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Impact of TNF inhibitor medication on working ability in axial spondyloarthritis: an observational national registry-based cohort study

Impact of TNF inhibitor medication on working ability in axial spondyloarthritis: an... Objective: The aim was to investigate the effect of TNF inhibitor (TNFi) initiation on working ability and health-care resource utilization among axial SpA patients in a real-life setting. Methods: Patients with a clinical diagnosis of non-radiographic (nr-axSpA) or radiographic axial SpA initiating their first TNFi were identified from the National Register for Antirheumatic and Biologic Treatment in Finland. Sickness absences, including sick leave and disability pension, in- and outpatient days and rehabilitation rates, 1 year before and after initiating the medication were retrieved from national registries. Factors affecting result variables were studied using multivariate regression analysis. Results: Overall, 787 patients were identified. Rates of work disability days per year were 55.6 the year before treatment onset and 55.2 the year after, with significant differences between patient subgroups. The rate of sick leave decreased after starting TNFi treatment. However, the rate of disability pension continued to rise. Patients with a diagnosis of nr-axSpA experienced a decrease in overall work disability and, especially, fewer sick leaves. No sex differences were detected. Conclusion: TNFi interrupts the increase in work disabled days evident during the year before its initiation. However, the overall work disability remains high. Treating patients earlier in the nr-axSpA phase, regardless of sex, appears important in maintaining the ability to work. Lay Summary What does this mean for patients? Maintaining the ability of patients to work is a complex and challenging task that deserves special attention when treating people with chronic in- flammatory diseases, such as ankylosing spondylitis and non-radiographic SpA (nr-axSpA). Work disability remains a problem among these patients despite the evolving treatment options. We investigated how a type of drug called a tumour necrosis factor inhibitor (TNFi) affects work- ing ability in people with nr-axSpA in a real-life setting in Finland. We used data on patients and their treatment from a database called the National Register for Antirheumatic and Biologic Treatment in Finland. We compared data on sick leave, in- and outpatient days and rehabilitation 1 year before and after starting TNFi medication. Our results show that TNFi medication substantially reduces the amount of sick leave that patients need to take, especially for people with nr-axSpA. However, we found that the amount of disability pension claimed rises steadily de- spite patients starting TNFi medication. Taking these results together, we conclude that starting TNFi medication might interrupt the decline in the ability to work in nr-axSpA patients. However, effective ways of maintaining patients’ ability to work are still needed. Keywords: work disability, TNF inhibitor, axial SpA, AS, non-radiographic axial SpA, register study Key messages Rise of absenteeism subsided with the initiation of TNFi. Beneficial effect on work absenteeism was more pronounced with the diagnosis of non-radiographic axial SpA regardless of sex. Long-term work disability increased despite TNFi initiation. Received: 20 January 2023. Accepted: 3 May 2023 V The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Anna-Mari Hokkanen et al. Introduction treating physicians using a standardized protocol. The data were collected with paper forms or by applying the GoTreatIt AS and non-radiographic axial SpA (nr-axSpA) are inflamma- computer software platform. Missing baseline data were im- tory rheumatic diseases. These conditions initiate typically be- puted by multiple imputation with predictive mean matching fore the age of 40 years, and AS patients have been shown to and 10 imputed data sets. have increased working disability and health-care resource use in comparison to the general population [1–5]. The inflamma- Outcomes and follow-up tory activity varies over time, but delayed diagnosis and insuf- The study was conducted as an observational cohort study. ficient treatment can lead to considerable disability [6–9], as The outcomes of interest in this study comprised days absent also highlighted by van Hoeven et al. [5]. Delayed diagnosis from work owing to sick leave, disability pension or rehabili- was connected to unemployment in a recent study in the USA tation and the number of inpatient days and outpatient visits [10]. The main cause of disability is spinal stiffness and pain. to specialized health-care facilities. In addition, peripheral arthritis and uveitis often The Finnish social insurance system provides financial sup- occur, sometimes also with other extra-articular manifesta- port for individuals of working age in the event of illness or tions, such as IBD. Co-morbidities, such as fatigue and depres- injury. We defined sick leave as days with sickness allowance sion, are also present. Loss of effective working years results in of any degree paid by the Social Insurance Institution of indirect costs to society [4, 7, 8, 11–13]. Finland (SII). All sick leaves with a duration of 10 days are nr-axSpA was recognized as an entity in 2009 [14], and registered continuously and prospectively by the SII. Sick since 2013 the diagnosis has entitled patients in Finland to bi- leaves shorter than this are not registered, because the em- ological drug reimbursement, if traditional anti-rheumatic ployer provides the pay. Sick leave is paid for 300 days. drugs are insufficient to control the disease. In Finland, the in- After this, the patient can apply for a fixed-term rehabilitation cidence of AS has been reported to be 7.3 per 100 000 and subsidy, which is granted for the time it is needed for medical unspecified SpA 18 per 100 000 [15]. The incidence rate for and/or vocational rehabilitation to restore the ability to work. all SpA has risen from 12 to 18 per 100 000 between 2000 If the rehabilitation measures are not able to restore working and 2014 [16, 17]. ability, the patient applies for a disability pension. In our Work ability is an important goal when treating patients of study, we viewed sickness absences as temporary leaves (sick working age. The expansion of medication alternatives and leave and rehabilitation subsidy) and as permanent incapacity progress in treatment strategies are expected to improve work to work, i.e. disability pension. capability and employment. TNF inhibitors (TNFi) have been Information on