Frequency of peripheral diseases in Korean patients with ankylosing spondylitis and the effectiveness of adalimumab

Abstract Aim Peripheral features contribute to disease burden in ankylosing spondylitis (AS). This study investigated the frequency of peripheral disease and effectiveness of adalimumab among Korean patients with AS. Methods Peripheral disease was evaluated in consecutively enrolled patients with active AS (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score ≥ 4). An adult subpopulation was subsequently enrolled in a prospective, observational study and received adalimumab 40 mg, every 2 weeks. During a 52‐week follow‐up, AS disease activity was assessed by BASDAI score, and effectiveness in peripheral disease assessed via changes in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES; 0‐13), swollen joint and tender joint counts (SJC, 0‐44; TJC, 0‐46), and dactylitic digits from baseline. Results Of 1161 Korean patients with AS, 178 (15.3%) and 306 (26.4%) had enthesitis and peripheral arthritis, respectively; dactylitis was diagnosed in 28 patients (2.4%). Of 201 patients enrolled in the observational study, 46.3%, 33.3%, and 3.0% had enthesitis, peripheral arthritis, and dactylitis, respectively. Overall, 75.1% of patients achieved >50% improvement in BASDAI score by week 12. Mean MASES was significantly reduced from 2.67 at baseline to 0.85 and 0.34 at weeks 12 and 52, respectively (P < .0001). Similarly, SJC and TJC improved significantly from 2.58 and 3.49 at baseline to 0.80 and 1.68, respectively, by week 12 (P < .0001). Dactylitis was resolved in all affected patients by week 28. Conclusion Of these Korean patients with AS, those who received adalimumab demonstrated higher prevalence for peripheral symptoms and, subsequently, adalimumab treatment improved peripheral features of their AS.


| INTRODUC TI ON
Ankylosing spondylitis (AS) is a chronic rheumatic disorder, primarily associated with inflammation of the spine. 1 In addition, peripheral disease, encompassing enthesitis, dactylitis and peripheral arthritis, contributes to the overall disease burden of this condition. 2 In Korea an increasing prevalence of AS is being observed, with 47%-70% of patients reported to experience associated peripheral disease. [3][4][5] Alongside nonpharmacological interventions, nonsteroidal anti-inflammatory drugs (NSAIDs) represent first-line therapy for AS. 1 In patients who require additional treatment, tumor necrosis factor-alpha (TNFα) inhibitors are well tolerated and have been shown to improve clinical symptoms. 6 Adalimumab (anti-TNFα) has demonstrated efficacy in the reduction of symptoms in AS in multiple randomized controlled trials (RCTs), and is approved for the treatment of AS in Korea. [7][8][9] More recently, the sustained benefits of adalimumab treatment on spinal mobility, health-related quality of life, physical function and disease activity have been confirmed in a long-term study over a period of 5 years. 10 A meta-analysis of 8 studies in AS estimated the prevalence of arthritis, enthesitis, and dactylitis as 29.7%, 28.8% and 6.0%, respectively, 11 although individual studies have reported a history of peripheral disease in more than 50% of patients. 12 In a multicenter study of patients with AS in Europe, frequency of enthesitis and peripheral arthritis were 54.9% and 22.5%, respectively. 13 Efficacy of adalimumab treatment on peripheral disease features in AS has previously been shown. In an RCT of over 300 patients with active AS, adalimumab significantly reduced enthesitis versus placebo over 24 weeks. 8 Consistent with these data, in an uncontrolled, open-label study in 1250 patients, adalimumab therapy was shown to be effective in the reduction of peripheral arthritis, and associated with a significant improvement in enthesitis by week 12. 13 In Korea, studies investigating the clinical spectrum of AS are limited; to date, no studies have examined the efficacy of adalimumab on peripheral joint involvement in AS. Enthesitis has a reported prevalence of 53%, 4 while 2 separate studies conducted in Korea estimated peripheral arthritis symptoms in 47% and 70% of AS patients. 3,4 The occurrence of peripheral arthritis has also been significantly associated with a higher risk of TNFα inhibitor treatment discontinuation in Korean patients with AS. 14 Thus, we conducted an observational, prospective study to investigate the frequency of peripheral disease in Korean patients with AS, and to determine the efficacy of adalimumab treatment on these extra-axial manifestations.

| Study population
Patients with AS were enrolled consecutively from 13 sites in South Korea (Table S1)

| Study design
We conducted a prospective, noninterventional, observational study between December 2014 and August 2017 (NCT02333383). Peripheral arthritis was defined as at least 1 swollen joint, excluding the hip joints, while dactylitis was measured by a simple count of dactylitic digits. All patients received a follow-up assessment within approximately 70 days of their last dose of adalimumab during the study period. Adverse events (AEs) were recorded via case report forms, and classified by system organ class and preferred terms as per the Medical Dictionary for Regulatory Activities hierarchy.

| Outcomes
The study's primary endpoint was the frequency of peripheral disease (peripheral arthritis, enthesitis and dactylitis) at baseline. Secondary endpoints were assessed at each study visit (12,28,36 and 52 weeks) and included: the percentage of patients with a 50% improvement in BASDAI score (BASDAI 50) from baseline; change in MASES from baseline; prevalence of enthesitis of the plantar fascia; change of TJC and SJC in patients with peripheral arthritis, defined as ≥1 swollen joint at baseline; and dactylitis score from baseline.

