Paul Tan

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.

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.

Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study

Background The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. Methods We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). Results DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. Conclusions Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

Peripheral blood T lymphocytes in systemic vasculitis: increased T cell receptor Vβ2 gene usage in microscopic polyarteritis

Antigen recognition by T lymphocytes is mediated by cell surface receptors. T cell specificity depends on the variable, diversity and junctional (VDJ) regions of the α and β polypeptide chains of the T cell receptor (TCR). The expression of the variable region genes of the β chain (Vβ) has been analysed to study the involvement of peripheral blood T cells in systemic vasculitis. RNA was extracted from peripheral blood lymphocytes of 12 patients with microscopic polyarteritis, 10 with Wegeners granulomatosis, six with unclassified vasculitis, and 28 healthy age‐ and sex‐matched individuals. Complementary DNA was made from RNA and amplified by the anchored polymerase chain reaction (PCR) using redundant oligonucleotide primers for the TCR Vβ genes. To determine if the dominant usage of a Vβ gene family reflected the presence of particular T cell clones, cDNA was amplified with primers for the specific Vβ gene family. The product was screened for sequence homogeneity by single‐stranded conformational polymorphism (SSCP) and cloned to sequence the adjoining TCR (Dβ)Jβ region. A significant increase in the mean percentage expression of the Vβ 2.1 gene was seen in vasculitis patients (11·4+1·0% (mean + s.e.m.)) compared with controls (6·6 + 0·6%; P < 0·003). The most marked increase was seen in microscopic polyarteritis (13·9 + 1·7%; P < 0·0001). There were also increases in the expression of Vβ3, 13 and 14 in peripheral blood of vasculitis patients compared with controls. SSCP analysis of Vβ 2.1 amplified products indicated the presence of oligoclonal bands in a smaller proportion of patients (8/27) than controls (12/28). There was no strong evidence for the conservation of the TCR Vβ 2.1 junctional region sequence data from a sample group of three patients with oligoclonal bands. Thus, a subset of patients with systemic vasculitis, particularly those with microscopic polyarteritis, have increased TCR Vβ 2.1 gene expression in their peripheral blood T cell repertoire. As superantigens binding Vβ 2.1 are postulated to activate T cells with diverse CDR3 sequences, it is proposed that a superantigen is involved in the immunopathogenesis of vasculitis.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl−1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl−1 on allopurinol ⩽300 mgd−1 and poor response as SU⩾6 mgdl−1 despite allopurinol >300 mgd−1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70–4.48), P=6.0 × 10−5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl−1 despite allopurinol >300 mgd−1.

Population study of T cell receptor Vβ gene usage in peripheral blood lymphocytes : differences in ethnic groups

The T ceil receptor (TCR) Vβ repertoire in peripheral biood lymphocytes (PBL) of a largc number of healthy individuals was analysed by quantifying Vβ‐specific mRNA using the method of anchored muitiprimer DNA ampiification and a reverse dot blot assay. Among 16 Vβ gene families examined, particular Vβ genes were noted to be unequally expressed in the PBL of 70 healthy donors. The frequently used genes belong to the Vβ4, 5, 6, 8 and 13(12) families, while Vβ 1,9 and 15 were the least frequently used gene families. This bias in gene usage was observed in all individuals. Marked deviation from the mean percentage usage was noted for some Vβ genes in individuals when their PBL were examined serially. but the common pattern of biased usage was not grossly distorted. When the TCR repertoire of different ethnic groups was examined, a lower mean frequency of Vβ 3.2 was seen in the repertoire of 19 Caucasians compared with 25 age‐matched Samoans (P< 0.003). Conversely, the expression of Vβ 5.1 and of Vβ 5.3 was higher in Caucasians than in 5 age‐matchcd Polynesians (Maoris and Samoans, P< 0.003). Considering the 20% co‐efficicnt of variation in the estimate of Vβ gene usage, our data from 70 unrelated individuals suggest that in PBL, individual variations in the TCR repertoire were superimposed upon a common biased usage of Vβ genes in the general population.

A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout

Objectives To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach. Methods A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months. In the dose escalation group, allopurinol was increased monthly until SU was <6 mg/dL. The primary endpoints were reduction in SU and adverse events (AEs). Results 183 participants (93 control, 90 dose escalation) were recruited. At baseline, mean (SD) urate was 7.15 (1.6) mg/dL and allopurinol dose 269 mg/day. 52% had CrCL<60 mL/min. Mean changes in SU at the final visit were −0.34 mg/dL in the control group and −1.5 mg/dL in the dose escalation group (p<0.001) with a mean difference of 1.2 mg/dL (95% CI 0.67 to 1.5, p<0.001). At month 12, 32% of controls and 69% in the dose escalation had SU <6 mg/dL. There were 43 serious AEs in 25 controls and 35 events in 22 dose escalation participants. Only one was considered probably related to allopurinol. Five control and five dose escalation participants died; none was considered allopurinol related. Mild elevations in LFTs were common in both groups, a few moderate increases in gamma glutamyl transferase (GGT) were noted. There was no difference in renal function changes between randomised groups. Conclusions Higher than CrCL-based doses of allopurinol can effectively lower SU to treatment target in most people with gout. Allopurinol dose escalation is well tolerated. Trial registration number: ANZCTR12611000845932; Results.

Role of miR-146a in regulation of the acute inflammatory response to monosodium urate crystals

Objectives MicroRNAs (miRNA) are small non-coding RNAs that function as post-transcriptional repressors of gene expression. We hypothesised that miRNA regulate gene expression of proinflammatory cytokines in response to monosodium urate (MSU) crystals. Methods We stimulated human monocytic THP-1 cells with MSU crystals and examined miRNA and proinflammatory cytokine gene expression. The effects of miR-146a overexpression were examined by transfecting THP-1 cells with miR-146a precursor. miR-146a expression was examined in the urate peritonitis model, in peripheral blood mononuclear cells from people with gout and control participants, and in gouty tophus samples. Results MSU crystals increased miR-146a expression in THP-1 cells, but not other miRNA implicated in interleukin (IL)-1β regulation. Overexpression of miR-146a expression reduced MSU crystal-induced IL-1β, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and IL-8 gene expression. In the urate peritonitis model, reduced miR-146a expression was observed during the acute inflammatory response to MSU crystal injection. In people with intercritical gout, peripheral blood mononuclear cells expressed significantly higher levels of miR-146a, compared with normouricaemic and hyperuricaemic control participants and those with acute gout flares. Expression of miR-146a was also observed in all tophus samples. Conclusions Collectively, these data suggest that miR-146a is a transcriptional brake that is lost during the acute inflammatory response to MSU crystals.

Improvement in psoriasis after intradermal administration of heat‐killed Mycobacterium vaccae

Background New treatments for psoriasis are being developed, but many are associated with limited efficacy, side‐effects, or rapid recurrence after discontinuation. Thus, the aim of new agents is to induce longer term remissions with fewer side‐effects. Preliminary studies have shown that Mycobacterium vaccae, a nonpathogenic organism prepared as a heat‐killed suspension, may induce periods of remission in some psoriasis patients when administered intradermally.

Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

Objectives To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. Methods People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24. Results The mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups. Conclusions The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment. Trial registration number ACTRN12611000845932