sick leaves were retrieved from the SII, proved to be clinically beneficial, safe and cost effective in whereas the data on pensions were gathered from SII and both AS and nr-axSpA [18, 19]. Evidence from clinical trials Finnish Centre for Pensions. The information on the outpa- suggests that TNFi are able to prevent work disability in tient and inpatient visits was gathered from Care Registers for patients with AS [20], but these findings might not be general- Social Welfare and Health Care. The data on deaths and emi- izable to routine clinical practice owing to the stringent inclu- grations were retrieved from Statistics Finland. sion criteria for clinical trials [21]. Results from the British The baseline visit took place when TNFi treatment was ini- Society for Rheumatology biologics register and meta- tiated. The follow-up time was 1 year before and 1 year after analysis show significant improvement in work productivity, the start of a TNFi. However, follow-up was terminated in although absenteeism was seen to remain high [22]. the event of death or emigration. When analysing sick leaves The aim of this study was to evaluate the effect of starting a and disability pensions, the patients were also censored when TNFi on absenteeism and the use of health-care resources in a they became pensioners (excluding disability pension) or national cohort of axSpA patients including both nr-axSpA turned 63 years old, which is the common retirement age in and AS patients. Finland. A favourable ethical board statement was granted by the Helsinki and Uusimaa Hospital District coordinating ethical Methods committee (73/13/03/00/2014), and permission for the study Patients was obtained from the National Institute for Health and Patients were identified from the National Register for Welfare (THL/6752/14.06.00/2020). Written informed pa- Antirheumatic and Biologic Treatment in Finland (ROB-FIN), tient consent were acquired from patients who had been in- which is a longitudinal cohort study with data dating back to cluded in ROB-FIN before the introduction of the electronic 1999. ROB-FIN was established initially to monitor the effec- patient monitoring systems covered by the permission above. tiveness and safety of biologic DMARDs (bDMARDs) in Statistical methods rheumatic diseases. Inclusion for this study was limited to TNFi treatments started as the patient’s first bDMARD treat- Baseline characteristics at initiation of TNFi treatment are ment between 2007 and 2015. presented as the mean along with standard deviations or According to the Finnish treatment guidelines and the re- percentages. The outcomes are reported as events per patient- stricted reimbursement confirmed by the Finnish year, with the 95% CI calculated via non-parametric boot- Pharmaceuticals Pricing Board, patients with AS and strapping. The missing values among patient characteristics nr-axSpA must be refractory to at least one conventional were imputed using a multiple imputation method. The an- synthetic DMARD (csDMARD) before they are entitled to re- nual change in the rate of the outcomes before and after the imbursement for bDMARDs. initiation of TNFi was modelled with linear regression, with We included patients with a clinical diagnosis of AS or nr- an additional error term for repeated measures. The explana- axSpA (ICD10 diagnosis codes M45 and M46). At the start tory variables included age, sex, HLAB27, CRP, ASDAS- of TNFi therapy, baseline characteristics were reported by the CRP, TNFi agent, concomitant use of csDMARDs and the TNF inhibitors in axial spondyloarthritis 3 Table 1. SpA patient characteristics at baseline year of treatment onset. The year of treatment onset was di- vided into three periods of equal length (2007–2009, 2010– Variable Mean (S.D. or percentage) 2012 and 2013–2015) to examine whether the availability of All patients AS Nr-axSpA new TNFi drugs (certolizumab pegol and golimumab) and the (n¼ 787) (n¼ 684) (n¼ 103) expansion of medication use would have an effect on work outcome. Data management and statistical analyses were car- Age, years 40 (11) 40 (11) 38 (11) ried out using R software v.3.6.2 (R Foundation for Statistical Sex 442 (56% male) 405 (59% male) 37 (36% male) Computing, Vienna, Austria). Weight, kg 79 (16) 79 (15) 80 (18) Height, cm 172 (10) 173 (9.4) 171 (9.1) Patient global 47 (26) 47 (25) 48 (25) Results assessment Investigator 35 (22) 35 (20) 30 (19) Patients and follow-up global Overall, 787 patients were included in the study, of whom assessment 684 and 103 were diagnosed with AS and nr-axSpa, respec- HAQ 0.70 (0.5) 0.71 (0.49) 0.68 (0.51) Pain 52 (25) 52 (26) 51 (23) tively. A full year worth of follow-up was available for 783 ASDAS 3.0 (1.0) 3.0 (1.0) 2.8 (1.1) patients, whereas 4 were censored during the follow-up owing BASDAI 44 (20) 44 (21) 44 (19) to death or emigration. Of the overall population, 734 were ESR, mm/h 17 (18) 17 (17) 14 (16) of working age the year before initiation of TNFi, and among CRP, mg/l 13 (17) 13 (16) 11 (15) this subgroup an additional 27 patients were censored owing Time from 6.7 (7.6) 7.1 (7.8) 4.2 (5.5) diagnosis, to retirement, death or emigration. years Baseline characteristics are described in Table 1. The mean age was 40 years, and 56% of the patients were men. The mean DAS according to ASDAS was 3.0 and BASDAI 44. Patient global assessment was 47 and investigator global as- Table 2. Medication when first TNF inhibitor initiated sessment 35. Mean baseline ESR was 17 mm/h, and CRP was Medication n (%) 13 mg/l. The AS patients were predominantly male (59%), whereas nr-axSpa patients were mostly female (64%). The TNF inhibitor time from diagnosis to starting treatment was 4.2 (S.D. Adalimumab 277 (35) Etanercept 238 (30) 5.5) years for nr-axSpA and 7.1 (S.D. 7.8) years for AS. Infliximab 175 (22) At the initiation of TNFi medication, 73% of the patients Golimumab 82 (10) received concomitant csDMARD treatment, while the remain- Certolizumab pegol 15 (1.9) ing 27% of the patients received biologic monotherapy. MTX Concomitant medication was used by 46% of the patients and SSZ by 41% . Oral low- Any conventional DMARD 577 (73) MTX 357 (46) dose glucocorticoids were used by 27% of the patients. SSZ 322 (41) Adalimumab was the most frequently used TNFi, by 35% of Glucocorticoids 161 (27) the patients, followed by etanercept (30%), infliximab (22%) Other conventional DMARD 78 (9.8) golimumab (10%) and certolizumab pegol (1.9%) (Table 2). Outcomes rates of inpatient days and outpatient visits were similar be- The annual number of sick disabled days decreased slightly in fore and after the initiation of TNFi therapy. the overall population: from 47.3 (95% CI 40.9, 53.8) days Of the 48 patients who were absent from work for the during the year before TNFi initiation to 43.6 (95% CI 36.5, whole year before TNFi treatment began, only 7 (15%) 50.8) days the year after (Table 3). The 90-day rate of work returned to work during the 1-year follow-up. Additionally, absence days increased during the first year of follow-up until 17 patients who were working at least part time during the TNFi initiation and decreased thereafter (Fig. 1). year before treatment initiation were absent for the entire sub- The rate of days on sick leave decreased after TNFi initia- sequent year after treatment initiation. tion within the subgroup of patients of working age (Fig. 1). Regression analyses The incidence of sick leaves during the first and second time periods in this subgroup was 32.90 (95% CI 27.9, 38.1) and Based on the linear regression analysis, disease activity at 26.5 (95% CI 22.4, 31.1), respectively (Table 3). Meanwhile baseline (ASDAS-CRP) did not demonstrate a statistically sig- an increasing trend for days absent from work owing to dis- nificant association with the annual change in absenteeism, ability pensions was observed in the overall population: from nor did HLAB27, HAQ, smoking or BMI. Even age did not 14.8 (95% CI 9.7, 19.7) to 17.1 (95% CI 11.4, 22.7) days. seem to change the outcome; CRP was associated with a mod- The same trend was seen both in AS and nr-axSpA patients. est increase in the number of days absent from work among Absenteeism reduced to a larger extent among the nr- nr-axSpA patients, but not in AS patients (1.06, 95% CI axSpA patients, from 38.2 (95% CI 23.5, 55.6) days per pa- 0.058, 2.0 vs 0.19, 95% CI 0.16, 3.2; Fig. 3). However, the tient year the year before to 22.83 (95% CI 12.1, 36.7) days small values do not appear clinically significant. The choice of per patient year the year after. Among AS patients, the values TNFi agent was not a statistically significant predictor of im- changed from 48.6 (95% CI 41.2, 56.5) to 46.6 (95% CI provement in absenteeism, aside from certolizumab pegol 39.3, 54.1) days per patient year. reaching statistical significance in comparison to adalimumab No statistically significant changes were observed in health- among axSpA patients (64, 95% CI 18, 110), but this was care resource utilization between the two periods (Fig. 2). The probably attributable to bias caused by the small number of 4 Anna-Mari Hokkanen et al. Table 3. Crude annual incidence rates of outcome variables by diagnosis Days during 1 year Days during 1 year Days during 1 year Days during 1 year Days during 1 year Days during 1 year pre-TNFi post-TNFi pre-TNFi post-TNFi pre-TNFi post-TNFi [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] Incidence rate AS (n¼ 640) nr-AxSpA (n¼ 94) All (n¼ 734) Rate of work disabled 48.6 [41.2, 56.5] 46.6 [39.3, 54.1] 38.2 [23.5, 55.6] 22.83 [12.1, 36.7] 47.3 [40.9, 53.8] 43.6 [36.5, 50.8] days Rate of sick leave days, 32.1 [27.0, 37.7] 28.1 [23.5, 33.3] 38.2 [23.5, 55.6] 16.1 [8.9, 24.8] 32.90 [27.9, 38.1] 26.5 [22.4, 31.1] all causes Rate of sick leave days, 19.6 [15.0, 24.3] 16.61 [12.9, 21.2] 18.8 [7.8, 32.9] 7.4 [3.0, 13.2] 19.5 [15.5, 23.6] 10.3 [6.1, 14.7] SpA Rate of disability 16.9 [11.5, 23.3] 18.7 [12.8, 24.5] 0 [0.0, 0] 6.7 [0.0, 17.6] 14.8 [9.7, 19.7] 17.1 [11.4, 22.7] pension days, all causes Rate of disability 9.5 [5.5, 14.2] 11.35 [7.0, 15.9] 0 [0.0, 0] 3.1 [0.0, 9.9] 8.3 [4.86, 11.9] 10.3 [6.1, 14.7] pension days, SpA AS (n5 684) nr-AxSpA (n5 103) All (n5 787) Rate of outpatient visits 6.4 [5.9, 6.8] 7.2 [7.00, 7.5] 7.6 [6.54, 8.6] 6.4 [6.0, 8.1] 6.5 [5.1, 6.9] 7.4 [6.9, 7.8] (visits per year) Rate of inpatient days 1.0 [0.8, 1.3] 1.1 [0.8, 1.3] 1.2 [0.6, 1.9] 1.6 [1.0, 2.3] 1.6 [1.3, 2] 1.5 [1.3, 1.9] (days per year) nr-AxSpA: non-radiographic axial SpA. Figure 1 Number of days absent from work as 90-day rates. Sick leave, disability pension and pooled work disability 1 year before and after TNF inhibitor treatment onset (i.e. baseline) among the patients of working age patients in the certolizumab pegol group (15 patients). population (P¼ 0.039) and also when age, sex, HLAB27 sta- However, the decrease in absenteeism in the nr-axSpA tus, time from diagnosis and CRP were standardized population was significantly more pronounced than in the AS (P¼ 0.056). TNF inhibitors in axial spondyloarthritis 5 Figure 2 Ninety-day rates 1 year before and after TNF inhibitor treatment onset. (A) Hospital in-patient days. (B) Health-care visits in specialized health care. (C) Rehabilitation days. Discussion treated primarily with NSAIDs or cDMARDs. One of the rea- sons for these Finnish treatment guidelines is that Finnish Our results showed that the rate of sick leaves decreased nota- patients using co-medication with cDMARDs and biologics bly after the initiation of TNFi treatment in the nr-axSpA show added beneficial effect [24, 25]. Moreover, recent inter- group. Meanwhile the rate of disability pension days contin- national register data have replicated these findings [26]. ued to rise slightly throughout both follow-up years. The These studies shed light on the disparity of results on this sub- number of sick leave days remained high in the AS group. A ject across publications from different national registries over lack of improvement in overall work absence was shown pre- the past decade. They also suggest that, in contrast to current viously by a British observational study [22]. However, in this international treatment guidelines, csDMARD co-therapy study the nr-axSpA patients benefitted especially from the should not necessarily be disregarded in axSpA. However, in TNFi treatment. the present study, co-medication with csDMARD did not The need for inpatient care was low, although there was a show added benefits in terms of working ability. slight increase in inpatient days around the beginning of drug The TNFi are shown to be effective in both AS and nr- treatment. The non-significant increase in outpatient visits axSpA, when objective signs of inflammation are present during the follow-up year after initiating TNFi treatment [27]. In nr-axSpA with no objective signs of inflammation, compared with the year before TNFi is probably because the the efficacy has been shown to be lower [28, 29]. The associa- baseline visit was included in the former. Defining the follow- tion between CRP levels and an increase in the days absent up period in this way was intentional because prescribing the from work is in contrast to our expectations of patients with new treatment warrants a visit to a rheumatologist. ASAS/EULAR guidelines recommend TNFi as a second-line higher disease