Overall long-term impact of total hip and knee joint replacement surgery on patients with osteoarthritis and rheumatoid arthritis.

All patients with OA or RA entering an orthopaedic waiting list for total hip or knee replacement surgery over a period of 2.5 yr were prospectively assessed for overall pain (Visual Analogue Scale) and disability (Health Assessment Questionnaire) prior to and following their operation at annual intervals for up to 5 yr. A total of 293 patients had 335 operations (OA, hip 164; OA, knee 76; RA, hip 41; RA, knee 54). A few patients (14) showed a deterioration in pain and function 1 yr after surgery, but the remainder showed improvements which took 1 yr or more to reach maximum and were maintained for at least 3 yr. Although greater for OA hip patients, improvements occurred and were maintained in all groups, in spite of the polyarticular nature of RA.

A comparison of the ability of 28 articular indices to detect an induced flare of joint inflammation in rheumatoid arthritis.

Comparison of the ability to detect a flare of joint inflammation provoked by withdrawal of non-steroidal anti-inflammatory drugs from 10 patients with rheumatoid arthritis was made between 28 computer generated articular indices. The results suggest that this method can be used to compare the sensitivity of articular indices. Identifying joint inflammation by the simultaneous presence of tenderness and swelling and weighting for joint size produced the most sensitive indices. Identifying inflamed joints by swelling alone, or swelling and/or tenderness, grading for the severity of the signs, or selecting a restricted range of joints provided no advantages.

Serum cytidine deaminase levels after withdrawal of non-steroidal anti-inflammatory treatment in rheumatoid arthritis.

Increases in joint inflammation in nine patients with rheumatoid arthritis were provoked by withdrawal of their non-steroidal anti-inflammatory drugs. Pain score, duration of morning stiffness, Ritchie articular index score, and the number of analgesic tablets consumed reached peaks after five, three, five, and five days respectively compared with values during six days of normal treatment. Changes in serum cytidine deaminase (believed to reflect polymorph turnover in inflamed joints) showed a different pattern, with a sharp peak after two days and a subsequent trough. Possible mechanisms for these differences are discussed.

Analysis of clinical judgment helps to improve agreement in the assessment of rheumatoid arthritis.

Experienced rheumatologists differ widely in their assessments of rheumatoid arthritis even after extensive efforts to improve agreement by discussion and consensus. The use of computer feedback to provide an analysis of clinicians' judgment policies in a highly structured investigation has been shown to improve agreement, but this may not apply in normal clinical practice. Here the successful convergence of clinical agreements by three rheumatologists using computer assisted feedback over several months in a National Health Service outpatient department is reported. In the three months without feedback their pooled agreement for assessing the severity of rheumatoid arthritis was r2 = 0.62. During the three months in which feedback was provided agreement rose to r2 = 0.92. The principal component of all three judgment policies at the end of the feedback period was 'articular index'.

Articular indices of joint inflammation in rheumatoid arthritis. Correlation with the acute-phase response.

The joints of 30 rheumatoid arthritis patients were assessed by one observer for signs of inflammation. Computer analysis was then used to calculate 70 different articular indices for each patient. Pearson correlation coefficients were calculated between serum C-reactive protein levels and the articular indices. The results show that: findings in a restricted set of examined joints were equivalent to those in a more complete set; the simultaneous presence of joint tenderness and swelling yielded higher correlation than did either variable alone; and joint "weighting" for size yielded higher correlation than did simple counts.

Failure to find disease similarity in sibling pairs with rheumatoid arthritis.

