Influence of Disease Activity on Functional Capacity in Patients with Rheumatoid Arthritis

Background/Aim. Progressive erosive changes in cartilage and bone in rheumatoid arthritis (RA) ultimately lead to joint deformities and disability which may be early, severe and permanent. Consequently, there is the reduction of functional ability and changes in the quality of life. The aim of this study was to estimate the impact of disease activity on functional status of patients with RA. Methods. A prospective investigation included 74 patients with RA who were treated in the Rheumatology Clinic of the " Niška Banja " Institute. Assessment of functional status (capacity) was measured by the Health Assessment Questionnaire (HAQ) with the values from 0 to 3 that patients fill out on their own. The patients were then divided into three groups: the group I with the HAQ values from 0.125 to 1.000, the group II with the values from 1.125 to 2.000 and the group III with the values from 2.125 to 3.000. Disease activity was measured by Disease Activity Score (DAS28). The assessment also included sedimentation rate (SE) influence, IgM rheumatoid factor (RF) and C-reactive protein (CRP) positivity, age, and disease duration. Results. The patients with the most severe functional damage estimated by the HAQ – the group III, had the highest values of DAS28 SE (7.4 ± 0.8) compared to the


Introduction
Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease which is characterised by symmetric inflammatory changes of synovial joints.During the course of the disease, progressive erosions in cartilage and bone appear, finally leading to characteristic deformities of joints and possible disability, which can be early one, severe and permanent 1 .Consequently, the patients' quality of life deteriorates including both self care and everyday activities and there is also a decrease in functional ability and productivity concerning professional activities, which leads to economical consequences because of treatment, rehabilitation and possible surgical methods of treatment.Success in the treatment of RA significantly depends on good and prompt assessment of disease activity 2 .RA activity determines the speed of the disease advancement and its potential for the development of anatomical and functional disorders 3 .
Because of the variables of signs and symptoms manifestations, clinical trials use summary indices which overcome the problems of validity, reliability and sensitivity to changes, noticed in some characteristics 4,5 .For the time being, the best tools for this assessment in individual patients are the Disease Activity Index and its validated modifications which include the Disease Activity Score (DAS) and DAS28 4 developed by the European League Against Rheumatism (EULAR) 6 .Those indexes show a significant correlation with functional abilities, as well as with the outcome of the disease -radiographic progression of the disease [3][4][5] .
The aim of this study was to examine the influence of disease activity on the functional status of RA patients.

Methods
This prospective study included 74 RA patients with the diagnosis established according to a revised American College of Rheumatology (ACR) criteria from 1987.The patients were hospitalized at the Rheumatology Clinic of the "Niška Banja" Institute.There were 57 (77%) women and 17 (23%) men.The average age of patients was 58.3 ± 8.6 years, and the average duration of the disease 7.8 ± 6.6 years.Assessment of the functional status (ability) was performed by the Health Assessment Questionnaire (HAQ) with the values from 0 to 3, which the patients filled out themselves.The patients were then divided into three study groups: group I -the subjects with smaller degree of functional damage with HAQ values 0.125-1.000,the group II with HAQ values 1.125-2.000-subjects with moderate functional damage and the group III -subjects with complete functional disability and HAQ values from 2.125-3.000.The disease activity was assessed by the disease index activity DAS28, calculated on the basis of the number of painful and swollen joints out of a total of 28 examined, sedimentation rate (SE) for DAS28 SE, C-reactive protein (CRP) values for DAS28 CRP and assessment of general state of the patients by the use of the visual analogue scale (VAS, 0-100).DAS 28 values higher than 5.1 suggest a high disease activity, the values from 3.2 to 5.1 suggest moderate disease activity and the values from 2.6 to 3.2 suggest low disease activity.DAS28 value less than 2.6 suggests remission.Analysis also included SE rate, positivity of IgM Rheumatoid factor (RF) and CRP, age and disease duration.Analyzed data were presented by absolute and relative numbers (category variables), arithmetic mean and standard deviations (continuous numeric features).Comparison of numeric variables distributed by the type of normality, was performed by analysis of variance (ANOVA) test, while variables which were not distributed by the type of normality were compared by Kruskal-Wallis test.Mann Whitney U-test and Bonferroni test were used in the Post hock procedure.The definition of risk factors was done by univariate logistic regression.Statistical significance is regarded to be at the level of p < 0.05, defined by the statistical package SPSS (version 18).