activity gaining more benefit from TNFis. The treatment, if disease activity remains high despite NSAID ther- finding was, however, only borderline significant in the nr- apy [23]. In Finland, SII requires a treatment attempt with axSpA group and absent in the AS group, which is why we re- cDMARDs before reimbursement for TNFis is granted. frain from drawing any definite conclusion on this topic. Patients treated with TNFi are the subgroup of most severe We discovered that despite initiation of TNFi, the amount cases, because patients with a milder disease course are of disability pensions rises steadily. The results emphasize the 6 Anna-Mari Hokkanen et al. Figure 3 Correlation coefficients between explanatory variables and the change in annual rates of work disabled days. AxSpA: Ankylosing spondylitis; NR AxSpa: Non-radiographic spondyloarthritis importance of managing the disease in a multidisciplinary Previous studies have observed correlations between dis- fashion, managing pain and taking work ability and rehabili- ease activity and health-care resource use or work absence tation into consideration early in the disease course. in rheumatic diseases, which have, in turn, been used as There is little evidence of non-pharmacological interven- inputs for modelling cost-effectiveness of TNFis. Whether tions improving employment among patients with SpA [30]. the treatment response achieved with TNFis manifests as In a Swedish study, the sick leave and disability pension rates savings in health-care costs and productivity losses can be remained higher in SpA patients than in the general popula- analysed by examining the incidence of in- and outpatient tion despite pharmacological interventions [31]. TNFi therapy visits and work absence days before and after the treatment combined with physiotheraphy could offer a synergistic effect initiation [38, 39]. Unlike the typical assumption in cost- [32]. More research is needed on the possibilities of enhancing effectiveness models, improved well-being of an individual work rehabilitation of patients with SpA [33–35]. might not lead to improved employment for all individuals SpA also causes decreased presenteeism, work productivity if they are still eligible to enter or remain on disability pen- loss and inability to succeed in daily unpaid activities, as seen sion. Notably, our results showed that only a fraction of in research using patient surveys [4, 13, 36, 37]. patients who were on disability leave for the entire year be- Unfortunately, we did not have the tools to examine these fore TNFi onset returned to work during the subsequent aspects in our study. year. SpA patients are likely to experience other health- There have been studies considering work-related issues re- related concerns, such as fatigue, sleep and emotional prob- lated to sex, evaluating differences between males and females lems [40]. These symptoms are not alleviated by TNFi ther- in the treatment response to TNFi [10]. Therefore, we in- apy as well as inflammation-mediated pain and stiffness cluded sex as a factor in the regression model. However, we [41]. did not detect a significant difference between males and Our results showed an increasing trend in the incidence of females in the decrease of work disability in either the AS or work disability during the year before TNFi initiation. This is the nr-axSpA population (Fig. 3). probably attributable to the worsening of symptoms, which TNF inhibitors in axial spondyloarthritis 7 eventually qualify the patient for reimbursement criteria for expressed in this paper are those of the authors and do not TNFis. Together with the selection criteria for the study and necessarily represent those of MSD Sharp & Dohme Corp. the temporal variability in symptom severity, this means that Disclosure statement: D.N. has received concultancy fees at the baseline of their first TNFi, the patients might be at the from AbbVie, BMS, Lilly, Novartis, Pfizer, Roche and UCB peak of their symptoms. The impact of the regression-to-the- and research grant from MSD, outside this work. A.-M.H. mean phenomenon cannot be ruled out when interpreting the has received a grant from MSD for this work and reimburse- decreasing incidence of outcomes during the subsequent year. ment for travel costs from Janssen-Cilag outside this work. Given that SpA has a chronic and progressive disease course, the short study period of 1 year after treatment initia- H.R. has received concultancy fees from Abbvie, Pfizer and tion does not fully describe the effect of TNFi medication UCB, outside this work. K.P. has received honoraria from upon the individual’s health over the years [38]. It is reason- Abbvie and Participated on a Data Safety Monitoring Board able to compare the years before and after the initiation of the or Advisory Board of Pfizer outside this work. K.T. has re- TNFi treatment. In a Finnish study from 1987, the disability ceived honoraria for lectures from Abbvie, Pfizer and Roche, rate at 8 years was 15% since the diagnosis of AS. The major support in travel and attending fee from Pfizer and stocks of cause for limited working capacity was disease severity [42]. Orion. A.K. has attended treatment study of BMS, Novartis In another study from the 1980s, in which the natural disease and Abbvie and Participated on a Data Safety Monitoring course of AS was investigated, disability generally developed Board or Advisory Board of Novartis and support for parti- within first 10 years of disease [43]. After 25 years of AS, pation fee by Novartis and honoraria of lecture by Abbvie. 48% of the patients were working in their original occupa- The remaining authors have declared no conflicts of interest. tions and 30% were unable to work at all. Seventeen per cent of the patients were forced to change their occupation [44]. An advantage in this study is that missingness does not oc- Acknowledgements cur in endpoint data, because all sick leaves >10 days, disabil- We thank Mr Pasi Aronen for his expert opinion on statistical ity pensions and hospital stays are collected from official methods. records. However, patients who are waiting for a disability pension decision after 300 days of sick leave have a status of unemployment and are not recorded in the registries. Also, References short (<10 working days) sick leaves are not recorded and 1. Lee JS, Oh B-L, Lee HY, Song YW, Lee EY. 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Impact of TNF inhibitor medication on working ability in axial spondyloarthritis: an observational national registry-based cohort study

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© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.
