Studies on the relative effects of prostaglandins, bradykinin, 5-hydroxytryptamine and histamine on the synovial microcirculation in dogs.

1 The relative effects of prostaglandins E1, E2, F1alpha, F2alpha, bradykinin, histamine and 5-hydroxytryptamine (5-HT) on the canine synovial microcirculation were investigated using the rate of clearance of radioactive xenon (133Xe) as an index of synovial perfusion. 2 All the compounds tested, except prostaglandin F1alpha, produced a vasodilator effect. The descending order of potency of the active compounds was (i) prostaglandin E1, (ii) prostaglandin E2 and bradykinin, (iii) histamine and 5-HT, (iv) prostaglandin F2alpha. The most potent compound tested, prostaglandin E1 produced an effect in nanogram amounts in each joint. 3 Prostaglandin F2alpha has been reported to have an anti-inflammatory action; however no evidence was found of antagonism of prostaglandin E1 by two dose levels of prostaglandin F2alpha. 4 Preliminary studies showed that threshold doses of prostaglandin E1 did not potentiate the vasodilator action of threshold or sub-threshold doses of bradykinin in the dog synovium.

The effects of prostaglandin E1, bradykinin and histamine on canine synovial vascular permeability.

1 The relative effects of prostaglandin E1, bradykinin and histamine on canine synovial vascular permeability were investigated by a method based on the measurement of the amounts of radiolabelled dextran (molecular weight 20,000) leaking from the circulation into the synovial cavity. 2 Bradykinin, prostaglandin E1 and histamine in that order of potency all increased synovial vascular permeability. Threshold concentrations were 0.3 micrometer, 3 micrometer and 30 micrometer respectively. 3 The effects of infusion of prostaglandin E1 combined with either bradykinin or histamine were greater than mere summation.

Lack of association between DQ A and DX A polymorphisms with rheumatoid arthritis and Felty's syndrome.

DQ A and DX A RFLPs were studied in DR4-positive rheumatoid arthritis, Felty's syndrome, and in DR4-positive control subjects, and in the light of the previously documented association between Felty's syndrome and the DQ B 3.1 allele (3b RFLP). In these DR4-positive subjects there were no preferential associations between DQ A or DX A polymorphisms and rheumatoid arthritis or Felty's syndrome and no evidence for unusual DQ A-B haplotypic associations in Felty's or rheumatoid subjects.

Lack of association of the alpha-1-antitrypsin PIZ allele with rheumatoid arthritis or with its extra articular complications.

PIZ allele frequencies were defined by PCR amplification and hybridization using a PIZ SSO (sequence specific oligonucleotide) probe. The groups studied included 64 normal controls, 104 subjects with rheumatoid arthritis (RA) without any extra-articular features, 29 of whom had severe arthritis and 31 of whom had mild RA. The extra-articular subsets include 41 with RA-bronchiectasis (RA-BR), 21 with bronchiectasis without RA (BR), and 23 with RA and pulmonary fibrosis (RA-PF). Fifteen RA subjects with obstructive airways disease (RA-OAD) were compared to 25 RA patients with normal lung function tests. Using Fishers' exact test and chi-squared statistical analysis with Yates correction, no statistically significant associations were found between PIZ and any of the groups studied. Thus in this population there is no evidence that PIZ either increases susceptibility to rheumatoid arthritis or affects the risk of pulmonary complications or the severity of arthritis in subjects with rheumatoid arthritis.

Are major histocompatibility system class III products independent markers for susceptibility to rheumatoid arthritis?

Three components of the complement pathway C2, Factor B, and C4 are coded for by four genes C2, Bf, C4A, and C4B in the class III region of the major histocompatibility system in man. Studies of the polymorphism of these plasma proteins have shown associations of BfS, C2C, and C4B3 (2.9) with RA. Family studies have shown that these markers occur together, usually on DR4 positive haplotypes and in particular on the A2-Cw3-Bw62-C4B3-C4A3-BfS-C2C-DR4 haplotype. It is argued that Class III gene products are unlikely to be independent markers of susceptibility to RA.

Rheumatoid arthritis: inheritance and association with other autoimmune diseases.

This paper reviews the significance of the associations between rheumatoid arthritis (RA) and both diabetes mellitus and autoimmune thyroid disorders (ATD). All three disorders are thought to result from an interaction between genetic susceptibility and environmental factors. There is a probable real but not dramatic aggregation of insulin-dependent diabetes mellitus (IDDM) in the families of RA probands and a significant aggregation of ATD in both first- and second-degree relatives of RA probands. HLA-linked genes predispose to all three disorders while genes linked to Gm have been implicated in predisposition to RA and ATD. Within the HLA region two or more genes may predispose independently to RA; one of these genes is in linkage disequilibrium with HLA-DR4 and a second is in linkage disequilibrium with DR1 and 3. The familial aggregation of RA and IDDM is at least partially attributable to a single gene linked to HLA-DR4 predisposing to both disorders. By contrast, although 'DR4 negative RA' seems more frequent in sibships containing members with ATD, the familial aggregation of RA and ATD cannot be accounted for by a single gene linked to HLA predisposing to both disorders. Neither can this familial aggregation be accounted for by a single gene linked to Gm predisposing to RA and ATD so that any genetic predisposition common to both disorders is likely to involve at least a third locus which is still to be defined. A simple model with an interaction between at least three independent genetic loci and genetic heterogeneity is proposed to account for the known facts concerning the genetic susceptibility to RA.

