What factors influence functional ability in patients with rheumatoid arthritis. Do they alter over time?

OBJECTIVES: To describe the changes in functional ability (FA) taking place over 5 yr in patients with rheumatoid arthritis (RA) starting disease-modifying anti-rheumatic drug (DMARD) therapy, to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment. METHODS: Three hundred and sixty-six patients with active RA were studied as part of a 5-yr randomized controlled study of DMARD therapy. FA was assessed by Health Assessment Questionnaire (HAQ) score every 6 months. Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr. The independent variables used were age, sex, visual analogue scale (VAS) pain, Ritchie articular index, C-reactive protein (CRP), Larsen score and log-transformed morning stiffness (EMS). RESULTS: Mean HAQ score was 1.64 at baseline, improved by 21% at 1 yr and gradually returned towards baseline levels by 5 yr. At baseline only 34% of variance in HAQ score could be explained; the most significant explanatory variables were the Ritchie articular index and CRP. At 5 yr the variance explained was 60%. The Ritchie articular index remained the strongest factor followed by VAS pain, log(10) EMS and Larsen score. CONCLUSIONS: Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr. The most consistent factor affecting function was joint tenderness. Global pain and duration of EMS were of lesser importance. Disease activity measures such as the CRP exerted an influence in the earlier, more active stages of disease: radiographic damage assumed greater importance as the arthritis progressed.

Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double blind trial of sulphasalazine vs diclofenac sodium.

BACKGROUND: Current disease management in rheumatoid arthritis (RA) has moved towards "inverting the therapeutic pyramid" by introducing disease-modifying anti-rheumatic drugs (DMARDs) early. Despite the logic of early DMARD therapy, there is a dearth of supportive evidence for this approach. We report a randomised controlled trial comparing sulphasalazine monotherapy with diclofenac monotherapy in early RA. The primary aim was to provide unequivocal evidence that early DMARDs prevent erosive damage. The secondary aim was to evaluate if sulphasalazine used alone has comparable symptomatic benefits to NSAIDs. METHODS: 117 patients with RA for under 12 months of diagnosis (mean 2 months) were randomised (62 sulphasalazine; 55 diclofenac). Sulphasalazine patients comprised 76% women, and 58% were rheumatoidfactor positive. Diclofenac patients comprised 74% women, and 54% were seropositive. 36% completed 12 months of therapy (16 sulphasalazine; 26 diclofenac); sulphasalazine was given for a mean period of 21 weeks and diclofenac for a mean period of 33 weeks. Results were analysed on an intention to treat basis. RESULTS: After 12 months the mean number of new erosions in patients randomised to receive sulphasalazine was 2.0 (95%CI 0.9, 3.1) and in patients randomised to receive diclofenac was 7.5 (95%CI 4.1, 10.9; p = 0.002 by Student's unpaired t-test). An analysis of valid compliant completers showed the mean number of new erosions in patients who received 12 months therapy with sulphasalazine was 2.3 (95%CI 0.6, 4.0) and in patients who received 12 months diclofenac was 10.5 (95%CI 5.0, 15.9; p = 0.018 by Student's unpaired t-test). The Ritchie articular index, swollen joint counts and pain scores decreased with both sulphasalazine and diclofenac, with mean falls in both groups of 15-20% at 2 weeks and 30-40% at 4 and 8 weeks. There were no differences between treatments. Disease activity scores showed similar highly significant mean decreases within both treatment groups (P < 0.001 in all cases) of 0.5 at 2 weeks and 1.0 at 4 weeks; at 12 and 26 weeks they were significantly lower with sulphasalazine (p = 0.036 and 0.045). 75% of the patients given sulphasalazine and 65% of those given diclofenac had one or more adverse events with no major differences between treatments. CONCLUSIONS: These results show that an accelerated dosing schedule of sulphasalazine has identical effects to diclofenac in reducing symptoms, indicating it is a rapidly effective DMARD. They also provide unequivocal evidence, analysed on an intention to treat basis, that early treatment with sulphasalazine significantly reduces the extent of radiological progression in active RA.

Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis.

OBJECTIVE: An elevated acute-phase response is associated with increased radiologic damage in rheumatoid arthritis (RA), but development of damage in previously normal joints ("new joint involvement") has not previously been investigated. This study was undertaken to investigate the hypothesis that when there is suppression of disease activity as judged by the C-reactive protein level, new joint involvement is reduced to a greater extent than is progression in already damaged joints ("damaged joint progression"). METHODS: Three hundred fifty-nine patients with active RA were studied as part of a 5-year randomized, prospective, open-label study of disease-modifying antirheumatic drug therapy. Time-averaged CRP was calculated from samples obtained every 6 months, and patients were divided into groups with CRP values of <6, 6-<12, 12-<25, and > or =25 mg/liter. Radiographs of the hands and feet were scored by the Larsen method; a damaged joint was defined as one with a score of > or =2. RESULTS: The rank correlation between time-integrated CRP and increase in Larsen score was 0.50; the correlation increased to 0.59 for patients entering the study with disease duration of < or =2 years. The percentage of new joint involvement over 5 years varied markedly with time-integrated CRP, from 7.3% in the CRP <6 mg/liter group to 39.1% in the CRP > or =25 mg/liter group (5.4-fold increase). The percentage of damaged joint progression increased from 26.1% in the CRP <6 mg/liter group to 41.6% in the CRP > or =25 mg/liter group (1.6-fold increase). CONCLUSION: The results of this study provide further confirmation that high CRP levels over time are associated with greater radiologic progression. Although radiologic progression still occurred in both previously normal and damaged joints despite the presence of normal CRP levels, this consisted of proportionately less new joint involvement compared with damaged joint progression. These findings support the idea that disease-suppressive therapy should be instituted at an early stage in patients with RA, before erosive damage has occurred.

The influence of HLA-DRB1 alleles encoding the DERAA amino acid motif on radiological outcome in rheumatoid arthritis.

OBJECTIVES: To investigate the influence of HLA-DRB1 alleles encoding the QK/RRAA shared epitope (SE) on radiological outcome in rheumatoid arthritis (RA), and to determine whether it is modulated by alleles carrying the putative rheumatoid arthritis-protective (RAP) sequence DERAA. Patients and methods. The association between erosive damage and HLA-DRB1 status was examined in 315 RA patients with a disease duration of 5-30 yr. Radiological outcome was measured by scoring X-rays of the hands and feet using the standard radiographs of Larsen (Larsen score). HLA-DRB1 typing was carried out using polymerase chain reaction methodology. RESULTS: Patients with two alleles encoding the QK/RRAA SE had significantly higher Larsen scores than SE-negative patients (96.9 vs 83.3; P=0.04, after correction for multiple testing), with DRB1*0401/*0401 homozygotes demonstrating the greatest radiological damage (99.9). The lowest Larsen score (65.6) was observed in patients carrying the DERAA motif without an accompanying SE allele (RAP+/SE-). This was significantly lower than in patients with RAP+/SE+ (105.6; P=0.04), RAP-/SE- (88.2; P=0.05) and RAP-/SE+ (95.8; P=0.009), after correction for multiple testing. There was no evidence that the RAP sequence was modulating the effect of the SE since radiological outcome in RAP+/SE+ patients was not significantly different to that in RAP-/SE+ individuals. CONCLUSIONS: Our data support a possible role for DRB1 alleles encoding the DERAA motif in protection against severe erosive damage in patients lacking the QK/RRAA SE, but not in patients heterozygous for the SE. This suggests that DRB1 alleles encoding the SE have a dominant influence over 'protective alleles' and are not merely 'non-protective'.

A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis.

