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Rheumatoid Arthritis
ter Wee, M.M.
2016
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ter Wee, M. M. (2016). Rheumatoid Arthritis: Strategies that Work.
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1
General introduction
Chapter 1
10
Rheumatoid arthritis
In the Netherlands, approximately 1% of the population suffers from the chronic disease rheumatoid arthritis (RA). The impact of this disease influences many aspects of patients’ life, such as performing daily activities. To categorize all these aspects, the World Health Organization developed a framework to assess the impact of a disease: the International Classification of Functioning, Disability and Health (the WHO ICF) framework (2001). In this framework the impact of a disease can be assessed through five components: ‘body functions and structures’, ‘activities’, ‘participation’, ‘environmental factors’ and ‘personal factors’, as shown in Figure 1.[1] All these components influence each other.
Most articles published on RA use a disease perspective, only reporting on body functions and structures and activity measured as functional ability. The WHO ICF framework also incorporates a functioning perspective in which the influence of personal and environmental factors on performing activities, participation and body functions and structures is measured.[3]
HEALTH CONDITION (disorder or disease) ACTIVITY (limitations) PERSONAL FACTORS ENVIRONMENTAL FACTORS PARTICIPATION (restrictions)
BODY FUNCTIONS & STRUCTURES
(impairments)
Contextual factors
Figure 1: WHO ICF framework [1]
1
11 The disease perspective
RA is an autoimmune disease characterized by synovial inflammation of joints. In a later stadium the cartilage and bone of affected joints are damaged, which is mostly irreversible. Patients suffer from pain, the most fundamental symptom of RA, swollen joints, morning stiffness, fatigue, and negative emotions, all part of the component ‘body functions’. Physical health and joint damage are usually measured by the components of the WHO-ILAR core set,[4] including indices such as the disease activity score (DAS), and the Sharp van der Heijde Score (SHS) for joint damage. The true impact of the disease on performance of activities is challenging for several reasons. These include variability of pain and associated avoidance , as well as coping behaviour. In the field of rheumatology, performing daily activities is often measured by generic health status measures such as the Health Assessment Questionnaire (HAQ), that only assesses the possibility to perform a certain activity.[3] Medical treatment of the disease aims at improving the above mentioned aspects. Suboptimal treatment of RA leads to deformations and functional limitations, but also to comorbidities such as elevated risk on cardiovascular diseases and osteoporotic fractures.
The treatment of RA patients has altered throughout the years. Earlier, the pyramid model was used as drugs became available: starting with non-steroidal anti-inflammatory drugs (NSAIDs); when not efficient enough, monotherapy with a disease modifying anti rheumatic drug (DMARD), such as sulfasalazine (SSZ), methotrexate (MTX) or hydroxychloroquine (HCQ) was added, and so on.[5-7] What we learned from these trials was that DMARDs need approximately three to six months to start exerting their effect, and that damage of joints already occurred during this period. Eventually the reverse pyramid model became more and more accepted, in which aggressive treatment was started, and medication was only tapered on clinical improvement. The hypothesis was that initial aggressive treatment would have a positive effect on long-term outcome, the so-called “window of opportunity”. Ultimately, this would result in less disability. The original COBRA (COmbinatietherapie Bij Reumatoïde Artritis) study,[8] later on the Behandel STrategieën trial (BeSt),[9] the Finnish Rheumatoid Arthritis Combination therapy trial (FIN-RACo)[10], as well as the PROMPT study [11] are examples of combination strategies applying the reverse pyramid model.
