Quantitative measures for assessing rheumatoid arthritis in clinical trials and clinical care

There is no single 'gold standard' quantitative measure to assess and monitor the clinical status in patients with rheumatoid arthritis (RA). Therefore, a variety of measures have been used in clinical research and clinical care, including laboratory tests, radiographic scores, formal joint counts, physical measures of functional status, global measures and patient self-report questionnaires. These measures may address disease activity, joint damage, both activity and damage, or long-term outcomes. Measures of disease activity, such as joint swelling, are reversible and are emphasized in clinical trials. However, activity measures may be improved over 5 years while measures of damage, such as radiographic score, indicate disease progression. Two quantitative indices which are widely used in clinical trials are the (1) American College of Rheumatology (ACR) Core Data Set, which includes swollen joint count, tender joint count, physician assessment of global status, acute-phase reactant-erythrocyte sedimentation rate or C-reactive protein, functional status, pain, patient estimate of global status, a radiograph in studies over 1 year or longer, and (2) the disease activity score(DAs), which includes a swollen joint count, tender joint count, acute-phase reactant, and patient assessment of global status. Randomized controlled clinical trials provide the optimal method to evaluate new therapies, by comparing a therapy with a placebo or another therapy without selecting patients for specific therapies. However, randomized trials in chronic diseases have important limitations, including a relatively short observation period, patient selection for inclusion and exclusion criteria, inflexible dosage schedules, influence of the design on results despite a control group, emphasis on group data while ignoring individual variation in treatment responses, non-standardized interpretation of adverse effects, and others. Therefore, clinical trials in RA must be supplemented by long-term observational studies to assess results of therapy in regard to long-term outcomes such as work disability, joint replacement surgery and premature mortality. The most simple and effective method of collecting important long-term data from patients in routine clinical care is through patient self-report questionnaires.     

Quantitative measures and indices to assess rheumatoid arthritis in clinical trials and clinical care

Modern medical care has been advanced, in large part, by quantitative measures that provide single, easily-assessed end points for clinical trials, clinical research, or clinical care (eg, blood pressure, serum cholesterol). In rheumatoid arthritis, several types of quantitative measures are used to assess patient status, including formal joint counts; radiographic scores; laboratory tests; patient self-report questionnaire measures of physical function, pain, global status, morning stiffness, and fatigue; as well as physical measures of functional status. Each of these measures is effective to document changes of status with treatment in groups of patients; however, no single measure can serve as a "gold standard" to document changes in each individual patient. Therefore, the measures have been combined into pooled indices that can be applied to individual patients in clinical research and clinical care.     

A clinical and biochemical assessment of methotrexate in rheumatoid arthritis

Summary Low-dose methotrexate has gained widespread acceptance as a second-line agent in rheumatoid arthritis (RA). The Leeds Human Model Screening System (LHMSS) is a validated screening mechanism allowing the rapid evaluation of compounds for their potential as anti-rheumatic agents, the results of which have been confirmed in longer term studies. We have evaluated methotrexate in patients with RA using the LHMSS at a maintenance dose of 10mg/week. Significant change occurred in four out of eleven variables over a 24-week period (p<0.01). This degree of change is greater than that seen with nonsteroidal anti-inflammatory agents but less than with other recognised second-line agents such as D-penicillamine, suggesting that methotrexate may have less potential as a second-line agent than D-penicillamine.     

Quantitative assessment of periarticular osteopenia in patients with early rheumatoid arthritis: a preliminary report