OBJECTIVE: To compare the efficacy of hydroxychloroquine, penicillamine, sodium aurothiomalate and auranofin in the treatment of active rheumatoid arthritis over a period of 5 yr. METHOD: Five hundred and forty-one patients with definite or classical rheumatoid arthritis were entered into an open randomized controlled trial with a flexible dose regimen designed to reflect clinical practice. Decisions to stop treatment with any one of the disease-modifying anti-rheumatic drugs (DMARDs) were based on an agreed trial protocol which defined criteria for adverse reactions and therapeutic failure. The managing physicians' decisions were confirmed in a separate monitor clinic. RESULTS: The proportion of patients who remained on their first DMARD or who were in remission at 5 yr was 53% for penicillamine, 34% for sodium aurothiomalate, 31%, for auranofin and 30% for hydroxychloroquine (P < 0.001). In patients who stayed on their first DMARD, all groups showed a 30-50% improvement in C-reactive protein, erythrocyte sedimentation rate, Ritchie Index and joint stiffness, and a deterioration in their Larsen score. There was no evidence of physician bias to explain the larger proportion of patients remaining on penicillamine for 5 yr. CONCLUSION: Despite the increased popularity of sulphasalazine and inmmunosuppressives, the drugs in this study continue to be used worldwide. The natural history of rheumatoid arthritis requires long-term follow up to establish drug efficacy. Evidence is needed as to whether the newer regimens will prove to be more effective and safer in the longer term than the commonly prescribed DMARDs. The data from this trial will provide a reference for comparison with future studies.

Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study.

OBJECTIVE: To describe the course of radiological progression in a cohort of 126 patients presenting with early nonerosive rheumatoid arthritis (RA). METHODS: Criteria for recruitment to the study were fulfillment of the 1958 American Rheumatism Association criteria, absence of erosive disease at presentation and duration of symptoms less than 3 years. Radiographs of hands and feet at 0, 1, 2, 5, and 8 years were available on 114 patients and were scored by Sharp's method for erosion (ERO) and joint space narrowing (JSN). Eighty-six patients were typed for the RA susceptibility shared HLA-DR epitope. RESULTS: The feet showed greatest initial radiological progression, but tended to reach an earlier and lower plateau. ERO progressed more rapidly than JSN in the first 2 years, but in parallel thereafter. The relative proportion of ERO:JSN varied, 1:1 for the wrists, 4:1 for the proximal interphalangeal joints. Thirty-eight percent of joints were eroded at 2 years, 63% at 8 years. Four patterns of radiological progression were identified: flat or nonerosive disease in 29 patients, linear in 51, lag in 13, and plateau in 19 (irregular in 2). Changes in the rate of radiological progression were reflected by the time-integrated C-reactive protein over the same period. Rheumatoid factor titer was higher in the progressive groups compared to the flat group (p = 0.01). The RA susceptibility shared HLA-DR epitope was more frequent in the linear compared to the flat group (p = 0.03). CONCLUSION: A large proportion of joints become eroded in the first 2 years of early RA. The subsequent course of radiological progression is highly variable and cannot be easily explained by any single model.

Radiographic patterns and response to corticosteroid hip injection.

OBJECTIVES: A prospective, open study of corticosteroid hip injection (CHI) was performed to determine if different radiological patterns of arthritis vary in their response. METHODS: Forty five patients (15 with rheumatoid arthritis, 27 with osteoarthritis, and three with anklyosing spondylitis) underwent hip injection with 80 mg methylprednisolone and lignocaine under x ray control. Outcome was assessed at two, 12, and 26 weeks for pain, range of hip movement, and graded functional questionnaire. Patients estimated their pain in four components, night pain, rest pain, weight bearing, and referred pain, each measured by 10 cm visual analogue score and summed to give a total score out of 40 cm. Hip radiographs were evaluated blindly for pattern and severity of arthritis, as well as for progression between 0 and 26 weeks. RESULTS: Median total pain score decreased from 29 cm at baseline to 22 cm at two weeks (p = 0.0001), 24 cm at 12 weeks (p = 0.03), but had returned nearly to baseline by 26 weeks (25 cm, p = 0.3). Greatest improvement was seen for night pain. Mean range of internal rotation increased from 16 to 28 degrees at two weeks (p = 0.03) and 21 degrees at 12 weeks (p = 0.06). Functional ability did not change. Hips with an atrophic pattern of arthritis on plain radiography gained negligible pain relief at two weeks compared with hips with a hypertrophic or mixed bone response (p = 0.04). The degree of pain relief was similar in patients with OA and RA, and was not influenced by radiographic severity or by the direction of migration of the femoral head. CONCLUSION: Pain and internal rotation improve for up to 12 weeks after CHI. CHI offers a useful and safe therapeutic option for patients with hip arthritis, with the exception of those with a purely atrophic radiological pattern.

