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.

Influence of transglutaminase treatment on some physico-chemical properties of milk.

Transglutaminase (TGase) is an enzyme that cross-links many proteins, including milk proteins. In this study, the effects of TGase on some physico-chemical properties of milk were studied. TGase-treated milk was not coagulable by rennet, which was due to failure of the primary (enzymic) stage of rennet action rather than the non-enzymic secondary phase. Dissociation of TGase-treated casein micelles by urea or sodium citrate or removal of colloidal calcium phosphate by acidification and dialysis was reduced, presumably due to the formation of cross-links between the caseins. Casein micelles in TGase-treated milks were also resistant to high pressure treatment and to hydrolysis by plasmin. Results of the present study show that milk proteins are fundamentally modified by the action of TGase, which may have applications in the manufacture of functional proteins for use as novel food ingredients.

Short communication: influence of transglutaminase on the heat stability of milk.

Skim milk powders were prepared from control and transglutaminase-treated skimmed milk. The heat stability of reconstituted transglutaminase-treated skimmed milk (9.0% total solids) was markedly increased in the pH region of minimum stability (pH 6.8 to 7.1) compared with control milk, while the heat stability of reconstituted concentrated transglutaminase-treated skimmed milk (22.5% total solids) increased progressively as a function of pH relative to control milk. The effect of transglutaminase treatment on the heat stability of skimmed milk may have commercial applications, but extensive research is necessary to gain a better understanding of the mechanism by which transglutaminase improves heat stability.

Glutathione S-transferase M1 polymorphism and lung cancer risk in African-Americans.

Glutathione S:-transferase M1 (GSTM1) can detoxify many carcinogens, including polycyclic aromatic hydrocarbons such as those from cigarette smoke. Though a number of studies have been published about the association between GSTM1 polymorphism and lung cancer, this association has received limited attention in the African-American population. We conducted a case-control study to investigate the role of GSTM1 polymorphism in the development of lung cancer in African-Americans. Specimens of DNA from 117 lung cancer cases and 120 controls were assayed for detection of GSTM1 genotype by polymerase chain reaction (PCR). The odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with homozygous deletion of the GSTM1 gene and other risk factors were estimated by logistic regression. Thirty-seven of the 117 cases (31. 6%) and 24 of the 120 controls (20.0%) had the GSTM1 null genotype; the OR was 2.10 (95% CI 1.07-4.11) after adjustment for age, gender and smoking. The association was higher for squamous cell carcinoma (OR 2.98, 95% CI 1.09-8.19) than for adenocarcinoma (OR 1.95, 95% CI 0.81-4.66). We observed a stronger association between GSTM1 null genotype and lung cancer among heavy smokers with > or =30 pack-years (OR 4.35, 95% CI 1.16-16.23). This association was also found in squamous cell carcinoma (OR 6.26, 95% CI 1.31-29.91). In the analysis combining GSTM1 polymorphism and smoking, smokers with the null genotype had high risk (OR 8.19, 95% CI 2.35-28.62) compared with non-smokers with the wild-type genotype, and the risk increased with smoking cigarette pack-years (P: = 0.0001 for trend). Our results suggest that GSTM1 polymorphism plays a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in African-Americans.

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.

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.

Chronic recurrent multifocal osteomyelitis: spinal involvement and radiological appearances.

We report a case of chronic recurrent multifocal osteomyelitis which presented as back pain in a 14-yr-old male. The full distribution of the spinal lesions was determined by MRI, which proved to be more sensitive than other imaging modalities. After 1 yr, in spite of a good symptomatic response to corticosteroid therapy, new MRI abnormalities had developed.

Bone turnover in non-steroid treated rheumatoid arthritis.

OBJECTIVE: To examine whether changes in cancellous bone turnover and resorption cavity depth contribute to bone loss in patients with non-steroid treated rheumatoid arthritis. METHODS: Iliac crest biopsies were obtained from 37 patients with non-steroid treated rheumatoid arthritis, 13 male and 24 female, aged 37-71 years. Bone turnover and resorption cavity characteristics were quantitatively assessed using semiautomated computerised techniques. RESULTS: When compared with age- and sex-matched control values, there was a significant reduction in bone formation rate at tissue level and activation frequency (P < 0.001) in the patient group. The eroded perimeter, mean and maximum eroded depth and cavity area were also significantly reduced (P < 0.01, < 0.005, < 0.01 and < 0.005 respectively). CONCLUSION: These results demonstrate low bone turnover in non-steroid treated rheumatoid arthritis and indicate that the reduced bone mass in these patients is due mainly to a negative remodelling balance.

Right and left lung perfusion: in vitro and in vivo validation with oblique-angle, velocity-encoded cine MR imaging.

Quantification of pulmonary flow is clinically important in the evaluation of both congenital and acquired heart disease. Velocity-encoded cine magnetic resonance (MR) is a promising technique for measuring velocity and volume of blood flow. The authors report validation of the accuracy of velocity-encoded cine MR for measurement of oblique-angle flow in vitro, with use of a constant-flow phantom, and in vivo, with nine healthy volunteers in whom velocities were measured separately in the main, right, and left pulmonary arteries. Findings at MR were compared with findings at Doppler echocardiography. Velocity measurements in a flow phantom with cine MR correlated well with direct measurements at Doppler echocardiography. Velocity-encoded cine MR enabled accurate and reproducible measurement of absolute blood flow in healthy subjects. Oblique-gradient flow encoding (ie, flow-encoding direction coinciding with the true direction of flow) was the method of choice for velocity measurements in the right and left pulmonary arteries.

