Serum interleukin-6 and thyroid hormones in rheumatoid arthritis.

Using rheumatoid arthritis (RA) as a model, we have investigated whether the activation of the cytokine system, in particular, activation of interleukin (IL)-6 production, is a major cause of the depressed serum T(3) seen frequently in the nonthyroidal illness syndrome (NTIS). RA was chosen because it is a chronic autoimmune disease leading to increased serum IL-6 concentrations. We studied 16 untreated RA and 35 treated RA patients. Twenty-seven treated and 27 untreated patients with noninflammatory musculoskeletal symptoms served as controls. The patient groups displayed similar age distribution and nutritional status. Untreated RA patients displayed elevations of serum IL-6 (mean, 37.5 pg/mL) and C-reactive protein (CRP; mean, 41.3 mg/L), consistent with the inflammatory nature of their disease. Treated RA patients had significantly reduced serum IL-6 (mean, 9.9 pg/mL) and CRP (mean, 13.3 mg/L) compared with untreated RA patients, while untreated and treated patients with noninflammatory musculoskeletal symptoms had near normal serum IL-6 (mean, 2.5, 6.6 pg/mL, respectively) and CRP levels (mean, 5.8, 8.1 mg/L, respectively). However, there were no significant differences in serum concentrations of free T(3) (FT(3)) and free T(4) (FT(4)) between groups, and thyroid indices were in the normal range in RA patients. Moreover, no significant correlations between serum concentration of IL-6 and any of the thyroid hormones were demonstrated for any of the patient groups. In conclusion, we have been unable to confirm in RA that IL-6 activation leads to the low T(3) state of NTIS.

Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis.

We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.

South Australian Scleroderma Register: analysis of deceased patients.

The demographic, clinical, pathological and serological features of 123 decreased patients with systemic sclerosis have been analysed. These patients consisted of all identified patients dying with this disease in South Australia between 1983 and 1996 inclusive. There were 85 females and 38 males, with the ratio of limited:diffuse:overlap disease subset being 9:5:1. Disease characteristics revealed that patients with the limited disease tended to be female with high frequencies of the centromere autoantibody, while patients with the diffuse disease had equal gender representation with the frequent presence of nucleolar, speckled or homogeneous antinuclear antibody. Mean duration of disease and mean age of death for the limited:diffuse:overlap subsets differed significantly between groups (p < 0.05) and were 16.5, 9.3 and 10.9 years and 71.9, 57.8 and 52.8 years respectively. Cumulative survival curves for the subsets differed highly significantly, with patients with the limited diseases dying more commonly from right heart failure (documented terminally in 25% of the centromere positive limited subset), cardiovascular disease or cancer, while patients with the diffuse subset died from respiratory failure, renal failure or cardiovascular disease. In conclusion, this retrospective analysis has revealed that scleroderma is a relatively common but clinically heterogeneous disorder. There are important clinical and prognostic implications in defining limited versus diffuse versus overlap disease.

Synovectomy of the elbow and radial head excision in rheumatoid arthritis. Predictive factors and long-term outcome.

We carried out a survival analysis of elbow synovectomy (ES) and excision of the radial head (RHE) performed on 171 rheumatoid elbows. The failure criteria were revision surgery (performed or desired) and/or the presence of significant or severe pain. The cumulative survival was 81% at one year which thereafter decreased by an average of 2.6% per year. The strongest predictor for success was a low preoperative range of supination-pronation when corresponding survival curves were compared. A low range of flexion-extension also predicted failure. Combining both factors gave better prediction (failure: 6.3% v 67%), but a long duration of elbow symptoms before surgery predicted failure (72%, p = 0.04). At review, there was a mean gain of 50 degrees in supination-pronation and 11 degrees in flexion-extension; both correlated with success. Failure correlated with recurrence of synovitis, elbow instability, ulnar neuropathy, poor general mobility and poor upper-limb function. The last was independently affected by the severity of RA in the ipsilateral shoulder. Our findings show that although the short-term result of ES and RHE in rheumatoid arthritis is good, the long-term outcome is poor except in a subgroup with more than 50% limitation of forearm rotation.

Osteoporosis screening in people with airways disease.

