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Rheumatology Advance Access published online on April 15, 2008
Rheumatology, doi:10.1093/rheumatology/ken137
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Morning stiffness and its influence on early retirement in patients with recent onset rheumatoid arthritis

G. Westhoff1, F. Buttgereit2, E. Gromnica-Ihle3 and A. Zink1,2

1Epidemiology Unit, German Rheumatism Research Centre, 2Department of Rheumatology and Clinical Immunology, Charité University Medicine and 3Medical Centre for Rheumatology Berlin-Buch, Berlin, Germany.

Correspondence to: G. Westhoff, Epidemiology Unit, German Rheumatism Research Centre Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail: Westhoff{at}drfz.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To describe the association between morning stiffness (MS) and early retirement in patients with early RA.

Methods. The study used data from a prospective RA cohort of 916 RA patients with disease duration ≤24 months. Data pertained to standard clinical measures and patients’ self-reports, such as functional capacity, pain and MS. Multivariate logistic regression analyses were performed to determine the association between MS and early retirement at 3 yrs, adjusting for sex, age, baseline working status, functional capacity, pain and 28-joint disease activity score (DAS28).

Results. MS was strongly associated with pain and functional capacity and to a lesser degree with joint counts and active phase responses. Severe MS in early disease had a significant impact on early retirement within the following 3 yrs. Of the 389 patients who were ≤61 yrs old and working at baseline, 80 (21%) had to take early retirement until the end of the study. Early retirement concerned 46% of the patients with severe and 10% of those with mild MS at study entry. Baseline working status was the strongest predictor and was severe compared with mild MS, the second strongest predictor of early retirement (adjusted odds ratio 6.0; 95% CI 2.9, 12.6).

Conclusions. Severe MS in the early course of the disease has a high impact on RA patients’ decision to withdraw from working life. Great attention should be paid to the effective treatment of MS in early RA, to prevent patients from possible untimely decisions that will have long-lasting and costly consequences.

KEY WORDS: Rheumatoid arthritis, Morning stiffness, Early retirement


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
RA is a chronic inflammatory disease characterized by inflammation of the synovial tissue, which causes damage to articular cartilage and subchondral bone [1, 2]. Pain, fatigue, morning stiffness (MS) and immobility are the common symptoms associated with RA, reducing quality of life and the ability to remain gainfully employed. Direct costs ensuing from work disability account for a large part of the total RA-related costs [3].

While the consequences of pain and functional limitations on quality of life and ability to work are frequently evaluated, MS remains relatively neglected in clinical studies. MS is part of the ACR classification [4] and remission criteria [5]; it is also part of the early referral recommendation for newly diagnosed RA [6]. However, MS remains a poorly understood phenomenon in RA as well as in other musculoskeletal conditions and is a rare target of basic research. The recognition of MS as a ‘complex symptom including pain and functional limitation’ [7, 8] indicates the difficulty of finding specific characteristics to describe the condition. The poor ability of MS to discriminate between RA and non-inflammatory joint diseases [9] as well as the difficulty in defining the start and end points of MS [8] may also add to its being recognized as ‘an inter-relationship of pain and limited movement’ [7] instead as a potentially specific biomechanical entity. The number of publications dealing directly with MS is small given the impact of MS on the lives of patients, who may view the condition as the most debilitating symptom of their disease [10]. Since even clinicians have difficulty describing MS [8], Lineker et al. [10] carried out a qualitative study to identify the characteristics of MS through the use of self-reports of RA patients, in order to develop a patient-centred description. Their findings resulted in the following definition: ‘Slowness or difficulty moving the joints when getting out of bed or after staying in one position too long, which involves both sides of the body and gets better with movement.’

Only recently has basic research offered approaches to understanding the typical early morning ‘slowness or difficulty moving joints’. As the nomenclature suggests, the stiffness follows a circadian rhythm, with a peak in the early morning hours, abatement during the day and a smaller new increase in the early evening [11].

A number of papers have reported a temporal relationship between elevated levels of pro-inflammatory cytokines and symptoms of RA, such as MS [12, 13]. These cytokines are highly elevated in patients with active RA in the early hours of the day; yet after the noon hour, cytokine levels are almost undetectable. The closest similarity to the daily pattern of RA symptoms (such as MS, joint pain and functional disability) are those exhibited by levels of TNF and IL-6. Both of these pro-inflammatory cytokines accumulate during the night and are considered to trigger the manifestation of the ‘gelling phenomenon’ when the patients wake up in the morning. This phenomenon lasts until the gradual activation of endogenous cortisol counteracts the inflammatory cascade of disease symptoms [14, 15].

