MRI bone oedema predicts eight year tendon function at the wrist but not the requirement for orthopaedic surgery in rheumatoid arthritis.

OBJECTIVE: To investigate the role of early magnetic resonance imaging (MRI) of the wrist in predicting functional outcome in rheumatoid arthritis. METHODS: MRI scans of the dominant wrist were scored for synovitis, tendon inflammation, bone oedema, and erosion at first presentation (n = 42), at 1 year (n = 42), and at 6 years (n = 31). At 8 years, clinical reassessment (n = 28) was undertaken. Tendon function was graded 0-3 for movement, tendon sheath swelling, and pain on resistance at nine flexor and extensor tendons of the hand. Hand function was also assessed using the Sollerman grip test. The requirement for joint or tendon surgery by 8 years was determined by telephone survey in 39 of the original 42 patients. RESULTS: At 8 years, tendon function was highly correlated with hand function (Sollerman score, R = -0.51, p = 0.005) and global function (health assessment questionnaire score, R = 0.53, p = 0.004). Using a model incorporating baseline and 1 year MRI scores, the MRI bone oedema score was strongly predictive of tendon function at 8 years (chi(2)(2) = 15.3, p = 0.0005), as was the MRI bone erosion score (chi(2)(2) = 9.23, p = 0.01). Hand function was also predicted by the baseline MRI erosion score (p = 0.02). MRI variables did not predict the requirement for surgery, but patients who had surgery were more likely to show progression of MRI bone erosion scores between baseline and 1 year (p = 0.008). CONCLUSIONS: Extensive MRI bone oedema and erosions at the wrist in early rheumatoid arthritis predict tendon dysfunction and impaired hand function in the medium term but not the requirement for joint or tendon surgery.

Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis.

BACKGROUND: Ligands of chemokine receptor CCR5, including MIP-1 alpha, MIP-1 beta, and RANTES, have been implicated in rheumatoid arthritis. OBJECTIVE: To test whether CCR5 d32 polymorphism has a negative association with rheumatoid arthritis in a New Zealand cohort. METHODS: 516 white patients with rheumatoid arthritis and 985 healthy controls were investigated by PCR amplification of the region flanking the known CCR5 d32 deletion, and the frequencies of CCR5 d32 compared. An early rheumatoid arthritis (ERA) cohort of 92 patients was followed prospectively for two years; disease severity and outcome were correlated with CCR5 d32 status. RESULTS: 12 control subjects (1.2%) were homozygous for d32; no d32 homozygous rheumatoid patients were detected (p = 0.012); 56 patients (10.9%) were heterozygous for the d32 polymorphism (d32/wt), compared with 169 controls (17.2%) (p = 0.0011). The CCR5 d32 allele frequency was lower in the rheumatoid patients than in the controls (frequencies of 0.054 and 0.098, respectively; p = 3.7 x 10(-5)). The frequency of CCR5 d32 did not differ significantly according to disease severity or outcome in the prospective ERA cohort, nor with HLA-DRB1 status. CONCLUSIONS: This study provides further evidence for a protective effect of the CCR5 d32 variant on rheumatoid arthritis, consistent with a role for CCR5 and its ligands in disease pathogenesis.

Relationship between serum hyaluronic acid level and disease activity in early rheumatoid arthritis.

OBJECTIVES: To measure hyaluronic acid (HA) levels, which are raised in active rheumatoid arthritis (RA), in patients with early RA, and to assess the correlation with clinical and laboratory indices of disease activity and with subsequent radiographic erosive status. PATIENTS AND METHODS: Patients fulfilling ACR criteria were recruited into a prospective cohort within 6 months of disease onset and reviewed every 6 months. An HA binding protein based sandwich ELISA was used to measure HA in 240 sera from 82 patients at regular intervals. RESULTS: Patients had higher HA levels than age matched healthy blood donor controls (median 37.4 v 29.1 ng/ml, respectively, p<0.02), which increased with more prolonged disease. Baseline HA level correlated with measures of disease activity, including swollen and tender joint counts, HAQ, global assessments, ESR, and CRP; was higher in men; and increased with age. There was no relationship with HLA-DRB1 shared epitope or rheumatoid factor status. At 6 and 12 month follow up visits, HA levels were higher in patients who later developed erosions. However, a raised HA level was not a good predictor of erosions. CONCLUSIONS: Serum HA level correlates with clinical and laboratory measures of disease activity in early RA, but is unlikely to be of practical use in clinical practice.