BACKGROUND: Involvement of the metacarpophalangeal (MP) joints is one of the major problems in patients with rheumatoid arthritis (RA). Although several data about the cumulative influence of steroid intake on bone are available, the course of demineralisation in RA has not been described by quantitative methods until now. PATIENTS AND METHODS: Computed tomography (CT) sections of 96 MP joints in 12 RA patients and of 32 MP joints in four age-matched healthy controls were investigated. Patients were classified according to Steinbrocker. Densitometric evaluation of subchondral bone density was performed by CT osteoabsorptiometry (CT-OAM). Quantitative CT-OAM was used to evaluate mineralisation of the articular surfaces in MP joints. RESULTS: In the distal articular surface of MP joints, the number of density maxima was reduced from 3 to 2.1+/-0.3, 1.9+/-0.5 and 1.3+/-0.3 in RA patients with early, mild to moderate, and severe disease, respectively. Means of calcium concentrations were 633.4+/-35. 3 mg Ca2+/mL, 518.9+/-56.2 mg Ca2+/mL, 497.7+/-23.8 mg Ca2+/mL and 455.1+/-28.6 mg Ca2+/mL for controls and RA patients with early, mild to moderate, and severe RA, respectively. Mineralisation of the distal articular surface was significantly reduced in all groups of RA patients [probability (p) = 0.005]. Regarding the number of density maxima, no differences were detected in the proximal articular surface of normal and RA fingers. However, mineralisation of the proximal articular surface was significantly reduced in all groups of RA patients (p = 0.004). Means of calcium concentrations of the proximal articular surface were 494.1+/-48.5 mg Ca2+/mL, 413.0+/-16.2 mg Ca2+/mL, 406.0+/-51.4 mg Ca2+/mL, 390,4+/-41.1 mg Ca2+/mL for controls and RA patients with early, mild to moderate, and severe RA, respectively. CONCLUSION: Patients with early and untreated RA show loss of mineralisation and altered morphology of the MP joints of the hand, even before corticosteroid therapy. CT-OAM provides evidence for an early alteration of functional anatomy in MP joints.     

Effectiveness of an integrated outpatient care programme compared with present-day standard care in early rheumatoid arthritis

Objectives: To investigate the effectiveness of an integrated care programme in daily practice compared with present‐day standard care for ambulatory early rheumatoid arthritis patients. Methods: In this cross‐sectional study, group A received programmed multidisciplinary outpatient care and group B standard rheumatologist‐centred care. Demographics, disease duration, initial and actual treatment, disease activity (Disease Activity‐28 Score), general health (Short Form‐36 [SF‐36]), functionality (Health Assessment Questionnaire [HAQ]), coping style (Utrecht's Coping List), illness perception (Dutch–Revised Illness Perception Questionnaire) and satisfaction about care were recorded. Results: Eight‐nine patients were included in group A and 102 in group B. Demographics, rheumatoid factor, antibodies against cyclic citrullinated peptides and disease duration were comparable. More patients in group A received initial combination therapy (35% versus 3%). Actual treatment regimens were comparable. More patients were in remission (69% versus 39%) or had low disease activity (80% versus 60%), mean HAQ‐scores were lower (0.52 versus 0.80), more patients had no functional impairment (38% versus 15%) and SF‐36 scores were higher in group A. Coping style and illness perception were similar, except for illness coherence. Satisfaction differed only for aspects typically favouring a care programme. Participation in a care programme independently predicted remission and absence of disability in a regression model, including gender and initial treatment as other predictors. Conclusion: Disease activity was better controlled and functionality and general health better preserved in patients following an outpatient care programme. This was partly due to the easier implementation of an intensive initial treatment strategy but apparently also to other aspects of organized pharmacological and non‐pharmacological care, to be defined in randomized, controlled studies. Copyright © 2008 John Wiley & Sons, Ltd.     

Clinical assessment and health status in standard care in Indian and Iranian patients suffering from rheumatoid arthritis (RA)

Disease activity and quality of life (QOL) including functional status in rheumatoid arthritis (RA) is influenced by several ethnic, cultural and other factors. Standard of care management should cater for country specific needs.ObjectivesTo assess and compare clinical disease characteristics and health status in patients with RA from two countries, India and Iran.Material and methodsA cross-sectional survey of 140 RA patients (Indian70 and Iranian70) was chosen from rheumatology outpatients (Bandar Abbas, Iran and Pune, India) in random manner. One of the authors evaluated all patients under Rheumatologist supervision. Standard evaluation was as per current American College of Rheumatology guidelines and included a 68/66 joint count and laboratory tests. Health assessment questionnaire (CRD Pune version HAQ) and SF36v2 was utilized to assess functional and health status. While Iranian patients were all Muslims, the Indian patients were predominantly Hindu.ResultsThe groups matched well for age, gender, duration of disease and rheumatoid factor. Patients in Iran had less years of education as compared to patients from India (p < 0.001), Pains and SF 36 domains (barring vitality, social function and mental health) and sedimentation rate (ESR) scored significantly higher in the Iranian group. Swollen joint counts, global disease assessment and blood hemoglobin were higher in the Indian group. The overall DAS 28 (disease activity score) index, general health (VAS), HAQ and SF 36 Mental health domain scores did not differ significantly in two groups.ConclusionsThough there were some important differences in pain perception, joint counts and QOL, the study cohorts of RA belonging to the Iranian and Indian ethnicity were similar for disease activity (DAS) and functional status (HAQ).     