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Abstract

Objective: The aim was to investigate the effect of TNF inhibitor (TNFi) initiation on working ability and health-care resource utilization among axial SpA patients in a real-life setting. Methods: Patients with a clinical diagnosis of non-radiographic (nr-axSpA) or radiographic axial SpA initiating their first TNFi were identified from the National Register for Antirheumatic and Biologic Treatment in Finland. Sickness absences, including sick leave and disability pension, in- and outpatient days and rehabilitation rates, 1 year before and after initiating the medication were retrieved from national registries. Factors affecting result variables were studied using multivariate regression analysis. Results: Overall, 787 patients were identified. Rates of work disability days per year were 55.6 the year before treatment onset and 55.2 the year after, with significant differences between patient subgroups. The rate of sick leave decreased after starting TNFi treatment. However, the rate of disability pension continued to rise. Patients with a diagnosis of nr-axSpA experienced a decrease in overall work disability and, especially, fewer sick leaves. No sex differences were detected. Conclusion: TNFi interrupts the increase in work disabled days evident during the year before its initiation. However, the overall work disability remains high. Treating patients earlier in the nr-axSpA phase, regardless of sex, appears important in maintaining the ability to work. Lay Summary What does this mean for patients? Maintaining the ability of patients to work is a complex and challenging task that deserves special attention when treating people with chronic in- flammatory diseases, such as ankylosing spondylitis and non-radiographic SpA (nr-axSpA). Work disability remains a problem among these patients despite the evolving treatment options. We investigated how a type of drug called a tumour necrosis factor inhibitor (TNFi) affects work- ing ability in people with nr-axSpA in a real-life setting in Finland. We used data on patients and their treatment from a database called the National Register for Antirheumatic and Biologic Treatment in Finland. We compared data on sick leave, in- and outpatient days and rehabilitation 1 year before and after starting TNFi medication. Our results show that TNFi medication substantially reduces the amount of sick leave that patients need to take, especially for people with nr-axSpA. However, we found that the amount of disability pension claimed rises steadily de- spite patients starting TNFi medication. Taking these results together, we conclude that starting TNFi medication might interrupt the decline in the ability to work in nr-axSpA patients. However, effective ways of maintaining patients’ ability to work are still needed. Keywords: work disability, TNF inhibitor, axial SpA, AS, non-radiographic axial SpA, register study Key messages Rise of absenteeism subsided with the initiation of TNFi. Beneficial effect on work absenteeism was more pronounced with the diagnosis of non-radiographic axial SpA regardless of sex. Long-term work disability increased despite TNFi initiation. Received: 20 January 2023. Accepted: 3 May 2023 V The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Anna-Mari Hokkanen et al. Introduction treating physicians using a standardized protocol. The data were collected with paper forms or by applying the GoTreatIt AS and non-radiographic axial SpA (nr-axSpA) are inflamma- computer software platform. Missing baseline data were im- tory rheumatic diseases. These conditions initiate typically be- puted by multiple imputation with predictive mean matching fore the age of 40 years, and AS patients have been shown to and 10 imputed data sets. have increased working disability and health-care resource use in comparison to the general population [1–5]. The inflamma- Outcomes and follow-up tory activity varies over time, but delayed diagnosis and insuf- The study was conducted as an observational cohort study. ficient treatment can lead to considerable disability [6–9], as The outcomes of interest in this study comprised days absent also highlighted by van Hoeven et al. [5]. Delayed diagnosis from work owing to sick leave, disability pension or rehabili- was connected to unemployment in a recent study in the USA tation and the number of inpatient days and outpatient visits [10]. The main cause of disability is spinal stiffness and pain. to specialized health-care facilities. In addition, peripheral arthritis and uveitis often The Finnish social insurance system provides financial sup- occur, sometimes also with other extra-articular manifesta- port for individuals of working age in the event of illness or tions, such as IBD. Co-morbidities, such as fatigue and depres- injury. We defined sick leave as days with sickness allowance sion, are also present. Loss of effective working years results in of any degree paid by the Social Insurance Institution of indirect costs to society [4, 7, 8, 11–13]. Finland (SII). All sick leaves with a duration of 10 days are nr-axSpA was recognized as an entity in 2009 [14], and registered continuously and prospectively by the SII. Sick since 2013 the diagnosis has entitled patients in Finland to bi- leaves shorter than this are not registered, because the em- ological drug reimbursement, if traditional anti-rheumatic ployer provides the pay. Sick leave is paid for 300 days. drugs are insufficient to control the disease. In Finland, the in- After this, the patient can apply for a fixed-term rehabilitation cidence of AS has been reported to be 7.3 per 100 000 and subsidy, which is granted for the time it is needed for medical unspecified SpA 18 per 100 000 [15]. The incidence rate for and/or vocational rehabilitation to restore the ability to work. all SpA has risen from 12 to 18 per 100 000 between 2000 If the rehabilitation measures are not able to restore working and 2014 [16, 17]. ability, the patient applies for a disability pension. In our Work ability is an important goal when treating patients of study, we viewed sickness absences as temporary leaves (sick working age. The expansion of medication alternatives and leave and rehabilitation subsidy) and as permanent incapacity progress in treatment strategies are expected to improve work to work, i.e. disability pension. capability and employment. TNF inhibitors (TNFi) have been Information on sick leaves were retrieved from the SII, proved to be clinically beneficial, safe and cost effective in whereas the data on pensions were gathered from SII and both