We tested associations between risk factors and bone mineral density in airways disease subjects, and developed a clinical screening tool to identify people who could benefit from bone mineral density testing. Subjects were recruited through hospital outpatients and pharmacies (Newcastle, n = 172). With survey refinement, we then tested a revised tool in a second sample (Adelaide, n = 317). Study factors included oral/inhaled corticosteroid use, asthma severity, respiratory admissions, physical activity, percent predicted forced expiratory volume in one second (FEV1), body mass index, and smoking history. Outcomes were bone mineral density of lumbar vertebra (L2-4) and total (or neck of) femur. Analysis was logistic regression with generation of a simple screening algorithm based upon coefficients. Scoring algorithm risk factors for T-score of < - 2.0: age > or = 68 = 10 points, bone mineral density < 20 = 25, weight < 60 kg = 20, 60-69 kg = 10, > or = 80 cigarette pack years = 15, low-level leisure activity = 5, area under receiver operator curve 0.83. For a cut-off score of 10, sensitivity was 91.2%, specificity 53.9%, positive and negative predictive values 52.3 and 91.7%, and 67.2% were correctly classified. In conclusions, our model has acceptable sensitivity, although limited specificity. Use of this tool may reduce unnecessary referrals for bone mineral density measurement.

Susceptibility to rheumatoid arthritis is not associated with a single common allele of the type 2 collagen gene (COL2A1)

Type 2 collagen is quantitatively the most important constituent of articular cartilage which is the target of progressive destruction in RA. Polymorphism of type 2 collagen could theoretically influence the development of RA either by rendering the cartilage matrix particularly susceptible to autoimmune attack or subsequent degradation. We have investigated the possibility that there is a common allele of type 2 collagen associated with RA by analysing a dimorphism of the corresponding structural gene (COL2A1) in healthy and diseased individuals. We compared haplotype frequencies, defined by the presence or absence of a Hind III restriction site at the COL2A1 locus (encoding type 2 collagen), in 98 patients with classical/definite RA and 158 controls. No differences were seen between the frequencies of individual genotypes in the two groups (maximum chi 2 = 0.7), indicating that susceptibility to this disease does not appear to be determined by the presence of a single common allelic variant at this locus.

Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?

There is a polygenic component to rheumatoid arthritis (RA) in addition to the known association with HLA-DR4. It has previously been shown in another autoimmune disease (type I diabetes mellitus) that a gene on chromosome 11p can act with HLA-DR4 to enhance susceptibility (relative risk 5-6). It is therefore possible that this locus may also affect the development of RA. Genotype frequencies at this locus, defined by a dimorphic Fok 1 restriction site, were compared in 139 healthy controls and 213 patients with classical/definite RA. In contrast with diabetes there was no increase in genotypes lacking the Fok 1 site, either in the rheumatoid group overall (125/211 compared with 86/139 controls) or in the DR4 positive rheumatoid group (76/140 compared with controls). These results indicate that the interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune diseases.

Polyarteritis associated with Yersinia enterocolitica infection.

A patient developed polyarteritis, predominantly affecting the muscles, 10 days after a Yersinia enterocolitica O:3 infection. Immunoperoxidase staining showed Yersinia enterocolitica O:3 antigen in the subendothelial layer of the blood vessels. This suggests that vasculitis should be considered as a rare manifestation of Yersinia enterocolitica infection.

Scleroderma with bilateral synovial fistulae.

Synovial fistulae developed in an elderly man with rapidly progressive scleroderma. We describe this case and review the literature on synovial fistulae.

Evaluation of hand function in patients undergoing long term haemodialysis.

OBJECTIVE: Haemodialysis is associated with the deposition of beta(2) microglobulin in musculoskeletal structures, leading to the syndrome of dialysis related amyloidosis and impairment of hand function. This study aimed at assessing hand function using the Sollerman test in a cross section of patients undergoing haemodialysis. METHODS: Recipients of haemodialysis underwent the Sollerman test of hand grip function, which assesses 20 activities of daily living using eight grip types, and the JAMAR grip strength test, visual analogue scales (VAS) for pain (VAS-P) and function (VAS-F), and Health Assessment Questionnaire (HAQ) were determined. Results-Thirty five subjects (26 male), with mean age 53.2 years, participated. The average duration of haemodialysis was 6.2 years (range one month to 25 years). The median Sollerman score was 77, with 19/35 (54%) patients receiving haemodialysis having a score below the lower normal value of 78-80. The log Sollerman score correlated poorly with age (rs=0.16, p=0.35), and significantly with the HAQ score (r(s)=-0.66, p<0.00005), duration of haemodialysis (rs=-0.39, p<0.05), VAS-F (rs=-0.41, p<0.05), VAS-P (rs=-0.34, p<0.05), and JAMAR score (rs=0.57, p<0.05). Sollerman scores were highly correlated between dominant and non-dominant hands (rs=0.69, p<000005). CONCLUSIONS: Hand dysfunction is a common finding among patients undergoing long term haemodialysis. The Sollerman test accurately reflects patient function as measured by HAQ, VAS-F, and grip strength, but less so pain. Its use for the early detection of dialysis related amyloidosis and in the serial monitoring of the effects of hand treatment programmes is encouraged.

Neurological side effects in two patients receiving gold injections for rheumatoid arthritis.