A randomised placebo controlled trial of delipidated, deglycolipidated Mycobacterium vaccae as immunotherapy for psoriatic arthritis.

OBJECTIVES: To test the hypothesis that PVAC, delipidated, deglycolipidated heat killed Mycobacterium vaccae, is an effective and safe treatment for psoriatic arthritis (PsA). This treatment has shown promising results in psoriasis. METHODS: 36 patients with PsA in two centres were studied in this double blind, placebo controlled, randomised trial. Patients were randomised to receive two intradermal injections of 50 micro g PVAC or placebo and were followed up for 24 weeks. The primary end point was the Psoriatic Arthritis Response Criteria (PsARC), a composite measure based on changes in joint tenderness and swelling scores and physician and patient global assessments. RESULTS: The PsARC response at either 12 or 24 weeks was achieved by 9/18 (50%) placebo and 9/18 (50%) PVAC patients (p = 1.0). No significant differences in the Psoriasis Activity and Severity Index (PASI), patient or physician global assessments, CRP, or Health Assessment Questionnaire score over time were found between the two groups. However, changes in the pain visual analogue scale over time did differ between the two groups (p = 0.006): at 24 weeks the mean score in the PVAC group had declined by 19.2 mm and in the placebo group had increased by 4.8 mm. PVAC was well tolerated with no increased incidence of adverse events compared with placebo. CONCLUSIONS: PVAC was not shown to be as effective as immunotherapy for PsA. The striking response to placebo in this study reinforces the importance of adequately controlling therapeutic trials in PsA.

MRI of the wrist in early rheumatoid arthritis can be used to predict functional outcome at 6 years.

OBJECTIVES: To determine whether magnetic resonance (MR) scans of the dominant wrist of patients with early rheumatoid arthritis (RA) can be used to predict functional outcome at 6 years' follow up. METHODS: Dominant wrist MR scans were obtained in 42 patients with criteria for RA at first presentation. Patients were followed up prospectively for 6 years, and further scans obtained at 1 year (42 patients) and 6 years (31 patients). Two radiologists scored scans for synovitis, tendonitis, bone oedema, and erosions. The Stanford Health Assessment Questionnaire (HAQ) score, indicating functional outcome, and standard measures of disease activity were assessed at 0, 1, 2, and 6 years. The physical function component of the SF-36 score (PF-SF36) was also used as a functional outcome measure at 6 years. RESULTS: Baseline MR parameters, including bone oedema score and the total baseline MR score, were predictive of the PF-SF36 at 6 years (R2 = 0.22, p = 0.005 and R2 = 0.16, p = 0.02, respectively). The PF-SF36 score correlated strongly with the HAQ score at 6 years (rs = -0.725, p<0.0001); none of the baseline MR parameters predicted the 6 year HAQ score. The total MR score obtained at 1 year was predictive of the 6 year HAQ (R2 = 0.04, p = 0.01). Standard clinical and radiographic measures at baseline were not predictive of the 6 year PF-SF36, but when combined in a model with baseline MR oedema score, prediction increased from 0.09 to 0.23, or 23% of the 6 year variance. CONCLUSION: MR imaging of the wrist in patients with early RA can help to predict function at 6 years and could be used to plan aggressive management at an earlier stage.

What is the fate of erosions in early rheumatoid arthritis? Tracking individual lesions using x rays and magnetic resonance imaging over the first two years of disease.