Clinical and laboratory measures of disease expression were compared within and between 33 families with two or more affected siblings with rheumatoid arthritis (RA). None of the variables studied--age and calendar year of disease onset, pattern of joint involvement, the presence of rheumatoid nodules, Sjögren's syndrome, a positive latex or antinuclear antibody (ANA) titre--showed a greater concordance within the families than between them. The families were then divided into those in which the affected sibling pairs were and were not HLA identical. Such a division did not alter the conclusion, with the possible exception of a positive latex titre. These results suggest that genetic or unique environmental factors within families may have only a limited role in explaining disease heterogeneity in RA. Conversely, the absence of homogeneity within the families justifies their use in genetic linkage studies and the extrapolation of results obtained from affected siblings to the commoner sporadic disease.

Experimental cryo-irrigation of the knee joint.

Experiments have been carried out to test the feasibility of using cryo-irrigation as a means of ablating the synovium in the rheumatoid knee joint. Cryo-irrigation was performed by a cooling machine and pump, which circulated cold 200/10 centistoke (cSt) silicone through the knee joint of rabbits anaesthetised with intravenous (IV) 'Saffan'. Fluid left the joint at -5 to -10 degrees C. Sixteen normal New Zealand rabbits received cryo-irrigation of one knee joint for 10-20 minutes and were killed at one day, and one, two, and 12 weeks thereafter. Judged by radioactive sulphate incorporation there was no impairment of chondrocyte function in the articular cartilage of irrigated joints. Histological examination showed mild synovitis and some loss of staining of superficial cartilage in 6/16 irrigated joints (v 1/16 control joints). Similar treatment of rabbit joints in which the Glynn model of synovitis had been induced showed marked reduction of synovitis 14-45 days after silicone treatment. Nine of 26 animals in which synovitis was induced in both knees and cryo-irrigation performed in one knee died either immediately postoperatively or during the next week. These deaths remain unexplained. A single dog received cryo-irrigation of one knee (-6 to -9 degrees C for 22 min) and remained perfectly well up to sacrifice at six months, when the joint appeared histologically completely normal.

Pepsinogen--an immunoglobulin binding artefact in 'collagen' preparations.

It has previously been shown that extracts of human articular cartilage, many many of which contain type II collagen, react with heat-aggregated immunoglobulin and artificially prepared immune complexes. Sera from patients with rheumatoid arthritis and psoriatic arthritis, but not from patients with inflammatory bowel disease, react with these extracts. There are two distinct patterns of binding, either as low molecular weight immune complexes or as free antibody directed against collagen. Aggregate-binding activity identified in extracts of human articular cartilage following pepsin digestion was found to be distinct from collagen in its salt solubility. Further purification of this aggregate-binding factor by SDS gel electrophoresis has shown it to be an artefact resulting from the binding of small immune complexes to pepsinogen present in the pepsin preparation used to digest the cartilage.

New HLA DNA polymorphisms associated with rheumatoid arthritis.

Studies of restriction enzyme fragment length polymorphisms (RFLP) have further clarified two DNA polymorphisms detected in DR4 positive individuals with a DQ beta probe. These patterns have been designated DQ beta omega, characterized in the Dw4 homozygous typing cell (HTC) BM14 and DQ beta phi, characterized in the Dw4 HTC MCF, and so do not correspond with different Dw types. These patterns clearly segregate in families with HLA haplotypes. We suggest that omega and phi may be polymorphisms of the DX beta gene. The previously reported DX alpha polymorphisms U and L were found with all DR types and in association with DQ beta omega (U) and DQ beta phi(L). In addition DQ beta phi was found to be strongly associated with TA10 positively (a subdivision of DQw3) although this association was not absolute. Associations between RFLP and other HLA Class II and I antigens seen in DR4 patients and DR4 controls suggest the existence of at least two preferential allelic associations (PAA), one containing omega/U and the other phi/L. PAA1: DX alpha U-DQ beta omega-TA10 negative-DQw3-Dw4-DR4----Bw62-Bw6-Cw3-A2 PAA2: DX alpha L-DQ beta phi-TA10 positive-DQw3-Dw4-DR4----B44-Bw4-Cw3-A2 The frequency of the omega pattern was higher, although not significantly in the RA patients compared with controls. However, a significantly higher frequency of omega was found in RA patients with extra-articular manifestations (EA) compared (a) with controls (p less than 0.04) and (h) with those patients without EA (p less than 0.05). In addition the frequency of phi was significantly higher in RA patients with nodules and/or erosions (N/ER) compared with patients without these features (p less than 0.008). When cumulative scores were assigned to patients after assessing the number of components fulfilled for each PAA, PAA1 appeared to be pronounced in patients with EA and PAA2 in patients with N/ER. The frequency of a previously reported DQ beta T6 band found with the enzyme Taq 1 and DQ-beta probe was found at a higher frequency in RA patients compared with controls. In addition a significantly higher frequency of this band was found in female RA patients compared to males.