We describe two patients who developed neurological side effects as part of the spectrum of nitritoid reactions. Both reactions occurred late in the course of treatment. The first patient developed mild nitritoid symptoms and pain in a band-like distribution, corresponding to T10-T12 dermatomes, shortly after gold sodium thiomalate (GSTM) injection. Further injections were followed by similar symptoms in addition to paraesthesiae and altered pin-prick sensation of anterior thigh and legs with no residual deficit. She has had no further episodes since substitution of aurothioglucose. The second patient experienced mild nitritoid symptoms following several GSTM injections prior experiencing a cerebrovascular accident within several hours of her next injection. She subsequently haemorrhaged into the infarcted area with residual neurological deficits. These cases highlight that nitritoid reactions can be severe and may be heralded by milder symptoms. Patients who develop these reactions whilst receiving GSTM can be successfully changed to aurothioglucose.

The clinical associations of mitotic spindle autoantibodies in a South Australian cohort.

BACKGROUND: The mitotic spindle apparatus (MSA) is a unique structure of microtubules and associated proteins involved in the segregation and reorganisation of chromosomes during cell division. Autoantibodies to the MSA (anti-MSA) are reported to occur rarely, but are easily identified during the immunofluorescent detection of anti-nuclear antibodies (ANA), and are generally reported as part of that investigation. AIMS: As the clinical significance of these antibodies is unknown, our aim was to identify the clinical features of subjects identified with anti-MSA, and in a subset investigate the co-association with organ specific anti-thyroid antibodies. METHODS: All ANA results from the three major immunology laboratories serving South Australia between January 1993 and June 1998 were retrospectively reviewed to identify anti-MSA subjects. Clinical details were extracted from hospital or general practice records using a standard proforma. Thyroid autoantibodies were measured using standard technique. A control group of consecutive ANA positive, anti-MSA negative individuals had anti-thyroid antibodies measured. Statistical comparison used chi2 test. RESULTS: Fifty-five subjects (43F) were identified with mean age 59.8 (range 17-91); 39 had specific diagnoses, with 16 identified as part of non-specific investigations. 'Arthritis' broadly accounted for the largest group, transient inflammatory arthritis n=7, degenerative joint disease n=6, rheumatoid arthritis n=5. Adenocarcinoma and mesothelioma accounted for one case each. Thirty-two subjects had anti-thyroid antibodies tested, with ten of 21 and two of 11 positive among the groups with anti-MSA titre >1:80 and <1:40 respectively, chi2=2.7, p=0.1. Anti-thyroid antibodies were detected more frequently among the high titre anti-MSA group (ten of 21) compared with high titre positive ANA, negative anti-MSA group (two of 11), RRisk 4.4, chi2=5.34, p=0.02. CONCLUSION: This study confirmed the relative rarity of anti-MSA and that its association is primarily with rheumatic diseases. The coincidence of mesothelioma is novel with only two previous reports of malignancy and anti-MSA. The co-association of high titre anti-MSA and thyroid autoantibodies suggest that the latter should be a follow up investigation if the former is identified as part of an investigative screen.

Analysis of a T-cell receptor V beta segment implicated in susceptibility to rheumatoid arthritis: V beta 2 germline polymorphism does not encode susceptibility.

OBJECTIVES: The assessment of allelic polymorphism of the T cell receptor gene segment, TCRBV2S1, in rheumatoid arthritis. METHODS: A total of 136 patients with rheumatoid arthritis (RA) (ACR criteria) and 150 controls were TCRBV2S1 genotyped using a nested PCR amplification strategy followed by single-strand conformation polymorphism (SSCP) analysis. RESULTS: The SSCP typing method detected two previously unknown alleles of the TCRBV2S1 gene segment. The TCRBV2S1 allele, genotype and inferred phenotype frequencies were similar in the RA patients and controls. No differences were apparent after the RA patients had been partitioned according to their HLA-DR genotypes. CONCLUSIONS: SSCP analysis is a rapid and efficient method of typing T cell receptor germline polymorphisms. Allelic polymorphism of the T cell receptor variable segment, TCRBV2S1, does not influence susceptibility to RA.

Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami.