OBJECTIVES: To investigate the progression of erosions at sites within the carpus, in patients with early rheumatoid arthritis (RA), using magnetic resonance imaging (MRI) and plain radiology over a two year period. METHODS: Gadolinium enhanced MRI scans of the dominant wrist were performed in 42 patients with RA at baseline (within six months of symptom onset) and one year. Plain wrist radiographs (x rays) and clinical data were obtained at baseline, one year, and two years. Erosions were scored by two musculoskeletal radiologists on MRI and x ray at 15 sites in the wrist. A patient centred analysis was used to evaluate the prognostic value of a baseline MRI scan. A lesion centred analysis was used to track the progression of individual erosions over two years. RESULTS: The baseline MRI erosion score was predictive of x ray erosion score at two years (p=0.004). Patients with a "total MRI score" (erosion, bone oedema, synovitis, and tendonitis) > or =13 at baseline were significantly more likely to develop erosions on x ray at two years (odds ratio 13.4, 95% CI 2.65 to 60.5, p=0.002). Baseline wrist MRI has a sensitivity of 80%, a specificity of 76%, a positive predictive value of 67%, and a high negative predictive value of 86% for the prediction of wrist x ray erosions at two years. A lesion centred analysis, which included erosions scored by one or both radiologists, showed that 84% of baseline MRI erosions were still present at one year. When a more stringent analysis was used which required complete concordance between radiologists, all baseline lesions persisted at one year. The number of MRI erosion sites in each patient increased from 2.1 (SD 2.7) to 5.0 (4.6) (p<0.0001) over the first year of disease. When MRI erosion sites were tracked, 21% and 26% were observed on x ray, one and two years later. A high baseline MRI synovitis score, Ritchie score, and erythrocyte sedimentation rate were predictive of progression of MRI erosions to x ray erosions over one year (p=0.005, 0.01, and 0.03 respectively), but there was no association with the shared epitope. Progression of MRI erosions to x ray erosions was not seen in those with transient polyarthritis. CONCLUSIONS: MRI scans of the wrist, taken when patients first present with RA, can predict radiographic erosions at two years. MRI may have a role in the assessment of disease prognosis and selection of patients for more or less aggressive treatment. However, only one in four MRI erosions progresses to an x ray erosion over one year, possibly owing to healing, observer error, or technical limitations of radiography at the carpus. Progression of MRI erosions to x ray erosions is greatest in those with high baseline disease activity.

Interferon-gamma microsatellite and rheumatoid arthritis.

Several non-HLA genes contribute to the susceptibility to rheumatoid arthritis (RA). A recent report noted an allele (126 bp [CA(13)]) of the interferon-gamma intron A microsatellite repeat strongly associated with both the occurrence and the severity of RA. We assessed this locus in an independent set of 128 controls and 93 prospectively recruited patients with early RA. The reported association could not be confirmed. This discrepancy might be due to technical problems, which could be avoided by the use of reference samples.

A 1-year follow-up study of dynamic magnetic resonance imaging in early rheumatoid arthritis reveals synovitis to be increased in shared epitope-positive patients and predictive of erosions at 1 year.

OBJECTIVES: Dynamic magnetic resonance imaging (MRI) allows visualization of the synovial membrane and measurement of synovitis within the joint. A cohort of patients with early rheumatoid arthritis (RA) were studied using MRI of the dominant wrist and clinical assessments. Associations between synovitis and the shared epitope genotype (SE) were looked for and synovitis as a predictor of joint erosion was examined. METHODS: Gadolinium-enhanced MRI scans of the dominant wrist were performed in 42 early RA patients at baseline (median disease duration = 4 months) and after 1 yr. Images were obtained at 42-s intervals over the first 6 min after gadolinium-diethylenetriamine pentaacetic acid injection using six cuts in the coronal plane, 2 mm apart. The site of maximal synovial enhancement was selected as the region of interest (ROI). The rate of enhancement (E-rate) was calculated and compared with synovitis scores from static MRI scans, clinical disease activity scores and HLA-DRB1*04/01 genotyping [sequence-specific primer polymerase chain reaction (SSP-PCR) and DNA sequencing]. RESULTS: Reproducibility of the E-rate measurement was assessed by re-evaluating 10 randomly selected scans in a blinded fashion. Intra-observer reliability was high with an intraclass correlation coefficient of 0.91, 95% confidence interval (CI) 0.65-0.97. The E-rate correlated strongly at baseline with the maximum level of synovial enhancement (E-max) (r = 0.88, P < 0.0001) and the static MRI synovitis score (r = 0.52, P = 0.0004). There was also a weaker but significant correlation between E-rate and the pain score (r = 0.29, P = 0.04). The E-rate fell from baseline to 1 yr (P = 0.02) concordant with clinical improvement after treatment with standard therapies. E-rate scores were higher in SE+ than SE - patients (F(1,25) = 5.19, P = 0.03) and were predictive of MRI erosions at 1 yr [chi-square = 5.0 (1 d.f.), P = 0.03]. The baseline C-reactive protein (CRP) was also predictive of MRI erosions at 1 yr to a similar degree [chi-square = 4.7 (1 d.f. ), P = 0.03] but the mean static synovitis score at baseline was the strongest predictor [chi-square = 9.2 (1 d.f.), P = 0.003]. CONCLUSIONS: These results show that dynamic MRI can be used to score synovitis objectively in early RA patients. Synovitis was greater in SE+ patients, suggesting an early genetic influence on joint inflammation, and was predictive for the development of erosions at 1 yr.

Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement.

OBJECTIVES: To investigate the progression of joint damage in early rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of the wrist and determine whether this technique can be used to predict prognosis. METHODS: An inception cohort of 42 early patients has been followed up prospectively for one year. Gadolinium enhanced MRI scans of the dominant wrist were obtained at baseline and one year and scored for synovitis, tendonitis, bone marrow oedema, and erosions. Plain radiographs were performed concurrently and scored for erosions. Patients were assessed clinically for disease activity and HLA-DRB1 genotyping was performed. RESULTS: At one year, MRI erosions were found in 74% of patients (31 of 42) compared with 45% at baseline. Twelve patients (28.6%) had radiographic erosions at one year. The total MRI score and MRI erosion score increased significantly from baseline to one year despite falls in clinical measures of inflammation including erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and swollen joint count (p < 0.01 for all). Baseline findings that predicted carpal MRI erosions at one year included a total MRI score of 6 or greater (sensitivity: 93.3%, specificity 81.8%, positive predictive value 93.3%, p = 0.000007), MRI bone oedema (OR = 6.47, p < 0.001), MRI synovitis (OR = 2.14, p = 0.003), and pain score (p = 0.01). Radiological erosions at one year were predicted by a total MRI score at baseline of greater than 13 (OR = 12.4, p = 0.002), the presence of MRI erosions (OR = 11.6, p = 0.005), and the ESR (p = 0.02). If MRI erosions were absent at baseline and the total MRI score was low, radiological erosions were highly unlikely to develop by one year (negative predictive value 0.91 and 0.92 respectively). No association was found between the shared epitope and erosions on MRI (p = 0.4) or radiography (p = 1.0) at one year. CONCLUSIONS: MRI scans of the dominant wrist are useful in predicting MRI and radiological erosions in early RA and may indicate the patients that should be managed aggressively. Discordance has been demonstrated between clinical improvement and progression of MRI erosion scores.

Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset.

OBJECTIVES: To evaluate the role of magnetic resonance imaging (MRI) of the wrist in detecting early joint damage in patients with rheumatoid arthritis (RA). METHODS: MRI was performed on 42 patients with early RA (median symptom duration of four months). Scans were scored separately by two musculoskeletal radiologists using a newly devised scoring system, which was validated. MRI findings were compared with plain radiography, clinical measures, and HLA-DRB*01/04 genotyping. RESULTS: Interobserver reliability for the overall MRI score was high (r = 0.81) as was intraobserver reliability (r = 0.94 for observer 1 and 0.81 for observer 2). There was more variation in scoring synovitis (interobserver reliability: r = 0.74). Erosions were detected in 45% of scans (19 of 42), compared with 15% of plain radiographs. The most common site for erosions was the capitate (39%), for synovitis the ulnar aspect of the radiocarpal joint, and for tendonitis, the extensor carpi ulnaris tendon. The total MRI score and MRI synovitis score correlated most significantly with C reactive protein (r = 0.40 and 0.42 respectively, p < 0.01). The MRI erosion score was highly correlated with MRI bone marrow oedema (r = 0.83) as well as the Ritchie score and disease activity score (r = 0.32, p < 0.05). HLA-DRB1*04 or *01 (shared epitope +ve) was found in 76% of patients; 84% of those with MRI erosions and 69% of those without (NS, p = 0.3). CONCLUSIONS: A high proportion of RA patients develop MRI erosions very early in their disease, when plain radiography is frequently normal. MRI of the dominant wrist may identify those requiring early aggressive treatment.

Expression of the interleukin 6 gene in rheumatoid synovial fibroblasts.