Management of oral complications of disease-modifying drugs in rheumatoid arthritis.

Stomatitis is a troublesome adverse effect of disease-modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.

Small joint synovitis in rheumatoid arthritis: should it be assessed separately?

In the assessment of disease activity in rheumatoid arthritis (RA) small joint synovitis is traditionally included only as a component of active, tender or swollen joint counts. By contrast, in the assessment of disease damage in RA, the X-ray score of hands and feet represents one of the most common parameters used and is regarded as a major indicator of outcome. Data presented in this study lead us to hypothesize that the small joints require separate assessment in any study of disease activity or outcome in RA: (i) there is clear evidence that small joint synovitis often occurs in the absence of an abnormal acute phase response (ESR or C-reactive protein) and (ii) measured synovitis is an individual (PIP) joint has been shown to be reliable and to be related to subsequent X-ray changes in the same joint. Our findings show that, in a study of a treatment of RA, it is quite possible for disease activity measures to appear controlled while inflammation continues in the small joints causing radiological damage. This radiological damage is reflected as an adverse outcome. Hence the paradox of improving disease activity but not outcome. We argue that small joint inflammation and damage should be recognized as one aspect of the RA disease process offering unique information and as such should be assessed independently.

Measurement and prediction of radiological progression in early rheumatoid arthritis.

OBJECTIVE: To compare radiological scoring systems in early RA, and then to determine if the rate of radiological progression in the first year of disease (RRP01) predicts the subsequent rate of progression up to 8 years (RRP1-8). METHODS: Hand and feet radiographs were performed at 0, 1, 2 and 8 years in 65 patients presenting with nonerosive RA and symptoms for less than 3 years. All films were scored by Sharp's method; Sharp, Larsen and carpometacarpal (CMC) ratio methods were compared in 23 patients. RESULTS: Significant change in score was detected over the first year using Sharp (median of 15.5 vs 7.5, p < 0.00002) and Larsen (30.5 vs 22.5, p < 0.0002), but not CMC ratio (1.13 vs 1.14, p = 0.07). Sharp had greater range and sensitivity of change, and had better inter and intraobserver reproducibility. RRP01 showed a skewed distribution (median 0.7 units/month; range -0.3 to +6.1). Spearman correlation between RRP01 and RRP1-8 was r = 0.57, p < 0.001. CONCLUSION: Both Sharp and Larsen indices are sensitive to change in the first year of RA, but Sharp has advantages of greater sensitivity and reproducibility: CMC ratio is not useful. Radiological progression rate in the first year correlates only moderately with subsequent rate of progression up to 8 years. This suggests that radiological progression is nonuniform and that different patterns of progression over time may exist.

Prediction of radiographic damage in hands and feet in rheumatoid arthritis by clinical evaluation.

Radiography of hands and feet is a standard measure of outcome in rheumatoid arthritis. We hypothesised that this radiological information can be reproduced by clinical evaluation. A rheumatologist examined 78 patients with rheumatoid arthritis and tried to predict the radiological Larsen score, for the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, ankle, and metatarsophalangeal (MTP) joints. Spearman correlation between clinical Larsen and X-ray Larsen was 0.79 for hands and 0.66 for feet. There was no significant difference in scores for PIP, MCP, wrists, or ankles, but MTP joints were underscored by clinical Larsen relative to X-ray Larsen (median of 20 vs 22 respectively, p = 0.04). Categorical data for index finger MCP joints showed significant proportional agreement of 37% (Kappa 0.24, p < 0.0001). In conclusion, the Larsen X-ray score can be predicted by clinical examination with surprising accuracy in the small hand joints but less so in the feet. Although the favourable agreement shown in this study does not make X-rays redundant, we suggest that clinical examination of the hands should be further refined and standardised as a measure of outcome.