Thus, the circadian rhythms of inflammatory cytokine release in the early morning and a delayed anti-inflammatory response may explain at least in part RA patients’ problems starting the day. It seems apparent though, that MS may have particular impact on patients who cannot delay getting up in the early morning hours because they are expected to be at work on time. Astonishingly, MS is not yet considered to be a risk factor for work disability. Of the potential disease parameters, it is usually pain, functional capacity, general well-being and disease activity that are taken into account when investigating the impact of RA on employment outcomes [16]. We therefore used data from an early RA inception cohort to answer the following questions:

  • What is the burden of MS in early RA and how is it related to disease activity, pain, function and radiographic joint damage?
  • What is the prognosis of MS over 3 yrs and how is MS in early disease correlated with disease outcome at 3 yrs?
  • What is the impact of MS on 3-yr employment status?


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
From January 2000 through June 2001, 1023 patients with recent onset RA (according to the revised ACR criteria [4]), who were ≥18 yrs, and whose disease duration was <24 months, were consecutively enrolled in a prospective observational 3-yr study by 54 rheumatological practices or outpatient clinics in Germany.

Baseline and 3-yr follow-up data included standard disease activity measures (ESR, CRP, swollen and tender counts of 28 joints), RF, comorbidity by means of a list of 24 common diseases, and radiographs of hands, wrists and forefeet [17]. Radiographic damage was assessed by the Ratingen scoring (RS) method [17], which evaluates 38 joints separately and has a maximum score of 190.

A patient questionnaire covered socio-demographic characteristics and patients’ employment and retirement status. Information was gathered at baseline and after 3 yrs using the following categories: full-time employed, part-time employed, on sick leave, unemployed, homemaker, retired due to disability and old-age pensioner. In the case of early retirement, patients had to indicate at 3 yrs whether they had to take early retirement due to RA or other chronic conditions or whether they were currently applying for early retirement.

Disease severity, such as functional disability [measured using the Hannover Functional Questionnaire (FFbH) with a range of 0–100] [18], pain and MS were assessed every 6 months. Since severity ratings of MS were found to be more responsive than duration [8, 19], MS was also assessed as severity on a 0–10 numerical rating scale (NRS) ranging from ‘no morning stiffness at all’ to ‘extremely severe morning stiffness’.

Physical exercise was questioned 6 and 24 months after study entry, covering the frequency of exercising at home, taking a walk, riding a bike, going for a run, swimming and organized sports (daily/at least every second day/once a week/rarely). Those who estimated not doing enough were asked whether inertia, pain, fatigue or lack of time prevented them from doing so.

Anti-rheumatic drugs were reported by the patients and coded as DMARD (synthetic or biologic), glucocorticoid or NSAID.

The ethics committee of the Charité Medical School, Berlin, approved this study and all patients gave written informed consent before entering the study.

Statistics
On the basis of baseline MS severity, patients were categorized as having mild (NRS 0–2), moderate (NRS 3–6) or severe MS (NRS 7–10).

Descriptive statistics and Spearman's rank correlations were used to determine the association between severity of MS and disease activity (DAS28, CRP, ESR and 28 swollen and tender joint count), disease severity (function, pain) and radiographic joint damage at study entry and at 3 yrs, respectively. Since the higher responsiveness of MS severity (compared with duration, as found by Vliet Vlieland et al. [19]) was also confirmed in our study, MS severity was used in all equations. Another reason for this preference was the rather high proportion of missing reports on the duration of MS. To compare 3-yr improvement of DAS28 and MS, standardized response means (SRM) were calculated by dividing the difference between T0 and T6 measures by the respective S.D. of the difference.