Inability of rheumatologists to describe their true policies for assessing rheumatoid arthritis.

Eighty nine British and Australian rheumatologists took part in a study to discover how accurately they could describe their procedures for measuring disease severity in rheumatoid arthritis. The relative importance they attached to different clinical and laboratory variables showed a very wide variation, and these stated policies were generally poor at predicting their actual judgments when assessing 'paper patients' (r2 = 39%). Policies based on equal weighting of all variables, while also poor predictors (r2 = 41%), were nevertheless superior to their stated policies for 49 respondents. Policies calculated by judgment (linear regression) analysis were much more successful predictors (R2 = 73%). Unhurried, detailed interviews with four experienced rheumatologists provided carefully considered statements of assessment policy, but these also were poor predictors of routine assessments of outpatients (r2 = 34%) compared with policies calculated by clinical judgment analysis, even when these were applied to new data (R2 = 88%).

Cytidine deaminase activity as a measure of acute inflammation in rheumatoid arthritis.

Cytidine deaminase (CD), a cytoplasmic enzyme, is thought to leak out of damaged cells and can be measured in fluids by a simple biochemical assay. This study has shown that serum CD activity is raised in rheumatoid arthritis (RA) compared with osteoarthritis (OA). Synovial fluid (SF) CD activity was always less than the corresponding serum activity (mean SF/serum ratio = 0.6) in OA but up to 22 times greater than the corresponding serum activity in RA (mean SF/serum ratio = 13.1), suggesting CD production in inflammatory joints. Evidence to support the SF neutrophil as a cell of CD origin is provided by the CD gradient running from cells to SF to synovium. The close correlation between SF CD activity and neutrophil count (r = 0.93) indicates that SF CD activity is an accurate measure of acute synovial inflammation. Weak correlation of serum CD activity with erythrocyte sedimentation rate (ESR) (r = 0.44) and C-reactive protein (CRP) (r = 0.49) implies that CD estimations supply different though related information about rheumatoid disease activity. We suggest that CD released from damaged neutrophils diffuses from all inflamed joints into the blood, so that serum CD activity may provide an integrated measure of joint inflammation more specific than traditional measures such as the ESR.

Measuring physicians' judgment--the use of clinical data by Australian rheumatologists.

Most therapeutic decisions depend upon the clinical judgment of physicians assessing their patients. However the inherent and wide variation in such judgments is usually ignored. Rheumatoid arthritis typifies those diseases in which much information is available on which to base decisions, but little is known about how physicians combine the data to evaluate their patients' response to treatment. Thirty-four Australian rheumatologists recorded their assessments of the progress of 50 rheumatoid patients treated with 'second line' agents, based on data presented on previously validated written forms. Clinical judgment analysis, a form of multiple regression analysis, was then used to model the way physicians' judgments related to the available data. There were major differences of judgment in the assessments of response to therapy. This was so even when only 'clinically important' changes were identified. The variance in judgments which could be modelled by clinical judgment analysis ranged from 45% to 94%. Both individual inconsistency and differences in the underlying use of data contributed to disagreements between clinicians' assessments of identical cases. Identifying underlying differences in the way clinical data relate to clinicians' judgments is a step towards improving clinical consistency.