The original COBRA study showed that patients treated with either sulfasalazine (monotherapy) or a combination of SSZ, MTX and initially high
Chapter 1
12
dose prednisolone (60mg/day) tapered to 7.5 mg/day in seven weeks, was effective in suppressing disease activity, increasing functional ability, and preventing short and long-term radiological joint progression.[8, 12] Later on, the BeSt trial was performed in which the COBRA strategy was compared to monotherapy with DMARDs , step-up therapy, and a biological (infliximab, a TNFα-blocking agent plus MTX). Biological treatments were discovered in the past two decades and were developed through biotechnology. These drugs target several cytokines: not only tumour necrosis factor (TNFα), but also IL-6, B-cells and T-cells. They proved to be very effective in the treatment of RA, alone or in combination with DMARDs.[13] The BeSt trial showed that COBRA strategy was superior to sulfasalazine monotherapy, step-up therapy and as effective as infliximab treatment plus MTX, as can been seen in Figure 2.[9]
Although proven to be very effective in the treatment of RA, ten years after the COBRA trial, the COBRA strategy was only marginally used in daily practice. In in depth focus-interviews, physicians expressed hesitation to use the strategy mainly for fear of possible side effects of GCs, while, strikingly, the patients were less worried about the side effects, because of the favourable effects on disease activity.[14-16]
During these interviews, rheumatologists were also asked what they prescribe to the patients in daily practice. All mentioned only MTX and different dosages of prednisolone, varying from low dose to higher oral dosages, and parenteral injections: this variation is clearly suboptimal. Based on that, the COBRA-light strategy was born, as a compromise between rheumatologists. This strategy comprises start with high dose MTX (25 mg/week) and 30 mg/ day prednisolone, tapered to 7.5 mg/day in nine weeks. To assess if this light version was non-inferior to the original COBRA strategy, the COBRA-light trial was performed. Study questions of this trial were: 1) is COBRA-light non-inferior to COBRA strategy after 26 weeks of treatment (chapter 1.1). 2) After 52 weeks, is non-inferiority maintained; did radiological joint progression occur; what is the effect of additional etanercept (chapter 1.2). And 3) is COBRA-light therapy as cost-effective as COBRA strategy (chapter 1.3)?
1
13 0 20 40 60 80 100 0 3 6 9 12 15 18 21 24 % wit h DA S44 <1. 6 Time (months)sequential mono step-up combination
combi with prednisone combi with infliximab
Figure 2: Percentage of patients in remission (DAS44<1.6) over time, per group in the BeSt trial
The functioning perspective
To apply the whole ICF framework, the components ‘activities and participation’ and environmental and personal factors’ should also be considered. These items comprise daily activities (such as performing household, self-care), relationships with others, leisure time activities, participating at work (paid and unpaid), and social network. Unfortunately, these items are often disregarded in daily practice and research. Therefore, as an initiative of the European League Against Rheumatism (EULAR), the Rheumatoid Arthritis Impact of Disease (RAID) score was developed in 2008.[17] Aim of this initiative was to develop a score entirely based on patient-reported outcome (PRO) which could be used in clinical trials in RA. As the domains of the RAID were initially identified by ten patients, including one Dutch representative, we deemed it necessary to document content validity in Dutch patients as well as comprehensibility before implementation in The Netherlands. In chapter 2.1, we assessed if all items included in the score are an adequate reflection of the construct that the score aims to measure. This was done both by comparing the RAID score with the WHO ICF core set for RA, and by focus group interviews with patients, aimed at eliciting which domains their disease had impact on.
The components ‘Activities and participation’ and ‘Environmental factors’ also include performing paid (or unpaid) work, and all items related to performing a job. Although we are now more able to control disease activity, RA still has a major impact on work participation. Compared to the general
Chapter 1
14
population, patients with RA in the Netherlands have approximately 12-20% less paid jobs, experience 2-3 times more days of sick leave, and are about 7 times more work disabled.[18] At this moment, a so called continuum of work is being recognized (Figure 3): presenteeism (productivity loss at work) may lead to absenteeism (days on sick leave), and long absence from work may lead to work disability.[2] Therefore, benefi ts of therapy can emerge from preventing both work disability and loss of work productivity. This is especially pertinent in the case of biological agents, as their cost-prices are high, strongly increasing the overall health care costs of RA in recent years.[19-21] It has been proposed that early treatment with biological agents can improve work productivity, decrease sick leave and work disability, compared to standard of care. This would result in a decrease in indirect costs, compensating the high cost price of these therapies, and possibly decreasing total (societal) costs of RA. Studies of the eff ect of biological treatment on indirect costs are increasing, but little is known about their eff ects on productivity at work (presenteeism), and sick leave (absenteeism). We performed a systematic review in this topic, presented in chapter 2.2.