C3, Gm, and Pi polymorphisms in rheumatoid arthritis.

This paper reviews the associations between RA and three non-MHS genetic markers: C3, Gm, and Pi. There is no evidence to suggest that genes linked to C3 predispose to RA. However, there is evidence to suggest that genes on chromosome 14, linked to both Gm and Pi, do influence susceptibility to RA and further studies of this chromosome are indicated.

X-chromosome inactivation in monozygotic twins with systemic lupus erythematosus.

The hypothesis that a low concordance rate in monozygotic (MZ) twins with systemic lupus erythematosus (SLE) may be accounted for by differences in X-chromosome inactivation was examined. Five MZ twin pairs, four discordant and one concordant, were recruited, zygosity confirmed by DNA fingerprinting, and their pattern of X-chromosome inactivation in DNA samples prepared from peripheral blood and buccal cells were examined. X-chromosome inactivation was assessed by the methylation status of the CpG region near trinucleotide repeats in exon 1 of the androgen receptor gene on X-chromosome after digestion with the methylation-sensitive enzyme HpaII or HhaI and PCR amplification. X-chromosome inactivation patterns were found to be the same between affected and non-affected twins in all four discordant twin pairs, with random patterns in two pairs and skewed patterns in the others. The concordant twins demonstrated the same random patterns. X-chromosome inactivation was also examined from buccal smear DNA and shown to have the same pattern as that noted from peripheral blood DNA in one informative twin pair. Differences in X-chromosome inactivation patterns were not observed in these five MZ twin pairs. The results could not support the hypothesis that differences in X-chromosome inactivation is the mechanism accounting for the low concordance rate noted in MZ twins with SLE.

HLA-DPA1 and HLA-DPB1 in rheumatoid arthritis and its subsets.

The aim of this study was to examine the relationship between HLA-DP and susceptibility to articular and extra-articular features (Felty's syndrome and vasculitis) of rheumatoid arthritis (RA). The possible association of DP types with severity of articular disease was also analysed. No statistically significant associations were observed between HLA-DP alleles and articular or extra-articular features of RA, or to the severity of the arthritis when p was corrected for the number of alleles tested.

DNA variants of alpha-1-antitrypsin in rheumatoid arthritis with and without pulmonary complications.

Restriction fragment length polymorphisms (RFLPs) of alpha-1-antitrypsin were studied in 99 subjects with rheumatoid arthritis alone, 21 subjects with rheumatoid arthritis and pulmonary fibrosis, 26 subjects with rheumatoid arthritis and bronchiectasis, and 86 controls. No associations with either rheumatoid arthritis itself or with the associated pulmonary disorders were noted in this U.K. Caucasoid population.

Interactive effect of HLA and Gm and genetic heterogeneity tested in 79 rheumatoid arthritis families.

The hypothesis that there is an interactive effect between HLA and Gm genes in rheumatoid arthritis (RA) was tested in a sample of 79 RA families. An analysis, of the joint segregation of these two markers in RA sibpairs, confirmed the previously described effect of HLA in RA but did not provide evidence of an independent effect of Gm alone or in interaction with HLA. The additional hypothesis that the previously described correlation between RA and autoimmune thyroid disease is due to genetic factors, was also investigated in relation to HLA and Gm. Therefore, we examined the segregation of HLA and Gm in RA sibships depending on the presence or the absence of autoimmune thyroid disorder. This analysis showed significant heterogeneity in HLA segregation (P = 0.02) with an HLA effect restricted only to sibships without thyroid disease. There was no evidence that thyroid disease influenced Gm segregation (P = 0.19). The effect of thyroid disease on HLA segregation suggests that the familial association between RA and autoimmune thyroid disease is at least partially due to genetic factors.

Family and twin studies in systemic lupus erythematosus.

We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.

Fenbufen compared with indomethacin in osteoarthrosis.

A double-blind, crossover clinical trial was carried out with a new propionic acid derivative, fenbufen, versus indomethacin and placebo in 20 patients with osteoarthrosis. Active drug dosages of 75 mg indomethacin daily and 600 mg fenbufen daily were used. Fenbufen scored significantly better than placebo with respect to two and indomethacin better than placebo with respect to five of the assessment indices used. Indomethacin was significantly better than fenbufen with respect to two indices and, overall, appeared more effective in the dosages tested. Biochemical abnormalities of liver function (serum alkaline phosphatase and/or SGOT) were noted in 5 patients after fenbufen therapy (in 3 patients after 4-weeks' treatment and in 2 after 6 weeks) but in none after indomethacin therapy. The significance of these findings is discussed. It is concluded that fenbufen should be withdrawn from further clinical use until the true incidence and significance of hepatotoxicity has been evaluated.

Clinical assessment of azapropazone in rheumatoid arthritis.