| Statistical analysis
Descriptive statistics were used to present patient demographics, disease and medication data. Continuous variables are described using mean and standard deviation (SD) values, as well as median and range (minimummaximum) measurements. Categorical variables are presented using frequency and proportions. All missing data were treated as missing values in the analysis. The study sample size was based on the frequency of peripheral disease in Korean patients 3,4 ; using a 95% confidence interval (CI) and 15% CI width, sample size was estimated at 144 patients with peripheral arthritis, and 171 patients with enthesitis. A final sample size of 200 was determined for enrollment taking into account a 20% dropout rate.
The study population comprised intention-to-treat (ITT) and per protocol (PP) sets. The ITT set included patients who received at least 1 dose of adalimumab and had peripheral disease assessed at baseline, while the PP subset of patients completed the study without deviation and met inclusion and exclusion criteria.
Post hoc analyses of secondary outcomes were performed for patient subgroups according to total number of adalimumab injections and use of prior TNFα inhibitor treatment. Analyses were performed using Fisher's exact test, and Chi-square test.
All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc, Cary, NC, USA). All statistical tests were 2-tailed paired t tests, and P < .05 was considered statistically F I G U R E 1 Patient flow diagram. ITT, intention-to-treat; PP, per protocol significant using Fisher's exact test, nonparametric Wilcoxon signed rank test or signed rank test.

| Patient clinical characteristics
In total, 1161 patients with AS were evaluated for study inclusion and for frequency of peripheral disease; mean (SD) age was 40.5

| Adalimumab significantly reduced AS disease activity
Responses to adalimumab treatment were assessed by improvement in BASDAI score from baseline. Mean (SD) BASDAI score for the ITT population (n = 201) was 6.80 (1.40) at baseline, which decreased to 1.98 (1.27) (P < .0001) by study end at week 52 (n = 144; Figure 2A and Table S2). Mean BASDAI score was shown to improve significantly between weeks 0 and 12, with a mean (SD) decrease of −4.24 (1.68). BASDAI score improved further over the full study duration  Table S4). There was no statistically significant difference in adalimumab efficacy based on a prior use of TNFα inhibitors (Table S5).

| Adalimumab efficacy in peripheral disease
Adalimumab was found to be effective in the treatment of peripheral  Figure 2C and Table S2).
At study entry, 9.5% patients had enthesitis of the plantar fascia. By week 12, this had reduced to 5.2%, and by treatment end reduced to 4.4% of patients with this peripheral disease feature ( Figure 2D).  Figure 2E and  Figure 2F and  Figure 2G and Table S2).

| Safety and tolerability of adalimumab
There were 22 AEs reported in 18 patients (9.0%) during the study (

| Adalimumab drug survival and patient discontinuation
For the ITT population, the median total administration frequency was 32 (range 1-62) injections of adalimumab, and the median total dose administered was 1280 mg (range 40-2480 mg). Adalimumab retention rate over the study period was assessed post hoc using Kaplan-Meier analysis, which showed that most patients persisted with therapy beyond the 52-week study period. In an analysis stratified by prior use of TNFα inhibitors, drug survival was numerically superior in TNFα inhibitor-naïve patients, but not significantly different for those who had switched from other TNFα inhibitor therapies ( Figure 3).  Serious adverse drug reaction a 5 (2.5) 7

| D ISCUSS I ON
AE leading to the discontinuation b 12 (6.0) 13 Abbreviations: AE, adverse event; SAE, serious adverse event. a Adverse drug reaction: AE the causality with adalimumab of which is probable, possible, probably not, or not assessable. b AE leading to discontinuation of adalimumab: an AE for which the action taken was transiently discontinued or permanently discontinued.

F I G U R E 3
Kaplan-Meier survival probability for adalimumab adherence. Tick marks reflect patient adalimumab discontinuation, censored symbols denote a patient's last follow-up date even though the patient continued the drug treatment.
Change of Maastricht Ankylosing Spondylitis Enthesitis Score, dactylitis score, tender joint count, and swollen joint count was tested with the paired t test or signed rank test (*P < .05). TNFα, tumor necrosis factor-alpha both studies, the frequency of peripheral arthritis was found to be higher (47.1% and 70%, respectively). These differences may reflect changes in the clinical management of AS over recent years, as well as variations in patient characteristics between the studies.
In terms of other comorbidities, 6.5% of patients enrolled in the study had uveitis, lower than the prevalence of 29% previously reported by Koo et al in a single-center study in Korean patients with AS. 19 The study may represent patients with severe disease and a long disease duration, which may explain the higher prevalence of uveitis reported. 19 In line with prior reports, adalimumab was effective for the treat- The strengths of this study are its noninterventional nature, and the broad patient population gathered from multiple centers across Korea. Our findings add to the limited current evidence surrounding prevalence of peripheral disease features among Korean patients with AS. This is also the first study to examine the efficacy of adalimumab on peripheral disease in this ethnic population. However, there were study limitations, which include potential variations in reporting across the 13 centers. It is also of note that the post hoc analyses were not powered for statistical significance. In order to confirm the findings observed, an appropriately powered study in a larger patient population would be required.
In summary, in this noninterventional, observational study of Korean patients with AS, enthesitis and peripheral arthritis were the most prevalent peripheral disease features, both occurring in more than one-third of patients. Adalimumab treatment was shown to be effective in reducing spinal symptoms and peripheral disease in these subjects.

DATA ACCE SS I B I LIT Y S TATE M E NT
The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files.

ACK N OWLED G M ENTS
Editorial assistance in manuscript preparation was provided by Susannah Thornhill and James Strutt of MediTech Media, Singapore, and funded by AbbVie Ltd, Korea.