OBJECTIVE: To determine whether regional cerebral blood flow (rCBF) is abnormal in any cerebral structure of women with fibromyalgia (FM), following a report that rCBF is reduced in the thalami and heads of caudate nuclei in FM. METHODS: Seventeen women with FM and 22 healthy women had a resting single-photon-emission computed tomography (SPECT) brain scan to assess rCBF and a T1-weighted magnetic resonance imaging (MRI) scan to enable precise anatomic localization. Additionally, all participants underwent 2 manual tender point examinations and completed a set of questionnaires evaluating clinical features. SPECT scans were analyzed for differences in rCBF between groups using statistical parametric mapping (SPM) and regions of interest (ROIs) manually drawn on coregistered MRI. RESULTS: Compared with control subjects, the rCBF in FM patients was significantly reduced in the right thalamus (P = 0.006), but not in the left thalamus or head of either caudate nucleus. SPM analysis indicated a statistically significant reduction in rCBF in the inferior pontine tegmentum (corrected P = 0.006 at the cluster level and corrected P = 0.023 for voxel of maximal significance), with consistent findings from ROI analysis (P = 0.003). SPM also detected a reduction in rCBF on the perimeter of the right lentiform nucleus. No correlations were found with clinical features or indices of pain threshold. CONCLUSION: Our finding of a reduction in thalamic rCBF is consistent with findings of functional brain imaging studies of other chronic clinical pain syndromes, while our finding of reduced pontine tegmental rCBF is new. The pathophysiologic significance of these changes in FM remains to be elucidated.

Validation of fully automatic brain SPET to MR co-registration.

Fully automatic co-registration of functional to anatomical brain images using information intrinsic to the scans has been validated in a clinical setting for positron emission tomography (PET), but not for single-photon emission tomography (SPET). In this paper we evaluate technetium-99m hexamethylpropylene amine oxime to magnetic resonance (MR) co-registration for five fully automatic methods. We attached six small fiducial markers, visible in both SPET and MR, to the skin of 13 subjects. No increase in the radius of SPET acquisition was necessary. Distortion of the fiducial marker distribution observed in the SPET and MR studies was characterised by a measure independent of registration and three subjects were excluded on the basis of excessive distortion. The location of each fiducial marker was determined in each modality to sub-pixel precision and the inter-modality distance was averaged over all markers to give a fiducial registration error (FRE). The component of FRE excluding the variability inherent in the validation method was estimated by computing the error transformation between the arrays of MR marker locations and registered SPET marker locations. When applied to the fiducial marker locations this yielded the surface registration error (SRE), and when applied to a representative set of locations within the brain it yielded the intrinsic registration error (IRE). For the best method, mean IRE was 1.2 mm, SRE 1.5 mm and FRE 2.4 mm (with corresponding maxima of 3.3, 4.3 and 5.0 mm). All methods yielded a mean IRE <3 mm. The accuracy of the most accurate fully automatic SPET to MR co-registration was comparable with that published for PET to MR. With high standards of calibration and instrumentation, intra-subject cerebral SPET to MR registration accuracy of <2 mm is attainable.

Immunoglobulin kappa light chain gene alleles are not associated with primary Sjögren's syndrome.

The immunoglobulin kappa (Km) light chain gene is polymorphic and is believed to play a role in the pathology of infectious and autoimmune diseases. Polymorphisms within the constant region of the Km gene encode three alleles designated Km1, Km1,2 and Km3. Previous studies using serological detection of Km allotypes reported associations between specific Km allotypes, systemic lupus erythematosus and the presence of anti-La antibodies, yet these findings were not confirmed in other studies. In order to more precisely define any associations between Km alleles and anti-Ro/La antibodies we used the polymerase chain reaction and restriction fragment length polymorphisms for Km genotyping in a large cohort of patients with primary Sjögren's syndrome (SS). No associations were observed between specific Km alleles and primary SS when compared with a control population, nor within serologically defined subsets of SS patients. We conclude that Km alleles are not associated with primary SS or the Ro/La autoantibody response.

HLA class II antigens associated with systemic lupus erythematosus in black South Africans.

OBJECTIVE: To assess the associations of HLA class II antigens with systemic lupus erythematosus (SLE) in black South Africans. METHODS: HLA-DRB1 genotype frequencies assigned by polymerase chain reaction (PCR) amplification and sequence specific oligonucleotide probes were compared between 49 black SLE patients from Baragwanath Hospital and 87 ethnically matched controls. HLA-DQA1 and -DQB1 genotypes were also assigned in 45 of the SLE patients and 74 controls by PCR using sequence specific primers. RESULTS: HLA-DRB1*02 was increased in the patients compared with controls (odds ratio = 3.67; 95% confidence interval = 1.49 to 9.02; p < 0.005). HLA-DQB1*0201 was not associated with development of the disease itself, but was associated with the presence of Ro antibodies (p = 0.01). HLA-DRB1*03 was less strongly linked to DQB1*02 in this population than in white populations and was not associated with SLE. CONCLUSIONS: In black South Africans there is evidence for a locus on DR2 haplotypes contributing to SLE. Another gene, possibly HLA-DQB1*02, not linked to DR2 is involved in the subset of patients exhibiting Ro antibodies.

Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes.

The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.