Only a few studies have assessed the eff ect of conventional DMARD treatment (such as COBRA and COBRA-light strategy) on work outcome. Therefore, we wanted to know whether intensive treatment with combination therapy (COBRA and COBRA-light) also resulted in positive work outcome in early RA patients, and if we were able to fi nd associations between several disease, personal and work related factors at baseline, and eventually predict sick leave over a one-year period. This is described in chapter 2.3.
Threshold Threshold
Threshold
Work status: employed not employed
Productivity: normal presenteeism absenteeismtemporary absenteeismpermanent - official short-term sick leave
- official long-term sick leave
- official work disability - economic unemployment - official early retirement - voluntary unemployment
1 2 3
Figure 3: Continuum of work [2]
1
15
REFERENCE LIST
1. WHO. WHO. International Classification of Functioning, Disability and Health: ICF. Geneva: 2001. 2. Boonen A, Severens JL. Worker participation in Rheumatic Disease: The socioeconomic perspective.
Keat A, Mawer F, editors. 3. 2009. Reports on the Rheumatic Diseases series 6. Topical Reviews: An overview of current research and practice in rheumatic disease. 3-3-2014. Ref Type: Report 3. Stucki G, Ewert T. How to assess the impact of arthritis on the individual patient: the WHO ICF. Ann
Rheum Dis 2005; 64(5):664-8.
4. Boers M, Tugwell P, Felson DT, van Riel PL, Kirwan JR, Edmonds JP et al. World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials. J Rheumatol Suppl 1994; 41:86-9. 5. Bagnalla W. The value of chloroquine in rheumatoid disease: a four-year study of continuous
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6. Sinclair RJ, Duthie JJ. Salazopyrin in the Treatment of Rheumatoid Arthritis. Ann Rheum Dis 1949; 8(3):226-31.
7. Ward JR. Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis. J Rheumatol Suppl 1985; 12 Suppl 12:3-6.
8. Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350(9074):309-18.
9. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van ZD, Kerstens PJ, Hazes JM et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52(11):3381-90. 10. Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M et al. Comparison
of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999; 353(9164):1568-73.
11. Van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, Hulsmans HM et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007; 56(5):1424-32.
12. Landewe RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002; 46(2):347-56.
13. Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A. Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70. Biologics 2012; 6:429-64.
14. Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997; 36(10):1082-8.
15. Van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. Why are Dutch rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis? Ann Rheum Dis 2007; 66(7):974-6.
16. Van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Kerstens PJ, Dijkmans BA et al. Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47(10):1571-6.
17. Gossec L, Dougados M, Rincheval N, Balanescu A, Boumpas DT, Canadelo S et al. Elaboration of the preliminary Rheumatoid Arthritis Impact of Disease (RAID) score: a EULAR initiative. Ann Rheum Dis 2009; 68(11):1680-5.
18. Chorus AMJ, Schokker DF. Nationale Peiling van het Bewegingsapparaat 2010. 2011. TNO, in order of the Dutch rheumatology foundation. Ref Type: Report
19. Boonen A, Mau W. The economic burden of disease: comparison between rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol 2009; 27(4 Suppl 55):S112-S117.
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20. Franke LC, Ament AJ, van de Laar MA, Boonen A, Severens JL. Cost-of-illness of rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol 2009; 27(4 Suppl 55):S118-S123.
21. Verstappen SM, Jacobs JW, Kruize AA, Ehrlich JC, van Albada-Kuipers GA, Verkleij H et al. Trends in economic consequences of rheumatoid arthritis over two subsequent years. Rheumatology (Oxford) 2007; 46(6):968-74.