The association between severity of MS and early retirement was demonstrated in the 389 patients who were not yet 65 yrs of age (the statutory retirement age in Germany) at the end of the observation period. A multivariate logistic regression technique was applied to investigate the impact of MS (NRS ≤2/3–6/7–10) on early retirement. Age, sex, working status at baseline (working/on sick leave/unemployed), years of education (<10/≥10 yrs), disease activity (DAS28 3.2–5.1/>5.1 vs < 3.2), pain (NRS ≤2/3–6/7–10) and number of comorbid conditions (0/1–2/≥3) were taken into account as covariates. Patients who were still working at the end of the study were set as the reference category for calculation of adjusted odds ratios (ORs). Age was used as continuous value. Since disease duration varied between 2 and 24 months at study entry and because 37% of the patients had only started a DMARD therapy when entering the study (mean duration 19 ± 29 weeks), the stratified T0 and the T1 measures of MS (NRS 0–2/3–6/7–10) were tested alternatively as predictors for early retirement.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Patients’ characteristics at baseline
Of the 1023 baseline patients, 916 completed the 3-yr follow-up. Forty-seven of the 107 dropouts had died, 35 had withdrawn due to serious health problems, 5 due to other burdens and 29 quit participation without giving reason or were lost to follow-up. Dropouts were significantly older (66 vs 56 yrs), had more comorbid conditions (2.4 vs 1.8), higher disease activity (DAS28 5.3 vs 4.8) and more severe MS at study entry (NRS 5.8 vs 4.5).

At baseline, the three severity strata of MS divided the remaining 916 patients into groups of nearly equal sizes (Table 1). According to this stratification, severity of MS was not associated with sex, age, RF and only a little with years of education. Strong associations existed between MS severity and disease activity or disease severity and patients’ reports on duration of MS. Patients with severe MS had the highest disease activity, the most tender or swollen joints, the worst pain and the lowest functional capacity.


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  		TABLE 1. Morning stiffness by patients’ characteristics at study entry

 
At baseline, patients of the three MS strata were treated alike with regards to DMARD therapy (95.2%) and oral glucocorticoid intake (67.3%), whereas NSAIDs were significantly more frequently taken by patients with severe MS (Table 1). However, duration under DMARD therapy varied significantly (mild MS = 23 weeks/moderate MS = 18 weeks/severe MS = 16 weeks; P = 0.027), since 23% of the patients started this therapy only at study entry.

Correlations between MS and disease activity or severity
MS severity was strongly correlated with its duration and also with other activity and severity parameters, indicating that patients with severe pain or functional limitations would also rate their MS as severe. The strongest correlation existed between MS and pain, which were both measured on numerical rating scales. Correlations with disease activity (DAS28) and tender joint count were also high, whereas correlations with swollen joint count and active-phase reactants were rather weak.

No correlation existed between MS and radiographic joint damage, measured according to the Ratingen scoring method [17]. Even more obviously, the patients without any erosion at 3 yrs (20%) rated their MS exactly the same as the patients with considerable erosions (RS ≥ 7; 28%): MS 3.2 ± 2.8 vs 3.3 ± 2.8. The same applied to the mean duration of MS, which was 42 min in patients without and 49 min in patients with considerable erosions. Overall, correlations between MS and the respective parameters tightened with disease duration, except for the correlation between MS and CRP or ESR (Table 2).


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  		TABLE 2. Association between severity of MS and concurrent disease parameters

 
Baseline predictors of severe MS at 3 yrs
MS ratings in early disease and at 3 yrs were strongly associated with each other. Of the patients rating their MS as ‘severe’ (NRS 7–10) at T1, 35% still did so at the end of the observation and only 22% had attained ‘mild’ MS at that time. Besides disease activity (DAS28) and functional capacity (FFbH), MS at T1 was a strong predictor of severe MS at 3 yrs in multivariate logistic regression analysis, which also considered age, sex, years of education, number of comorbid conditions, CRP titres and pain (DAS28 ≥5.1 vs <3.2; adjusted OR for severe MS at 3 yrs = 15.3; 95% CI 7.4, 31.5; P = 0.000 / FFbH <50 vs >70; adjusted OR for severe MS = 2.9; 95% CI 1.7, 4.7; P = 0.000). This association was also seen when the T0 measures of MS were used as predictors.

MS and use of anti-rheumatic drugs
Due to the observational design of the study, no dose–effect relationships could be demonstrated between type or amounts of antirheumatic drugs taken and MS. In contrast, escalated therapies, such as multiple DMARDs or biologicals in combination with NSAIDs and glucocorticoids, were indicators for severe MS. There were also no associations with doses of glucocorticoids taken. Patients with high doses reported more severe MS than did patients with low doses.

MS and physical exercise
Patients with severe MS reported significantly more often to exercise at home at least every second day than did patients without or with mild MS (48% vs 35%). Younger and/or working patients reported less frequently (~20%) than older and/or retired patients (~50%) to do regular home exercises. MS was not associated with taking a walk (70% of all patients), riding a bike (30%), going for a run (2%), swimming (6%) or organized sports (3%). Two years after entering the study, 409 patients estimated not doing enough physical exercise (45%). Of them, those with severe MS argued significantly more often (44%) that pain hindered them to do more, than did patients without or with mild MS (5%).