AS and nr-axSpA [18, 19]. Evidence from clinical trials Finnish Centre for Pensions. The information on the outpa- suggests that TNFi are able to prevent work disability in tient and inpatient visits was gathered from Care Registers for patients with AS [20], but these findings might not be general- Social Welfare and Health Care. The data on deaths and emi- izable to routine clinical practice owing to the stringent inclu- grations were retrieved from Statistics Finland. sion criteria for clinical trials [21]. Results from the British The baseline visit took place when TNFi treatment was ini- Society for Rheumatology biologics register and meta- tiated. The follow-up time was 1 year before and 1 year after analysis show significant improvement in work productivity, the start of a TNFi. However, follow-up was terminated in although absenteeism was seen to remain high [22]. the event of death or emigration. When analysing sick leaves The aim of this study was to evaluate the effect of starting a and disability pensions, the patients were also censored when TNFi on absenteeism and the use of health-care resources in a they became pensioners (excluding disability pension) or national cohort of axSpA patients including both nr-axSpA turned 63 years old, which is the common retirement age in and AS patients. Finland. A favourable ethical board statement was granted by the Helsinki and Uusimaa Hospital District coordinating ethical Methods committee (73/13/03/00/2014), and permission for the study Patients was obtained from the National Institute for Health and Patients were identified from the National Register for Welfare (THL/6752/14.06.00/2020). Written informed pa- Antirheumatic and Biologic Treatment in Finland (ROB-FIN), tient consent were acquired from patients who had been in- which is a longitudinal cohort study with data dating back to cluded in ROB-FIN before the introduction of the electronic 1999. ROB-FIN was established initially to monitor the effec- patient monitoring systems covered by the permission above. tiveness and safety of biologic DMARDs (bDMARDs) in Statistical methods rheumatic diseases. Inclusion for this study was limited to TNFi treatments started as the patient’s first bDMARD treat- Baseline characteristics at initiation of TNFi treatment are ment between 2007 and 2015. presented as the mean along with standard deviations or According to the Finnish treatment guidelines and the re- percentages. The outcomes are reported as events per patient- stricted reimbursement confirmed by the Finnish year, with the 95% CI calculated via non-parametric boot- Pharmaceuticals Pricing Board, patients with AS and strapping. The missing values among patient characteristics nr-axSpA must be refractory to at least one conventional were imputed using a multiple imputation method. The an- synthetic DMARD (csDMARD) before they are entitled to re- nual change in the rate of the outcomes before and after the imbursement for bDMARDs. initiation of TNFi was modelled with linear regression, with We included patients with a clinical diagnosis of AS or nr- an additional error term for repeated measures. The explana- axSpA (ICD10 diagnosis codes M45 and M46). At the start tory variables included age, sex, HLAB27, CRP, ASDAS- of TNFi therapy, baseline characteristics were reported by the CRP, TNFi agent, concomitant use of csDMARDs and the TNF inhibitors in axial spondyloarthritis 3 Table 1. SpA patient characteristics at baseline year of treatment onset. The year of treatment onset was di- vided into three periods of equal length (2007–2009, 2010– Variable Mean (S.D. or percentage) 2012 and 2013–2015) to examine whether the availability of All patients AS Nr-axSpA new TNFi drugs (certolizumab pegol and golimumab) and the (n¼ 787) (n¼ 684) (n¼ 103) expansion of medication use would have an effect on work outcome. Data management and statistical analyses were car- Age, years 40 (11) 40 (11) 38 (11) ried out using R software v.3.6.2 (R Foundation for Statistical Sex 442 (56% male) 405 (59% male) 37 (36% male) Computing, Vienna, Austria). Weight, kg 79 (16) 79 (15) 80 (18) Height, cm 172 (10) 173 (9.4) 171 (9.1) Patient global 47 (26) 47 (25) 48 (25) Results assessment Investigator 35 (22) 35 (20) 30 (19) Patients and follow-up global Overall, 787 patients were included in the study, of whom assessment 684 and 103 were diagnosed with AS and nr-axSpa, respec- HAQ 0.70 (0.5) 0.71 (0.49) 0.68 (0.51) Pain 52 (25) 52 (26) 51 (23) tively. A full year worth of follow-up was available for 783 ASDAS 3.0 (1.0) 3.0 (1.0) 2.8 (1.1) patients, whereas 4 were censored during the follow-up owing BASDAI 44 (20) 44 (21) 44 (19) to death or emigration. Of the overall population, 734 were ESR, mm/h 17 (18) 17 (17) 14 (16) of working age the year before initiation of TNFi, and among CRP, mg/l 13 (17) 13 (16) 11 (15) this subgroup an additional 27 patients were censored owing Time from 6.7 (7.6) 7.1 (7.8) 4.2 (5.5) diagnosis, to retirement, death or emigration. years Baseline characteristics are described in Table 1. The mean age was 40 years, and 56% of the patients were men. The mean DAS according to ASDAS was 3.0 and BASDAI 44. Patient global assessment was 47 and investigator global as- Table 2. Medication when first TNF inhibitor initiated sessment 35. Mean baseline ESR was 17 mm/h, and CRP was Medication n (%) 13 mg/l. The AS patients were predominantly male (59%), whereas nr-axSpa patients were mostly female (64%). The TNF inhibitor time from diagnosis to starting treatment was 4.2 (S.D. Adalimumab 277 (35) Etanercept 238 (30) 5.5) years for nr-axSpA and 7.1 (S.D. 7.8) years for AS. Infliximab 175 (22) At the initiation of TNFi medication, 73% of the patients Golimumab 82 (10) received concomitant csDMARD treatment, while the remain- Certolizumab pegol 15 (1.9) ing 27% of the patients received biologic monotherapy. MTX Concomitant medication was used by 46% of the patients and SSZ by 41% . Oral low- Any conventional DMARD 577 (73) MTX 357 (46) dose glucocorticoids were used by 27% of the patients. SSZ 322 (41) Adalimumab was the most frequently used TNFi, by 35% of Glucocorticoids 161 (27) the patients, followed by etanercept (30%), infliximab (22%) Other conventional DMARD 78 (9.8) golimumab (10%) and certolizumab pegol (1.9%) (Table 2). Outcomes rates of inpatient days and outpatient visits were similar be- The annual number of sick disabled days decreased slightly in fore and after the initiation of TNFi therapy. the overall population: from 47.3 (95% CI 40.9, 53.8) days Of the 48 patients who were absent from work for the during the year before TNFi