Clinical judgment in rheumatoid arthritis. III. British rheumatologists' judgments of 'change in response to therapy'.

A realistic analysis of the criteria used by rheumatologists in evaluating the progress of patients suffering from rheumatoid arthritis must be based on actual clinical judgments rather than on expressed opinions. A randomly selected 15% sample of British rheumatologists (48) recorded judgements on the progress of 50 'paper' patients, based on data taken from actual patients participating in clinical trials. The rheumatologists differed markedly in their assessments of the progress of disease, with serious disagreements even when only 'clinically important' changes were considered. Some clinicians showed little consistency in their judgments of duplicate cases. Multiple regression analysis of the patient data in relation to the disease assessments provided a model of each clinician's judgment policy. These judgment policy models showed that the differences in clinical assessment were greater than could be explained by the inconsistent application of similar assessment policies, and were a consequence also of differences in the underlying judgment policies themselves. Judgments related more closely to changes in ESR and other process measures than to changes in functional ability.

Clinical judgment in rheumatoid arthritis. IV. Rheumatologists' assessments of disease remain stable over long periods.

Seven rheumatologists made judgments about the improvement or deterioration of identical sets of 50 'paper' patients on two occasions one year apart. The stability of their judgments over one year (rs = 0.70) compared favourably with the reliability of duplicate judgments on each occasion (rs = 0.76). Multiple regression analysis of the patient data in relation to the disease assessments provided a model of each clinician's underlying judgment policy. The stability of judgments predicted by these policy models was even higher (rs = 0.83).

Incidence of metabolic bone disease in rheumatoid arthritis and osteoarthritis.

Bone biopsy specimens from the iliac crest were obtained during surgical operations from 45 patients with rheumatoid arthritis (RA) and 41 with osteoarthritis (OA). Control material was obtained from 20 cases of sudden death due to cardiovascular disease. By both conventional histology and image analysis techniques about a quarter of all patients showed some osteoporosis. This was equally common among the OA and RA patients. It was more common among those with transparent skin and those taking corticosteroids. The only case showing mild osteomalacia suffered from OA. No gross differences were apparent between the groups in relation to plasma biochemical studies, diet, or exposure to sunlight. These results are in striking contrast to the high incidence of osteomalacia in RA reported from the west of England; moreover they do not confirm reports of hypercalcaemia among rheumatoid subjects. We conclude that the differences regarding osteomalacia are due to selection of cases. We find no evidence that osteomalacia is specifically associated with RA.

Polymorphonuclear cell motility, ankylosing spondylitis, and HLA B27.

Polymorphonuclear leucocyte (PMN) function was studied in 29 subjects with ankylosing spondylitis (AS). Of these, 20 were HLA B27+ve and 9 B27-ve. There were 30 controls and, of these, 15 were B27+ve. Random and directed cell migration was measured by 2 techniques: migration through a micropore filter and migration under an agar film. The chemo-attractant was either case in-activated serum or zymosan-activated serum. By both techniques directed motility was increased in subjects with B27 or with AS when compared to the B27-ve controls. This suggests that the disease AS and the possession of B27 are both associated with increased PMN motility.

Binding of immunoglobulins and immune complexes to cartilage derived extracts.

Cartilage extracts with affinity for heat aggregated immunoglobulins were prepared from human articular and bovine nasal cartilage. These extracts, containing predominantly collagen, also bound both to immune complexes (IC) prepared in vitro and to immunoglobulins from sera of many patients with rheumatoid arthritis (RA). Cryoprecipitation of rheumatoid sera removed material reacting with the extract and density gradient fractionation of a positive serum showed correlation between binding to the extract and to C1q. These results indicate that the binding materials in rheumatoid sera were likely to be IC. We suggest that some assays which apparently demonstrate anti-collagen autoantibodies in fact measure IC. These findings also have implications for models of the pathogenesis of RA.