Established rheumatoid arthritis: clinical assessments

Clinical assessment of established rheumatoid arthritis (RA) can have several purposes. It can be used to evaluate prognosis, disease course or interventions at both the individual and the group level (i.e. in a clinical trial), over the short or long term. The instruments used for the different purposes are not always the same. For example, information on prognosis is very useful when assessing the risk:benefit ratio of early aggressive pharmacotherapy; however, established prognostic factors are currently of limited use in individual patients with established RA. As, at the individual patient level, disease activity, disability and joint damage have variable courses, the course of the disease should be evaluated regularly both with process (i.e. erythrocyte sedimentation rate, joint counts) and with outcome (i.e. radiological progression, sum of past process) measures. For the evaluation of interventions, 'core sets' of valid measures to assess disease activity, outcome and specific criteria for improvement are used; these can, to some extent, be useful in clinical practice.     

A clinical and biochemical assessment of prinomide in patients with rheumatoid arthritis

Prinomide (CGS-10787B), a potential disease modifying drug, was evaluated clinically and biochemically in 15 patients with active rheumatoid arthritis. The single group study design included monthly assessments of 7 clinical measures and 22 laboratory measures. Twelve patients completed 24 weeks' therapy with prinomide 1.2 g/day. All clinical variables showed improvement which consistently reached statistical significance for articular index from Week 8 (p less than 0.01), for summated change score from Week 12 (p less than 0.01) and for pain score from Week 16 (p less than 0.05). Sustained significant improvement in laboratory variables was seen by Week 2 for erythrocyte sedimentation rate and platelet count (both p less than 0.05), and by Week 4 for plasma viscosity (p less than 0.01), IgG, IgA, IgM (all p less than 0.05).     

Radiographic assessment in relation to clinical and biochemical variables in rheumatoid arthritis

Radiographs of hands and feet were obtained from 125 consecutive patients with rheumatoid arthritis (RA) and the degree of destruction was assessed numerically on a 200-point scale using Larsen's standard radiographs as reference. The method is shown to possess a satisfactory degree of reproducibility. In 96 of these 125 patients, values of another 15 simultaneously determined clinical and biochemical variables were obtained. On applying linear and quadratic multiple regression analysis to this set as well as to the male and female subsets, an 'automatic' selection procedure (stepwise regression) proved duration of disease to be the most important factor relating to the 'Larsen index'. The 96 patients were therefore ranked with respect to duration of disease and divided into 4 subsets of equal magnitude. In the 3 subsets with duration of disease less than 21 years, stepwise regression produced in the final step linear or quadratic combinations not containing duration of disease but correlating quite well with the 'Larsen index' (R = 0.64-0.96). A similar result was obtained upon performing an analogous procedure in the female subset. In all instances, positive contributions of varying degree were obtained from Ritchie's index, ESR, a-antitrypsin (A1-AT), orosomucoid, fibrinogen, and IgM, while negative correlations were associated with ceruloplasmin, IgG, and IgA.     

Standardising joint assessment in rheumatoid arthritis

Summary Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P<0.05) and the number of tender joints which increased by 41% (p<0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.     