initiation to 43.6 (95% CI 36.5, whole year before TNFi treatment began, only 7 (15%) 50.8) days the year after (Table 3). The 90-day rate of work returned to work during the 1-year follow-up. Additionally, absence days increased during the first year of follow-up until 17 patients who were working at least part time during the TNFi initiation and decreased thereafter (Fig. 1). year before treatment initiation were absent for the entire sub- The rate of days on sick leave decreased after TNFi initia- sequent year after treatment initiation. tion within the subgroup of patients of working age (Fig. 1). Regression analyses The incidence of sick leaves during the first and second time periods in this subgroup was 32.90 (95% CI 27.9, 38.1) and Based on the linear regression analysis, disease activity at 26.5 (95% CI 22.4, 31.1), respectively (Table 3). Meanwhile baseline (ASDAS-CRP) did not demonstrate a statistically sig- an increasing trend for days absent from work owing to dis- nificant association with the annual change in absenteeism, ability pensions was observed in the overall population: from nor did HLAB27, HAQ, smoking or BMI. Even age did not 14.8 (95% CI 9.7, 19.7) to 17.1 (95% CI 11.4, 22.7) days. seem to change the outcome; CRP was associated with a mod- The same trend was seen both in AS and nr-axSpA patients. est increase in the number of days absent from work among Absenteeism reduced to a larger extent among the nr- nr-axSpA patients, but not in AS patients (1.06, 95% CI axSpA patients, from 38.2 (95% CI 23.5, 55.6) days per pa- 0.058, 2.0 vs 0.19, 95% CI 0.16, 3.2; Fig. 3). However, the tient year the year before to 22.83 (95% CI 12.1, 36.7) days small values do not appear clinically significant. The choice of per patient year the year after. Among AS patients, the values TNFi agent was not a statistically significant predictor of im- changed from 48.6 (95% CI 41.2, 56.5) to 46.6 (95% CI provement in absenteeism, aside from certolizumab pegol 39.3, 54.1) days per patient year. reaching statistical significance in comparison to adalimumab No statistically significant changes were observed in health- among axSpA patients (64, 95% CI 18, 110), but this was care resource utilization between the two periods (Fig. 2). The probably attributable to bias caused by the small number of 4 Anna-Mari Hokkanen et al. Table 3. Crude annual incidence rates of outcome variables by diagnosis Days during 1 year Days during 1 year Days during 1 year Days during 1 year Days during 1 year Days during 1 year pre-TNFi post-TNFi pre-TNFi post-TNFi pre-TNFi post-TNFi [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] Incidence rate AS (n¼ 640) nr-AxSpA (n¼ 94) All (n¼ 734) Rate of work disabled 48.6 [41.2, 56.5] 46.6 [39.3, 54.1] 38.2 [23.5, 55.6] 22.83 [12.1, 36.7] 47.3 [40.9, 53.8] 43.6 [36.5, 50.8] days Rate of sick leave days, 32.1 [27.0, 37.7] 28.1 [23.5, 33.3] 38.2 [23.5, 55.6] 16.1 [8.9, 24.8] 32.90 [27.9, 38.1] 26.5 [22.4, 31.1] all causes Rate of sick leave days, 19.6 [15.0, 24.3] 16.61 [12.9, 21.2] 18.8 [7.8, 32.9] 7.4 [3.0, 13.2] 19.5 [15.5, 23.6] 10.3 [6.1, 14.7] SpA Rate of disability 16.9 [11.5, 23.3] 18.7 [12.8, 24.5] 0 [0.0, 0] 6.7 [0.0, 17.6] 14.8 [9.7, 19.7] 17.1 [11.4, 22.7] pension days, all causes Rate of disability 9.5 [5.5, 14.2] 11.35 [7.0, 15.9] 0 [0.0, 0] 3.1 [0.0, 9.9] 8.3 [4.86, 11.9] 10.3 [6.1, 14.7] pension days, SpA AS (n5 684) nr-AxSpA (n5 103) All (n5 787) Rate of outpatient visits 6.4 [5.9, 6.8] 7.2 [7.00, 7.5] 7.6 [6.54, 8.6] 6.4 [6.0, 8.1] 6.5 [5.1, 6.9] 7.4 [6.9, 7.8] (visits per year) Rate of inpatient days 1.0 [0.8, 1.3] 1.1 [0.8, 1.3] 1.2 [0.6, 1.9] 1.6 [1.0, 2.3] 1.6 [1.3, 2] 1.5 [1.3, 1.9] (days per year) nr-AxSpA: non-radiographic axial SpA. Figure 1 Number of days absent from work as 90-day rates. Sick leave, disability pension and pooled work disability 1 year before and after TNF inhibitor treatment onset (i.e. baseline) among the patients of working age patients in the certolizumab pegol group (15 patients). population (P¼ 0.039) and also when age, sex, HLAB27 sta- However, the decrease in absenteeism in the nr-axSpA tus, time from diagnosis and CRP were standardized population was significantly more pronounced than in the AS (P¼ 0.056). TNF inhibitors in axial spondyloarthritis 5 Figure 2 Ninety-day rates 1 year before and after TNF inhibitor treatment onset. (A) Hospital in-patient days. (B) Health-care visits in specialized health care. (C) Rehabilitation days. Discussion treated primarily with NSAIDs or cDMARDs. One of the rea- sons for these Finnish treatment guidelines is that Finnish Our results showed that the rate of sick leaves decreased nota- patients using co-medication with cDMARDs and biologics bly after the initiation of TNFi treatment in the nr-axSpA show added beneficial effect [24, 25]. Moreover, recent inter- group. Meanwhile the rate of disability pension days contin- national register data have replicated these findings [26]. ued to rise slightly throughout both follow-up years. The These studies shed light on the disparity of results on this sub- number of sick leave days remained high in the AS group. A ject across publications from different national registries over lack of improvement in overall work absence was shown pre- the past decade. They also suggest that, in contrast to current viously by a British observational study [22]. However, in this international treatment guidelines, csDMARD co-therapy study the nr-axSpA patients benefitted especially from the should not necessarily be disregarded in axSpA. However, in TNFi treatment. the present study, co-medication with csDMARD did not The need for inpatient care was low, although there was a show added benefits in terms of working ability. slight increase in inpatient days around the beginning of drug The TNFi are shown to be effective in both AS and nr- treatment. The non-significant increase in outpatient visits axSpA, when objective signs of inflammation are present during the follow-up year after initiating TNFi treatment [27]. In nr-axSpA with no objective signs of inflammation, compared with the year before TNFi is probably because the the efficacy has been shown to be lower [28, 29]. The associa- baseline visit was included in the former. Defining the follow- tion between CRP levels and an increase in the days absent up period in this way was intentional because prescribing the from work is in contrast to our expectations of patients with new treatment warrants a visit to a rheumatologist. ASAS/EULAR guidelines recommend TNFi as a second-line higher disease activity gaining more benefit from TNFis. The treatment, if