Azapropazone was investigated in a 2-week double-blind clinical out-patient trial against placebo in 23 patients with definite rheumatoid arthritis. The drug was given at a dose of 1200 mg. per day before food. At this dose level the drug was shown to have an antirheumatic effect in terms of pain relief, articular tenderness and duration of morning stiffness.

Comparison of azapropazone and naproxen in rheumatoid arthritis.

A double-blind crossover trial was carried out in 15 patients with definite rheumatoid arthritis to compare the effectiveness of 1200 mg azapropazone daily and 750 mg naproxen daily, each drug being given for 2 weeks. Patients also received placebo therapy before and between the two treatment periods. The results of subjective and objective assessments showed that both drugs were significantly superior to placebo, but no significant difference could be demonstrated between the two drugs.

Clinical evaluation of two daily doses of naproxen and indomethacin: result of a double-blind crossover trail.

A double-blind crossover clinical trial is reported on the effects of naproxen in two doses, 500 mg. and 750 mg. daily, and 100 mg. indomethacin daily in 23 patients with classical rheumatoid arthritis, each drug being given for 1 week. The results show that there was little to choose between the drugs and that there was clinical equivalence between the two doses of naproxen. Radioactive pertechnetate (99mTc) joint uptakes were depressed by both naproxen and indomethacin, indicating anti-inflammatory effect.

Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis.

A retrospective study is reported of 160 patients with definite or classical rheumatoid arthritis, in which changes in haemoglobin concentration were analysed against changes in various routine clinical and laboratory indices of disease activity over a period of time. Although statistically significant correlations were found between haemoglobin concentrations and the articular index of joint tenderness, serum albumin concentration, and erythrocyte sedimentation rate at one point in time, significant relationships in changes in haemoglobin concentration were only found with changes in the latter two laboratory indices. The significant correlations were weak and less important than the cumulative effect of unknown variables in determining haemoglobin level. The study shows that the routine clinical and laboratory parameters of disease activity in rheumatoid arthritis are of no value in predicting the haemoglobin concentration.

A single-blind crossover trial of the anti-inflammatory drug sodium meclofenamate and placebo, including an evaluation of hand grip and of lymphocyte responsiveness.

A single-blind crossover trial was carried out in 21 patients with active rheumatoid arthritis to assess the effectiveness and tolerance of sodium meclofenamate (300 mg per day) compared with placebo. After a 1-week washout period patients had two periods of active medication, each of 2 weeks, separated by 1 week on placebo. Morning stiffness, walking speed, pain score, patient impression of response, joint tenderness and power, work and maximum grip strength achieved by hand grip were all improved by sodium meclofenamate and an anti-inflammatory effect of the drug was demonstrated, with some reduction in the swelling of PIP joints. There was no advantage in assessing pain on full movement of the small joints of the hands in addition to direct tenderness. Power, work and rate of grip release achieved during hand grip provided more information about hand function than maximum grip strength alone. Lymphocyte transformation to non-specific mitogens was enhanced by the drug. Twelve patients had some form of gastro intestinal complaint during the study and it is suggested that diarrhoea is likely to prove to be the major limiting factor of acceptance by some patients.

TAP2D is associated with HLA-B44 and DR4 and may contribute to rheumatoid arthritis and Felty's syndrome susceptibility.

OBJECTIVES: TAP2 transporter gene polymorphisms have been ascertained in patients with rheumatoid arthritis (RA) and Felty's syndrome (FS) to determine whether particular alleles of this gene are disease associated. METHODS: TAP2 dimorphisms at amino acid positions 379, 565 and 665 were detected using ARMS-PCR in 89 RA patients, 24 FS patients and 64 control subjects. TAP 2 alleles were assigned from these results. RESULTS: The frequency of one particular allele, TAP2D, was increased in both RA (OR 2.6, 95% CI 1.2 - 5.8) and FS (OR 3.9, 95% CI 1.4 - 10.7). When individual amino acid polymorphisms were compared between patients and controls, isoleucine at position 379 (present in TAP2D and TAP2C) was significantly increased, indicating that this dimorphism itself may be associated with RA (OR 5.0, 95% CI 2.4 - 10.2) and FS (OR 5.0, 95% CI 1.91 - 3.2). DISCUSSION: The presence of TAP2D was greatly increased in HLA-B44/DR4 positive RA (83%) and FS (67%) patients. These frequencies were appreciably higher than in the HLA-B44/DR4 controls (11%), suggesting that linkage disequilibrium alone may not explain the increase in TAP2D frequency in patients and that this allele may represent an additional risk factor in these conditions.

Lateral subluxation of the atlas in rheumatoid arthritis.

Two patients with lateral subluxation of the atlas resulting from rheumatoid disease involving the upper cervical spine have been described. The deformity can be suspected on clinical grounds and in one of our two patients spinal cord damage was a sequel. Erosion of the opposing surfaces of the odontoid and lateral masses of the atlas with detachment of the transverse ligament and deeper fibres of the posterior longitudinal ligament appear to underlie this deformity. Radiological confirmation may require AP views with the head tilted to one or other side.