Disease activity, MS and early retirement
Of the 545 patients who were not older than 61 yrs at baseline, 80 were homemakers and 76 already early or before-hand retired, leaving 389 at risk of early retirement in the following 3 yrs.

Table 3 shows age, sex, years of education, disease activity, functional capacity, number of comorbid conditions and mean MS (NRS 0–10) of all patients not older than 61 yrs by their baseline occupational status. The currently working ones, who were neither on sick leave nor unemployed, were the youngest, had the best formal education, the lowest disease activity, the least comorbid conditions, the best functional capacity and the lowest ratings of MS. In contrast, those who were already early retired were the oldest, had the least formal education and the most comorbid conditions.


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  		TABLE 3. Baseline occupational status of patients aged ≤61 yrs

 
Within 3 yrs, 65 of the 389 patients who were working at baseline had taken early retirement due to RA; another 15 had done so for other chronic conditions or were currently applying for disability pension (Table 4). The patients who had taken early retirement within the observation period were significantly older (53 vs 48 yrs at 3 yrs) and had, except for ERS and CRP titres, significantly worse severity measures throughout the observation. Early retirement due to RA was three times more frequent in patients with severe MS than in those with mild MS or with long-lasting (vs short-lasting) MS (upper tertile >161 min = 33%; lower tertile <47 min = 8%).


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  		TABLE 4. MS and early retirement in patients who were still working at baseline

 
A multivariate logistic regression analysis, considering baseline employment status (currently working/on sick leave/unemployed), pain and the T1 severity variables shown in Table 3, revealed that taking early retirement (or currently applying for it) was most likely in patients who were unemployed or on sick leave at study entry and who had had severe MS in early disease. MS, therefore, was the only severity parameter that was predictive for early retirement at 3 yrs (Table 5). The strong impact of MS on early retirement was independent of type and amount of antirheumatic drugs taken and it was still confirmed when only the 65 cases who were already early retired due to RA, were considered in the equation (adjusted OR 3.5; 95% CI 1.6, 7.6). Similar risks, though to a somewhat lesser extent, were seen when the baseline instead of the T1 MS was used as predictor.


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  		TABLE 5. Adjusted ORs and 95% CIs for early retirement

 
However, MS lost its influence statistically when instead of the baseline severity measures the respective mean measures, all stratified accordingly, were considered in the same equation. While baseline occupational status kept its strong predictive power, a high mean DAS28 and low mean functional capacity replaced severe MS as risk for early retirement (adjusted OR for early retirement: mean DAS28 >5.1 vs <3.2 = 5.9; 95% CI 1.5, 22.5 / FFbH <50 vs ≥70 = 7.2; 95% CI 3.0, 17.4 and FFbH 50–69 vs ≥70 = 2.9; 95% CI 1.4, 6.2). Nonetheless, MS remained a significant risk factor when its mean duration (stratified in tertiles) was considered instead of MS severity (adjusted OR mean MS duration >161 vs < 47 min = 3.7; 95% CI 1.6, 8.6; P = 0.002).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Our investigation confirmed the findings of others, namely that MS reflects functional disability and pain better than the traditional markers of inflammation such as swollen joint count, ESR or CRP [20]. However, this might be explained, at least in part, by the observation that self-reported measures are generally associated more closely with other self-reported measures than with laboratory or physician-reported measures [21, 22].

The weak or missing association between somatic parameters and MS is most apparent with regard to radiographic joint damage. Since structural damage is the result of a lasting process unknown when it happens, an association between the highly variable measure of MS and the accumulated joint damage is not necessarily to be expected. However, our finding of an association between radiographic progression and MS may indicate that MS reflects the inflammatory process on some level.

Its variability is a problem in dealing with MS. Although we found significant associations between MS severity at study entry and at 3 yrs, MS is known to vary considerably from one day to another. Hazes et al. [8], who investigated the inter-individual consistency of self-reported duration of MS, suggested that asking a patient to report a typical day's MS is subject to considerable inaccuracy. Variability, weak reliability and its transient character make MS a rather intangible symptom, at least for the physician, who usually sees his patient after having recovered from it. Some of these problems may explain why MS is rather seldom the focus of research and why it has not been considered a risk factor for early retirement. Barrett et al. [23] found the peak rates for work disability to be in the early years of the disease. This finding agrees with other studies that found that many RA patients make the decision to stop working fairly early after disease onset. The majority of the studies report that about one-third of the gainfully employed patients took early retirement within the first years from onset. The prevalence of work disability was 37% at around 3 yrs in Swedish RA patients [24], 37% at 2.8 yrs in The Netherlands [25], 23% at 2 yrs in Finland [26], and 26% at 2 yrs [23] or 40% at 5 yrs [27] in the UK.