disease activity remains high despite NSAID ther- finding was, however, only borderline significant in the nr- apy [23]. In Finland, SII requires a treatment attempt with axSpA group and absent in the AS group, which is why we re- cDMARDs before reimbursement for TNFis is granted. frain from drawing any definite conclusion on this topic. Patients treated with TNFi are the subgroup of most severe We discovered that despite initiation of TNFi, the amount cases, because patients with a milder disease course are of disability pensions rises steadily. The results emphasize the 6 Anna-Mari Hokkanen et al. Figure 3 Correlation coefficients between explanatory variables and the change in annual rates of work disabled days. AxSpA: Ankylosing spondylitis; NR AxSpa: Non-radiographic spondyloarthritis importance of managing the disease in a multidisciplinary Previous studies have observed correlations between dis- fashion, managing pain and taking work ability and rehabili- ease activity and health-care resource use or work absence tation into consideration early in the disease course. in rheumatic diseases, which have, in turn, been used as There is little evidence of non-pharmacological interven- inputs for modelling cost-effectiveness of TNFis. Whether tions improving employment among patients with SpA [30]. the treatment response achieved with TNFis manifests as In a Swedish study, the sick leave and disability pension rates savings in health-care costs and productivity losses can be remained higher in SpA patients than in the general popula- analysed by examining the incidence of in- and outpatient tion despite pharmacological interventions [31]. TNFi therapy visits and work absence days before and after the treatment combined with physiotheraphy could offer a synergistic effect initiation [38, 39]. Unlike the typical assumption in cost- [32]. More research is needed on the possibilities of enhancing effectiveness models, improved well-being of an individual work rehabilitation of patients with SpA [33–35]. might not lead to improved employment for all individuals SpA also causes decreased presenteeism, work productivity if they are still eligible to enter or remain on disability pen- loss and inability to succeed in daily unpaid activities, as seen sion. Notably, our results showed that only a fraction of in research using patient surveys [4, 13, 36, 37]. patients who were on disability leave for the entire year be- Unfortunately, we did not have the tools to examine these fore TNFi onset returned to work during the subsequent aspects in our study. year. SpA patients are likely to experience other health- There have been studies considering work-related issues re- related concerns, such as fatigue, sleep and emotional prob- lated to sex, evaluating differences between males and females lems [40]. These symptoms are not alleviated by TNFi ther- in the treatment response to TNFi [10]. Therefore, we in- apy as well as inflammation-mediated pain and stiffness cluded sex as a factor in the regression model. However, we [41]. did not detect a significant difference between males and Our results showed an increasing trend in the incidence of females in the decrease of work disability in either the AS or work disability during the year before TNFi initiation. This is the nr-axSpA population (Fig. 3). probably attributable to the worsening of symptoms, which TNF inhibitors in axial spondyloarthritis 7 eventually qualify the patient for reimbursement criteria for expressed in this paper are those of the authors and do not TNFis. Together with the selection criteria for the study and necessarily represent those of MSD Sharp & Dohme Corp. the temporal variability in symptom severity, this means that Disclosure statement: D.N. has received concultancy fees at the baseline of their first TNFi, the patients might be at the from AbbVie, BMS, Lilly, Novartis, Pfizer, Roche and UCB peak of their symptoms. The impact of the regression-to-the- and research grant from MSD, outside this work. A.-M.H. mean phenomenon cannot be ruled out when interpreting the has received a grant from MSD for this work and reimburse- decreasing incidence of outcomes during the subsequent year. ment for travel costs from Janssen-Cilag outside this work. Given that SpA has a chronic and progressive disease course, the short study period of 1 year after treatment initia- H.R. has received concultancy fees from Abbvie, Pfizer and tion does not fully describe the effect of TNFi medication UCB, outside this work. K.P. has received honoraria from upon the individual’s health over the years [38]. It is reason- Abbvie and Participated on a Data Safety Monitoring Board able to compare the years before and after the initiation of the or Advisory Board of Pfizer outside this work. K.T. has re- TNFi treatment. In a Finnish study from 1987, the disability ceived honoraria for lectures from Abbvie, Pfizer and Roche, rate at 8 years was 15% since the diagnosis of AS. The major support in travel and attending fee from Pfizer and stocks of cause for limited working capacity was disease severity [42]. Orion. A.K. has attended treatment study of BMS, Novartis In another study from the 1980s, in which the natural disease and Abbvie and Participated on a Data Safety Monitoring course of AS was investigated, disability generally developed Board or Advisory Board of Novartis and support for parti- within first 10 years of disease [43]. After 25 years of AS, pation fee by Novartis and honoraria of lecture by Abbvie. 48% of the patients were working in their original occupa- The remaining authors have declared no conflicts of interest. tions and 30% were unable to work at all. Seventeen per cent of the patients were forced to change their occupation [44]. An advantage in this study is that missingness does not oc- Acknowledgements cur in endpoint data, because all sick leaves >10 days, disabil- We thank Mr Pasi Aronen for his expert opinion on statistical ity pensions and hospital stays are collected from official methods. records. However, patients who are waiting for a disability pension decision after 300 days of sick leave have a status of unemployment and are not recorded in the registries. Also, References short (<10 working days) sick leaves are not recorded and 1. Lee JS, Oh B-L, Lee HY, Song YW, Lee EY. 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Journal

Rheumatology Advances in Practice – Oxford University Press

Published: May 25, 2023

Keywords: work disability; TNF inhibitor; axial SpA; AS; non-radiographic axial SpA; register study

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