4% [41 patients]), IBD (1.5% [6 patients]), and psoriasis (1.3% [5 patients]), in Japanese patients, which were lower than that reported in the previous phase 3 trial from Japan (uveitis, 19.5% [8/41]; IBD, 4.9% [2/41]; psoriasis, 7.3% [3/41]) [Citation12]. However, a recent meta-analysis of cohort/cross-sectional studies [Citation20] reported a concurrent prevalence rate of uveitis (5.7%; historical rate, 23.0%), IBD (4.1%), and psoriasis (10.2%), which was higher than that reported in this study. It is suggested that these symptoms may be overlooked in daily clinical practice in Japan. Furthermore, the previous phase 3 study [Citation12] did not report the rate of symptomatic improvement/no change after 24 weeks of adalimumab administration in patients with each extra-articular symptom. This rate in the current study was 29.3%/48.8% for uveitis, 16.7%/33.3% for IBD, and 80.0%/20.0% for psoriasis, suggesting the possibility of improving these accompanying symptoms in clinical practice.
The average delay between the first symptoms of AS and an official diagnosis is substantially longer in HLA-B27–negative (11.4 years) than HLA-B27–positive AS patients (8.5 years) [Citation21]. Other than the genetic/racial background, differences in HLA-B27 positivity and its relationship to diagnosis indicate low awareness of AS among physicians in Japan, leading to delayed diagnosis [Citation5]. In our study, 131 of 236 patients with known HLA-B27 status (55.5%) were HLA-B27–positive. This rate was comparable to that reported in the previous phase 3 trial of adalimumab (48.8%) [Citation12], but was lower than that reported in the phase 3 trial of infliximab (72.7%) [Citation13]. Because of these factors, accurate diagnosis of AS in Japanese patients should be made on the basis of precise observations of each patient’s clinical symptoms, with a broader understanding of the clinical symptoms related to inflammatory pain, careful consideration of differential diagnoses, and detailed discussion with AS specialists. Overall, this study not only confirms the clinical effectiveness and safety of adalimumab demonstrated in the previous phase 3 trial [Citation12] but also provides knowledge on background factors of patients with AS from all over Japan.
Limitations
The limitations of this study were that the long-term effectiveness and safety of adalimumab were not evaluated and that there were no direct comparisons with control arms due to its study design as a PMOS.
Conclusion
The results of this all-case PMOS demonstrate that adalimumab is effective and generally safe in the treatment of patients with AS in routine clinical practice in Japan.
Conflict of interest
Shigeto Kobayashi has received advisory fees from Kyowa Hakko Kirin, Co, Ltd. and lecture fees from AbbVie GK, Actelion Pharmaceuticals Japan, Astellas Pharma, Bristol-Myers KK, Chugai Pharmaceutical, Eisai, Janssen Pharmaceutical KK, Nippon Shinyaku, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical, Teijin Pharma and UCB Japan. Tomoko Kashiwagi and Junko Kimura are full-time employees of AbbVie GK and may own AbbVie stock or stock options.
Acknowledgments
Editorial support, in the form of medical writing, assembling tables, and creating high-resolution images based on the authors’ detailed directions, collating author comments, copyediting, fact checking, and referencing, was provided by Annirudha Chillar, MD, PhD, and Maribeth Bogush, PhD, of Cactus Communications, and funded by AbbVie GK and Eisai Co. Ltd.
Additional information
Funding
References
- Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014;53(4):650–7.
- Ghasemi-Rad M, Attaya H, Lesha E, Vegh A, Maleki-Miandoab T, Nosair E, et al. Ankylosing spondylitis: a state of the art factual backbone. World J Radiol. 2015;7(9):236–52.
- Akkoc N. Are spondyloarthropathies as common as rheumatoid arthritis worldwide? A review. Curr Rheumatol Rep. 2008;10(5):371–8.
- Hukuda S, Minami M, Saito T, Mitsui H, Matsui N, Komatsubara Y, et al. Spondyloarthropathies in Japan: nationwide questionnaire survey performed by the Japan Ankylosing Spondylitis Society. J Rheumatol. 2001;28(3):554–9.
- Japan Intractable Diseases Information Center website. Ankylosing Spondylitis. http://www.nanbyou.or.jp/entry/4848. Accessed on April 25, 2018.
- Chatzikyriakidou A, Voulgari PV, Drosos AA. What is the role of HLA-B27 in spondyloarthropathies? Autoimmun Rev. 2011;10(8):464–8.
- Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002;136(12):896–907.
- Tanaka H, Akaza T, Juji T. Report of the Japanese central bone marrow data center. Clin Transpl. 1996;139–44.
- Baraliakos X, van den Berg R, Braun J, van der Heijde D. Update of the literature review on treatment with biologics as a basis for the first update of the ASAS/EULAR management recommendations of ankylosing spondylitis. Rheumatology (Oxford). 2012;51(8):1378–87.
- van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 2005;52(2):582–91.
- van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006;54(7):2136–46.
- Kobayashi S, Harigai M, Mozaffarian N, Pangan AL, Sharma S, Brown LS, et al. A multicenter, open-label, efficacy, pharmacokinetic, and safety study of adalimumab in Japanese patients with ankylosing spondylitis. Mod Rheumatol. 2012;22(4):589–97.
- Kobayashi S, Yoshinari T. A multicenter, open-label, long-term study of three-year infliximab administration in Japanese patients with ankylosing spondylitis. Mod Rheumatol. 2017;27:142–9.
- van der Heijde D, Landewé R, Baraliakos X, Houben H, van Tubergen A, Williamson P, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008;58(10):3063–70.
- van der Heijde D, Salonen D, Weissman BN, Landewé R, Maksymowych WP, Kupper H, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther. 2009;11(4):R127.
- Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, et al. TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum Dis. 2018;77(1):63–9.
- Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH, et al. The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65:2645–54.
- Maas F, Arends S, Brouwer E, Essers I, van der Veer E, Efde M, et al. Reduction in spinal radiographic progression in ankylosing spondylitis patients receiving prolonged treatment with tumor necrosis factor inhibitors. Arthritis Care Res (Hoboken). 2017;69(7):1011–9.
- Baraliakos X, Haibel H, Listing J, Sieper J, Braun J. Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis. 2014;73(4):710–5.
- de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18(1):196.
- Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int. 2003;23(2):61–6.