Immunogenetic heterogeneity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets.

Genetic variants at DRB1 (Dw subtypes), DQB, and C4 loci were compared in rheumatoid disease subjects with or without the extra-articular feature of Felty's syndrome or major vasculitis. DR4 positive subjects with rheumatoid arthritis alone showed no preferential associations with DQB or Dw variants or with C4 null alleles. Felty's subjects showed associations with the DQB encoded DQw7 allele and with the C4B null allele but no preferential associations with any Dw subtype of DR4. By contrast DR4 +ve rheumatoid-vasculitic subjects showed associations with the Dw14 as well as with DQw7 and the C4A null allele. These different MHC associations in different clinical disease subsets show that rheumatoid disease is immunogenetically heterogeneous and suggest that MHC genes outside the DRB1 locus may also influence susceptibility or modify expression of the rheumatoid disease process.

Recurrent papilloedema and early onset optic atrophy in Behçet's syndrome.

Two patients with Behçet's syndrome and intracranial hypertension are reported. One developed a recurrence of papilloedema while receiving treatment but eventually made a full recovery, whereas the other developed optic atrophy within three months of onset despite treatment.

Precision of Larsen grading of radiographs in assessing progression of rheumatoid arthritis in individual patients.

A study was designed to evaluate observer variation in the assessment of radiographic deterioration of individual patients using the Larsen grading system. Radiographs of hands and feet of 52 patients were assessed by three observers. Each patient had paired films taken one year apart which were assessed together for change in score. To assess within-observer variation each set of films was read twice by all observers. The average progression was 11.6 (SD 9.0). Analysis of the source of variation showed the single observer replication SD to be 3.7 but that for different observers to be 5.5. This may be interpreted as indicating that to achieve 95% confidence of detecting a true change an increase in Larsen score of 8 is required if the same observer assesses or up to 11 if a different observer assesses.

Complement-mediated inhibition of immune precipitation in rheumatoid vasculitis.

Complement-mediated inhibition of immune precipitation (CMIP) was measured in patients with rheumatoid arthritis (RA), rheumatoid vasculitis (RA VASC), patients with skin vasculitis not associated with a systemic connective tissue disease and normal healthy controls. CMIP was impaired in 100% (14/14) of the RA vasculitic patients, 60% (12/20) of the RA patients and 22% (2/9) of the dermovasculitic patients. The degree of impairment of CMIP was significantly greater in the RA vasculitic patients compared to the non-vasculitic patients. This difference was due to the significantly lower complement levels and the presence of higher concentrations of an inhibitor of CMIP in the RA vasculitic sera. The levels of this inhibitory activity correlated significantly with IgM rheumatoid factor concentration. Serial studies in three patients with RA vasculitis treated with corticosteroids and immunosuppressive drugs showed significant clinical improvement in two patients, which was associated with improvement in CMIP, reduction in circulating immune complex levels and reduction in IgM rheumatoid factor concentrations.

Unilateral palsy of the hypoglossal nerve in a patient with tuberculosis of the first cervical vertebra.

A 26-year-old female developed a unilateral hypoglossal nerve palsy in association with tuberculosis of the first cervical vertebra. The extensive soft tissue and bony abnormalities were demonstrated only by computerized axial tomography. Involvement of the hypoglossal nerve within the skull by tuberculous granulation tissue was the most likely mechanism for the nerve palsy.

Diaphragmatic dysfunction after open heart surgery: treatment with a rocking bed.

Of 1225 patients undergoing open heart surgery over an 18-month period, 13 had diaphragmatic dysfunction due to phrenic nerve injury; 11 of these had internal mammary artery grafting. Nine had diaphragmatic dysfunction on the same side as the internal mammary artery graft side (7 bilateral and 2 unilateral) as determined by fluoroscopy during phrenic nerve stimulation. Although topical cardiac hypothermia has been the prevailing mechanism for diaphragmatic dysfunction due to phrenic nerve injury after open-heart surgery, dissection of the internal mammary artery with electrocautery, traction, or vascular compromise to the phrenic nerve, or a combination, could be additional factors. Rocking bed ventilation was instituted to facilitate passive diaphragmatic movement and airway decannulation and was continued at home until the phrenic nerve or nerves recovered. These patients were followed up clinically and with serial measurements of vital capacity, respiratory muscle strength, phrenic nerve latency, and fluoroscopy to determine recovery rate. Phrenic nerve recovery occurred from 4 to 27 months after surgery. This recovery was heralded by the patients' ability to assume the supine position without dyspnea when use of the rocking bed was discontinued. Unilateral diaphragmatic recovery was sufficient for the restoration of symptom-free supine posture.

Anticentromere antibody positive CREST syndrome associated with polyarthritis, renal impairment and mixed cryoglobulinaemia.

We describe a 63-year-old female who developed the CREST syndrome within two years. Even though she was anticentromere antibody positive, her illness followed a very aggressive course and was associated with severe polyarthritis, renal impairment, hypocomplementaemia and mixed cryoglobulinaemia.