Results
A statistically significant difference (ANOVA), was noticed in the DAS 28 SE variable (F = 53.797,p < 0.001), and in SE variable (F = 8.253, p = 0.001).Post hock analysis showed that DAS28SE and DAS28 CRP values were statistically significantly higher in the group III, as compared to the group II and the group I, as well as that the values of the same parameters in the group II were higher than in the group I.
A significance of SE value difference was also noticed, but only between the group III and the group I (F = 8.253, p = 0.001).
In the univariate logistic model, the examined parameters of DAS28 SE, DAS28 CRP, SE, RF and CRP represent significant predictors of functional disability.The most significant factors which increase the chance for a patient to be in the HAQ III group, i.e. to have the most severe functional damage include DAS 28 SE which increases the odds by 5.5 times (OR = 5.450, 95% CI = 3.211-7.690,p = 0.001), DAS28 CRP by 5.1 times (OR = 5.111, 95% CI = 2.123-10.636,p < 0.01), and the presence of CRP (OR = 5.219, 95% CI = 1.305-18.231,p = 0.019) by 5.2 times.As the significant risk factor at the level p < 0.001, RF singled out by increasing the odds that the patient has functional disability by 2.1 times.

Discussion
Success in RA treatment largely depends on the right evaluation of the disease activity, when efficient administration of medicaments is possible, which change the disease course 2 .
Accurate measurement of the RA activity is not at all simple, and in the last 15 years it has become obvious that due to the varaibility of symptoms and signs manifestation 4 , it is not sufficient to determine only the number of painful and swollen joints and perform the basic laboratory analysis.It is necessary to monitor the collective indexes of the disease activity which overcome the problems with validity, reliability and sensitivity to changes noticed in some characteristics 4,5 .For the time being, the best tools for its assessment in individuals are the disease activity Score and its validated modifications DAS and DAS28 developed by the European League Against Rheumatism (EULAR) 6 .Those indexes show a significant correlation with functional abili-ties, as well as with the disease outcome -radiographic disease progression [3][4][5] .
The interaction between the disease activity and joint damage are the main factors which influence the functional ability.
Investigation of the relationship between the disease activity, joint destruction and functional capacity is very common in clinical investigations.This provides data on the degree to which the disease activity and current joint damage influence the functional ability of RA patients and their quality of life which has certain psychosocial and economic significance 2 .Functional capacity measured by Health Assessment Questionnaire Disability Index (HAQDI) deteriorates during the disease, If left untreated, 20-30% of RA patients will become permanently disabled for work within 3 years from the diagnosis, and after 10 years with the disease 80% of patients will be permanently incapable for work and become handicapped.
Functional disability assessment is the fundamental measurement in RA 7 , considering the chronic nature of this disease.The influence of the changes developed in RA on everyday activities, working ability, need for surgical treatment, increased mortality rate, suggest the convenience of the use of such investigation and is a significant addition to physical examination of the patient.
The HAQ, filled out by patients themselves, is a measure of the functional loss of everyday activities, such as dressing up, eating, using the toilet, shopping or house work.HAQ usually increases faster at the beginning of the disease 8 .Among the early reports, HAQ becomes a regular measure of the progression, damage and limited range of motion in RA, especially during the years of follow-up.Investigations which deal with the influence of the disease activity on functional status often have controversial results, and this diversity of the results is explained by the variability of symptoms and signs manifestations in patients with RA, prone to frequent and even daily variations.
Drossaers-Bakker et al. 9 investigated the relationship of the functional status which is represented by the HAQ score and the disease activity measured by DAS during the period of 12 years in 132 patients.At the beginning of the investigation there was a strong correlation of HAQ and DAS, that was maintained even after three years.In the following years, joint damage presented by Sharp's score had greater influence on HAQ, but at the end of the investigation, after 12 years of follow-up, the disease activity presented by DAS was the main factor of the functional disability represented by HAQ 9 .
Our results also show that subjects with the most severe functional damage estimated by HAQ -the group III, have the highest disease activity presented by DAS 28 SE whith the values 7.4 ± 0.8 compared to the group II (6.5 ± 1.2) and the group I (3.4 ± 1.2), as well as the highest values of DAS 28 CRP 7.1 ± 0.8 compared to the group II (6.7 ± 0.8) and the group I (3.6 ± 0.4).The findings have a high statistical significance.The subjects in the group II have a higher disease activity in comparison to those in the group I (statistically significant difference ANOVA, DAS28 SE (F = 53.797,p < 0.001) and DAS28 CRP (F = 10.084,p < 0.001).