A number of fibroblastoid synovial cell lines have been established from rheumatoid joints. These cell lines were shown to express the interleukin 6 (IL-6) gene constitutively, and exposure of these cells to 5 ng/ml of recombinant human interleukin 1 beta (IL-1 beta) increased IL-6 gene expression. Other recombinant human lymphokines, namely interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor had no enhancing effect on IL-6 gene expression. Dexamethasone added to the cultures at 10(-7) M concentration suppressed the constitutive expression of the IL-6 gene. At a concentration of 10(-5) M, dexamethasone partially suppressed the IL-1 enhanced expression of IL-6. The IL-6 gene probe also hybridized to RNA from unfractionated synovial fluid cells, peripheral blood T cells and non-T cells but not Epstein-Barr virus transformed peripheral blood B cells of patients with rheumatoid arthritis. Our results suggest that in rheumatoid arthritis, synovial fibroblasts actively participate in joint inflammation by lymphokine production. The coexpression of both IL-1 and IL-6 by one synovial fibroblast line suggests a mechanism for the perpetuation of synovitis.

B cell lymphokines in human systemic lupus erythematosus.

B lymphocytes of patients with systemic lupus erythematosus were studied to determine if they were intrinsically hyperresponsive to lymphokine mediators. Peripheral blood B cells from 25 lupus patients and 16 normal individuals matched for age and sex were cultured with recombinant lymphokines. B cells both from patients and normal subjects did not show increased [3H]thymidine uptake when cultured with interleukins 1, 2, and 4. The addition of Staphylococcus aureus Cowan I as costimulant increased [3H]thymidine uptake by B cells of patients and normal subjects. In the absence of T cells these recombinant lymphokines did not increase in vitro IgG or IgM production by lupus or normal B cells. Other recombinant lymphokines, interleukin 3, interferon gamma, lymphotoxin, tumour necrosis factor, and colony stimulating factors for granulocytes and macrophages were tested on lymphocytes from smaller numbers of patients and controls. Most patients in this study had inactive disease and all data suggested that B cells from patients with inactive lupus were not hyperresponsive to the lymphokines tested. In addition, the use of lymphokine gene probes for interleukins 2, 3, and 4 did not show spontaneous expression of these genes in circulating lymphocytes.

Effects of aminobisphosphonate infusion on biochemical indices of bone metabolism in rheumatoid arthritis.

In a phase 1 study, seven patients with classical rheumatoid arthritis were treated with intravenous 3-amino-1-hydroxypropylidene-1-1-bisphosphonate (APD). Following this treatment, bone resorption as measured by fasting urine calcium/creatinine and hydroxyproline/creatinine ratios, was reduced. This was sustained for 6 months in only three patients. Elevations of these ratios often coincided with flares of active arthritis in the remaining four patients. Bone turnover as measured by serum osteocalcin levels was reduced in all patients but serum alkaline phosphatase levels remained unchanged. There was no consistent improvement in clinical indices of disease activity.

The removal of phosphorus during wastewater treatment: a review.

Phosphorus removal from wastewater can be achieved either through chemical removal, advanced biological treatment or a combination of both. The chemical removal of phosphorus involves the addition of calcium, iron and aluminium salts to achieve phosphorus precipitation by various mechanisms which are discussed. In addition, the effects of operating conditions, especially wastewater characteristics; sludge production in terms of quality and quantity; optimisation of chemical use and re-use; points of chemical addition combined with biological treatment; alternative chemical/physical treatments and examples of full-scale applications are also reviewed. Biological phosphorus removal is dependent upon the uptake of phosphorus in excess of normal bacterial metabolic requirements and is proposed as an alternative to chemical treatment. Early developments and the postulated removal mechanisms are reviewed; these include either natural chemical precipitation, enhanced biological removal, or a combination of both. The nature of excess biological phosphorus removal in activated sludge wastewater treatment plants is evaluated, considering various operating parameters, bacteriology and process designs.

Biotechnology for phosphorus removal during wastewater treatment.

Advanced biological wastewater treatment for the removal of phosphorus in excess of the normal metabolic requirements of activated sludge type processes has been developed as an alternative to chemical addition. Current laboratory and pilot plant investigations have confirmed that a preliminary anaerobic zone and plug-flow type configuration are necessary for good enhanced biological phosphorus removal. Nitrate in the anaerobic stage inhibits the process whereas acetate enhances phosphorus uptake. The bacteria probably responsible are of the Acinetobacter genus and the presence of stored polyphosphate within these bacteria has been demonstrated. It has also been shown that pure cultures of Acinetobacter do not necessarily take up soluble substrate as phosphate is released during the anaerobic phase, in contrast to the current proposed mechanism, and that in certain cases natural chemical precipitation could make a significant contribution towards overall phosphorus removal. Several studies of pilot and full-scale plants have been reported.