The GALS locomotor screen and disability.

OBJECTIVES: Examination of the locomotor system is frequently neglected. Therefore, the GALS locomotor screen (Gait, Arms, Legs, Spine) has been proposed by Doherty et al as a practical method of identifying functionally important problems. This study was designed to test whether this screen reflects functional impairment, as measured by accepted health status measures. METHODS: Two observers performed the GALS screen in a total of 83 patients with a variety of musculoskeletal conditions. The examination components of GALS were rated by a simple 0 to 3 scale. Physical ability was further assessed by Health Activity Questionnaire (HAQ), Barthel index and Steinbrocker's ARA classification. RESULTS: For the total patient group, Spearman correlations between GALS and the three functional indices were good (r = 0.62 to 0.71, p < 0.001). Correlations were equally good for rheumatoid arthritis patients alone (r = 0.65 to 0.70, p < 0.001), but less good although still significant for the other miscellaneous rheumatic conditions (r = 0.31 to 0.46, p < 0.05). Observed proportional agreement between the two observers for the individual scores was > 70%, with a kappa statistic k = 0.49 to 0.74. CONCLUSIONS: The GALS screen is a reliable and valid measure of functional ability, compared with standard accepted indices in a variety of musculoskeletal diseases. This supports the proposal for its use as a screening test by general practitioners and medical students.

Continuous ambulatory peritoneal dialysis and haemodialysis in the elderly.

The clinical course and outcome of 58 patients receiving haemodialysis or continuous ambulatory peritoneal dialysis aged 65 years and above at the start of dialysis treatment was examined over a six-year period. Method of presentation and mode of treatment did not affect survival, but the presence of ischaemic heart disease or congestive cardiac failure was significantly associated with increased mortality. The actuarial two-year patient survival was 54 per cent. Survival on continuous ambulatory peritoneal dialysis was 75 per cent, and the incidence of peritonitis was one episode per 7.36 patient-treatment months. The mean duration of hospital admission was 57.2 days per patient year for continuous ambulatory peritoneal dialysis, and 19.9 days per patient year for haemodialysis patients.

Pregnancy in Jamaican women with homozygous sickle cell disease. Fetal and maternal outcome.

The outcome of 664 pregnancies in 297 Jamaican women with homozygous sickle cell (SS) disease over the period 1959-1984 was reviewed. Overall, the spontaneous abortion rate was 118 per 1000 pregnancies, the stillbirth rate 128 per 1000 births, and perinatal mortality 171 per 1000 births. There was a striking secular increase in both spontaneous abortions and stillbirths which was accounted for, in part, by a trend for abortions to increase with maternal age up to the age of 30 years, a greater proportion of patients in the high-risk 25-29 year age group occurring in the 1980-1984 period. Another factor contributing to the poor obstetric performance in the 1980-1984 period was probably an increased survival and pregnancy rate in high-risk patients. Seven women had pregnancy-related deaths giving a pregnancy mortality rate of 1.1%.

Pregnancy in Jamaican women with homozygous sickle cell disease: fetal and maternal outcome

The outcome of 664 pregnancies in 297 Jamaican women with homozygous sickle cell (SS) disease during the period 1959-84 was reviewed. Overall, the spontaneous abortion rate was 118/1000 pregnancies, the stillbirth rate 128/1000 births, and perinatal mortality 171/1000 births. There was a striking secular increase in both spontaneous abortions and stillbirths accounted for, in part, by a trend for abortions to increase with maternal age up to the age of 30, a greater proportion of patients in the high-risk group, ages 25-29, occuring during 1980-84. Another factor contributing to the poor obstetric performance during the 1980-84 period was probably an increased survival and pregnancy rate in high-risk patients. 7 women had pregnancy-related deaths giving a pregnancy mortality rate of 1.1 percent.(AU)