In the univariate logistic model, the most significant factor which increases the odds for a patient to be in the HAQ group III, i.e. to have the most severe functional damage is DAS 28 SE which increases these chances by 5.5 times (OR = 5.450, 95% CI = 3.211-7.690,p = 0.001).DAS28 CRP increases the odds for the subject to have the most severe functional damage by 5.1 times (OR = 5.111, 95% CI = 2.123-10.636,p < 0.01), and presence of CRP (OR = 5.219, 95% CI = 1.305-18.231,p = 0.019) by 5.2 times.RF was singled out as a significant risk factor at the level of p < 0.001, increasing the odds for the subject to have functional disability by 2.1 times.
In the five-year follow-up, Combe et al. 10 concluded that the final HAQ disability is caused by the initial value of the HAQ, pain, Ritchie index, the number of painful joints, disease activity score, SE, CRP and erosions.Using a multivariate analysis, they emphasized the following prognostic risk factors of HAQ disability: initial HAQ score, Ritchie index, SE, CRP, and the presence of erosions as the most significant prognostic factors of the functional disability.
Investigation by Courvaisir et al. 11 in a 10-year followup, defined the correlation between HAQ and disease activity which was presented by DAS and pain, both at the beginning and after five and 10 years.
The significance of investigation of the functional ability is also suggested by the Early Rheumatoid Arthritis Study (ERAS) which included 732 patients and showed that deterioration of the functional status later in the course of the disease was caused by a high HAQ at the beginning of the investigation 12 .Some studies showed that functional status at the early stages of the disease was first of all influenced by the disease activity, and that in later stages poor functional status was the consequence of joint damage 2 .
Our results suggest that the subjects with the most severe functional damage, the group III, have a statistically significantly higher SE value (increases the odds for the subject to be in the HAQ group III by 56%), frequently positive RF as significant risk factor at the level of p < 0.001, increasing the odds for the subject to be in the HAD group III by 2.1 times, compared to subjects with smaller and moderate functional damage.Gender did not significantly influence the functional ability.
Investigation of the influence of age and duration of the disease on the functional ability showed that older age and longer disease significantly contribute to the loss of the functional ability (patient's age observed as continued variable), increases the odds for the patient to be in the HAQ group III by almost 60% (OR = 1.572, 95% CI = 1.111-1.946,p < 0.001), disease duration (continuously) by 80% (OR = 1.792, 95% CI = 1.550-1.930,p < 0.001).These results are in accordance with investigations by Sokka et al. 13 who concluded that older age contributed to the decrease of the functional ability and with a study by Scott et al. 14 who compared the results of several research centers and showed that functional disability increases with longer disease and the increase is constant.
Investigation that involved 706 patients, studied the influence of demographic, laboratory and radiology parameters on HAQ.The loss of functional ability was significantly influenced by the number of painful and swollen joints, older age, longer disease duration and higher SE values.The crucial factor for the functional ability loss was female gender.RF and joint damage did not have significant influence 15 .
A study on 110 patients with RA showed a statistically highly significant correlation between HAQ with older patients, longer disease duration, progress on the walking path, longer morning stiffness, as lower values of Erythrocyte number and statistically significant correlation between HAQ and lower hemoglobin values and higher SE and CRP values 16 .
HAQ index was proved to be one of the best indicators of the long-lasting prognosis in RA-patients with high HAQ score who have increased mortality rate, working disability, pain and psychosocial changes.
Original DAS and DAS28 remain valid, reliable and sensitive indicators of the disease activity that can be used for the estmation of the total RA activity.They are relatively successful in determining the number of patients who will actually be affected by the consequences of RA 3 .

Conclusion
The Health Assessment Questionaire proved to be the standard in the evaluation of the functional status of rheumatoid arthritis patients due to its practicality and good correlation with parameters of disease activity, where the disease activity index DAS28 is singled out as the most significant factor.

Table 1 Patient characteristics, significance of numerical differences of continuous variables between the examined groups (I-III) with respect to the Health Assessment Questionnaire (HAQ)
DAS-disease activity score; CRP -C-reactive protein; SE -sedimentation rate; Group I -HAQ values from 0.125 to 1.000 Group II -HAQ values from 1.125 to 2.000 Group III -HAQ values from 2.125 to 3.000 A (I vs II), B (I vs III), C (II vs III) † p-value of ANOVA test, ‡ p-value of Kruskal-Wallis test.