Recent advances in therapeutic strategies and newly developed drugs seemingly caused no improvement. Barrett et al. [23] compared two British RA cohorts, one with disease onset between 1989 and 1992, and another with onset between 1994 and 1997 with regard to quality of treatment and work disability. They found no decrease of work disability, despite the fact that the more recent cohort was treated significantly earlier and more aggressively. The authors suggest that enhanced rheumatological care had no beneficial effect on ability or willingness of RA patients to remain economically active. This was confirmed by Reisine et al. [28] who compared two other RA cohorts. The rate of patients stopping work in the more recent cohort did not differ from that among patients diagnosed more than 16 yrs ago. As in the earlier study, ability to remain employed was more strongly associated with age and work characteristics than with disease severity [29].

However, there are several studies showing that early and aggressive treatments translate into maintenance of work capacity [30–32], but those were randomized clinical trials. Wolfe et al. [33] could not discern a positive effect of anti-TNF therapy on work disability in an observational cohort study.

The conflicting results point out the difficulties to really understand work disability. Work disability rates are highly dependent on the definitions of both work and disability, which differ widely across studies [16]. Researchers have to deal with very complex interactions of demographic, social, work, insurance and disease characteristics that are difficult to examine and analyse quantitatively.

In most of the studies, baseline functional capacity, physical job demands, old age or low education were the most important predictors of work disability, while joint counts and laboratory measures were not [19, 23, 34]. These findings are in accordance with our investigation, even if the influence of functional capacity was only evident when MS was removed from the multivariate equation. The commutability of MS and physical function points to the high inter-correlation of the two symptoms, as shown in Table 2. Our results indicate that, in particular, MS shortly after disease onset predicts early retirement. Since most patients are on long-term sick leave before applying for early retirement and the process lasts at least 6 months from request for retirement to receipt of a disability pension, it is obvious that in most of the cases with early retirement this process was initiated shortly after study entry.

This time span, therefore, seems to be a ‘window of opportunity’ for enhanced therapeutic efforts in offering patients relief from severe MS and to counsel them with regard to the expected disease course and job perspectives. The high proportion of patients with severe MS exercising at home shows that the patients were willing to cope actively with their disease, provided their daily schedule and pain allowed it. Another option to target MS is the application of anti-inflammatory drugs adapted to the circadian rhythms of endogenous cortisol and disease symptoms, both of which peak during the early morning hours. A recent study has shown that delayed release prednisolone taken late in the evening achieved a significant reduction of MS [11].

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors wish to thank those rheumatologists who enrolled at least 15 patients each: S. Wassenberg, Ratingen; M. Hammer, Sendenhorst; W. Demary and U. von Hinüber, Hildesheim; F. Hamann and A. Teich, Leipzig; K. L. Schmidt, Bad Nauheim; E. Gromnica-Ihle, Berlin; G. Hein, Jena; R. Haux, Berlin; R. Dreher, Bad Kreuznach; D. Pick, Grafschaft-Holzweiler; M. Stoyanova-Scholz, Duisburg; H. Menninger, Bad Abbach, H. Zeidler, Hannover, H. E. Schröder, Dresden; M. Braun, Cuxhaven; J Braun, Herne; J. Lautenschläger, Bad Pyrmont; B. Lang, Baden-Baden; A. Thiele, Wuppertal; and L. Gross, Bad Bramstedt.

Funding: The study was funded by the German Federal Ministry of Education and Research within the Rheumatology Competence Network (1999–2005).

Disclosure statement: F.B. is a consultant for and has received grant support from Merck Pharma GmbH and Nitec Pharma GmbH. F.B. has also received lecture fees from Merck Pharma GmbH. All other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 10 January 2008; revised version accepted 13 March 2008.
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N. A. KHAN, Y. YAZICI, J. CALVO-ALEN, J. DADONIENE, L. GOSSEC, T. M. HANSEN, M. HUISMAN, R. KALLIKORM, R. MULLER, M. LIVEBORN, et al.
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