Pathogenetic,clinical and pharmaco-economic assessment in rheumatoid arthritis (RA)

Recently, vitamin D has aroused considerable interest for several reasons. Many epidemiological studies have shown a widespread deficiency of vitamin D at all ages, and the recent finding that many organs and tissues have vitamin D receptors has fostered the clinical and biological relevance of vitamin D. Elderly people are at high risk for vitamin D deficiency if their life style entails few outdoor activities, their skin is thick and they exhibit impairment of renal function. In the elderly, vitamin D deficiency is very important because it can affect the function of many organs such as the muscle–skeletal, cardio-vascular systems and kidney, and may be involved in various diseases and pathological conditions including type II diabetes, cancer and cognitive decline. In the present review, the most relevant features of vitamin D are described as well as the clinical consequences of hypovitaminosis D in the elderly. Finally, the role of an adequate oral supplementation in the geriatric population is stressed.     

Pathogenetic, clinical and pharmaco-economic assessment in rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) has become one of the most studied autoimmune chronic inflammatory diseases (ACIDs), either from the pathogenetic or from the therapeutic point of view. It is recognized that synovial fibroblasts, TH1 and TH17 cells likely play along with the B cells the most relevant role. The disease has a polygenic background that characterizes the seropositive and the seronegative subsets. Over the years, we realized that no more than 15-20% of long-standing RA (LSRA) treated with conventional drugs can reach full remission, whereas the most recent data in early RA (ERA) have demonstrated that 40-60% can be put into clinical and biological remission. This of course is of crucial importance to avoid any progression of the structural damage that leads to functional disability. If we consider that a disability index score (Health Assessment Questionnaire 0-3) of a severe arthritis can cost up to 21,000 EUs, while a mild disease will cost not more than 5,500 EUs per year, it appears very clear that a low disease activity (LDA) or a remission state (Rem) should be the aim in each single patient, in order to keep the workability and maintain the productivity. This is and should be the major aim in each RA patient.     

Hand bone densitometry: a more sensitive standard for the assessment of early bone damage in rheumatoid arthritis

OBJECTIVE: To examine the role of hand dual-energy x ray absorptiometry (DEXA) compared with radiography in the assessment of bone involvement in patients with early rheumatoid arthritis (RA) who have active disease. METHODS: The study population (n = 79) had RA of <12 months' duration and were selected for poor prognostic features. Clinical data and bone mineral density (BMD) data were collected at baseline, 24 and 48 weeks. Hand radiographs were performed at baseline and 48 weeks. Bone damage analyses were performed for the group and individuals using the smallest detectable change (SDC) method. RESULTS: At baseline, mean disease duration was 8.5 months, erythrocyte sedimentation rate was 34.3 mm/hour, C-reactive protein was 40.2 mg/l, Health Assessment Questionnaire score was 1.35 and 81% of patients were positive for rheumatoid factor. Mean (95% CI) hand BMD loss was 2.5% (-3.5 to -1.5) at 24 weeks and 2.6% (-3.8 to -1.5) at 48 weeks. Individual hand bone loss exceeding the SDC was seen in 46.8% at 24 weeks and in 58.2% at 48 weeks. In the subgroup of 58 patients who had undergone radiography, radiographic joint damage score evaluated by the Sharp-van der Heijde method increased from 4.8 to 10.6 (p = 0.001). Individual hand bone loss in this subgroup exceeding the SDC was seen in 50.0% at 24 weeks and in 56.9% at 48 weeks, whereas at 48 weeks only 22.4% had deteriorated in modified Sharp score. CONCLUSION: The study results indicate that hand DEXA is a more sensitive tool than radiology (radiographic joint-damage scores), for measuring disease-related bone damage in early RA.     

The assessment of pain in rheumatoid arthritis

It is difficult to objectively measure pain in rheumatoid arthritis (RA). A behavioral observation method for the assessment of RA pain has been developed. In this study, videotapes were made of 53 RA patients while they performed standardized maneuvers. Trained raters viewed the videotapes and recorded the frequencies of 7 pain behaviors. Clinical and laboratory measures of rheumatoid disease activity also were recorded for each patient. Rheumatology fellows viewed 20 randomly chosen video recordings of the patients and made global estimates of the intensity and unpleasantness of pain. Significant positive correlations were found between total pain behavior scores and measures of disease activity. The fellows' estimates of the intensity and unpleasantness of the patients' pain also were significantly and positively correlated with the total pain behavior scores. The behavioral observation method may be useful in the assessment of RA pain and may be included as an objective outcome measure in clinical trials with RA patients.