Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Engaging medical students in occupational and environmental medicine--a new approach.

BACKGROUND: For a number of reasons, engaging the interest of medical students in the discipline of occupational and environmental medicine (OEM) can be challenging. AIMS: To renew a curriculum in OEM within a graduate medical programme with an emphasis on student involvement to maximize their interest in the topic. METHODS: A second year student cohort of a 4 year graduate medical programme was surveyed as to their preferences for the content of a short course of OEM embedded in their medical course. The course was extensively rewritten as a result of the student survey, with a number of topics deleted from the old course and new topics added. In order to validate the content of the new course, local occupational physicians (OPs) were also surveyed as to their opinion of an appropriate curriculum in OEM for medical students. The new course was taught to the subsequent cohort of second year medical students. The students' ratings of the course pre- and post-revision were compared. RESULTS: The student satisfaction rates of the course significantly improved as a result of the changes. The content of the student-led curriculum was strikingly similar to the course proposed by the local OP with a few key exceptions. CONCLUSIONS: Student involvement in curriculum design in OEM is entirely feasible. It can result in a curriculum similar to that designed by expert opinion but has the advantage of strongly engaging student interest.

Effect of intra-articular infliximab on synovial membrane pathology in a patient with a seronegative spondyloarthropathy.

OBJECTIVE: To demonstrate the efficacy of intra-articular infliximab in a patient with a persistent monarthritis who had previously had two arthroscopic synovectomies with limited success, and to determine the effect of intra-articular infliximab on synovial membrane pathology METHOD: Arthroscopic synovial biopsy specimens were collected before and after treatment with intra-articular infliximab. The synovial tissue was stained for a range of inflammatory cell subsets, cell adhesion molecules and cytokines using immunohistochemical techniques and quantified using digital image analysis and a semiquantitative scoring method. RESULTS: Clinical improvement in the knee synovitis was seen after the first two intra-articular infliximab treatments, with a sustained clinical remission lasting for more than 12 months after the third treatment. Significant changes in cellular infiltration and expression of cytokines and cell adhesion molecules occurred as a result of treatment with intra-articular infliximab, with a reduction in some but not all cells in the inflammatory infiltrate, as well as a reduction in the expression of cell adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1) and production of cytokines (interleukin 1beta and tumour necrosis factor alpha). CONCLUSION: Intra-articular infliximab administration is a viable treatment for a persistent monarthritis resistant to other treatment options and can successfully modulate the inflammatory milieu within the synovial membrane.

The effect of rheumatoid arthritis on personal income in Australia.

BACKGROUND: The aim of this study was to estimate the effect of rheumatoid arthritis (RA) on the personal income of a cohort of individuals with RA in Australia. METHODS: A cross-sectional study of a sample of 497 working age people with RA in Adelaide, South Australia was carried out. RESULTS: The average personal income of an individual with RA in our cohort in 2003-2004 was $A22 400 compared with the Australian mean annual income of $A38 000. When standardized, the income of our cohort was 66% that of the average income of the Australian population. Overall one-third of the RA cohort relied principally on the social security system for their income and more than 75% of the cohort estimated they had lost greater than $A10 000 per annum in personal income as a result of their disease. Individuals with RA who were not working had annual incomes on average of more than $A20 000 less than those who continued to work. CONCLUSION: The personal income loss associated with RA in Australia is of enormous significance. It reduces a large population of individuals to relative financial poverty and potentially limits their access to a range of services including private health services.

Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis.

OBJECTIVES: To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co-localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy. RESULTS: The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid- and plasmacytoid-type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon alpha and gamma. CONCLUSIONS: The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.

Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment.

BACKGROUND: Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA). OBJECTIVE: To examine the effect of successful disease-modifying antirheumatic drug (DMARD) treatment on the expression of Jak-STAT in a cohort of patients with active rheumatoid arthritis. METHODS: Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry. RESULTS: Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation. CONCLUSION: Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up-regulation of inhibitory pathways, or suppressing inflammatory paths.

Pharmaceutical Benefits Scheme criteria for the use of tumour necrosis factor-alpha inhibitors in the treatment of ankylosing spondylitis in Australia: are they evidence based?

BACKGROUND: In 2004, the Pharmaceutical Benefits Scheme (PBS) listed infliximab as a subsidised treatment for ankylosing spondylitis (AS). Eligibility to receive this treatment for AS involved fulfilling several criteria. AIM: To examine the medical literature concerning response to tumor necrosis factor (TNF)-alpha inhibitors in AS and compare with the PBS criteria for these agents. METHODS: Review of published studies and analysis of the PBS criteria for the prescription of TNF inhibitors for the treatment of AS to assess whether the published criteria are evidence based. RESULTS: The published findings on the prediction of response to TNF inhibitors in the treatment of AS suggest that age, duration of disease, disease activity, functional status at the time of commencement of TNF inhibitors and, possibly, level of acute phase reactants predict the outcome of treatment with TNF inhibitors in AS. The PBS criteria do not reflect the published findings on predictors of response to TNF inhibitors. CONCLUSION: The current PBS criteria that need to be fulfilled for patients to receive subsidised treatment with TNF inhibitors for AS are not evidence based and will lead to the selection of patients with established disease while excluding patients with early disease.

Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis.

BACKGROUND: Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis. OBJECTIVE: To document Jak-STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue. METHODS: Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3-STAT4 were assessed. RESULTS: STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6. CONCLUSION: CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro-apoptotic and anti-inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti-inflammatory effects.

The use of the hand anatomic index to assess deformity and impaired function in systemic sclerosis.

To determine the "hand anatomic index" (HAI--a quantitative measure of hand deformity) in systemic sclerosis (scleroderma) and to compare it with the other measures of hand deformity and functional impairment. The HAI (measure of open hand span minus closed hand span/lateral height of hand) was determined in 30 patients with scleroderma and compared with hand deformity (as assessed by two independent rheumatologists) and with the Health Assessment Questionnaire (mHAQ), hand strength and prehensile gripability data. The HAI was confirmed as a reliable measure which clearly distinguished patients with increasing hand deformity and separated patients with diffuse scleroderma (n=12) from limited scleroderma (n=18), P=0.005. The HAI correlated significantly with measures of global functional impairment (as measured by the mHAQ) r=-0.46, P=0.01, hand strength r=0.51, P=0.0001 and prehensile gripability, r=-0.37, P=0.05 but neither with disease duration r=-0.16, P=NS nor age at disease onset r=0.20, P=NS. It was estimated that the HAI accounts for ~25% of the total global disability (as measured by HAQ). Measurement of the HAI in scleroderma provides a reliable and objective measure reflecting variable degrees of hand deformity and functional impairment and might provide a valid clinical outcome measure in patients with this disabling disorder.

Isolated pulmonary hypertension in scleroderma.

BACKGROUND: Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival. AIM: To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients. METHODS: Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma. RESULTS: Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT. CONCLUSION: Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.

Scleroderma in Australian aborigines.

Scleroderma (systemic sclerosis) has not been reported before in Australian Aborigines. We describe in detail a community middle-aged Aboriginal woman whose diffuse scleroderma terminated fatally with a renal crisis. Moreover, we have identified a further five Aboriginal patients on the South Australian Scleroderma Register (two with diffuse, two with limited and one with overlap scleroderma), a number consistent with that expected from the 2001 census data for our state. However, an analysis of all antinuclear antibody (ANA) requests from the Top End of Australia over a 6-year period revealed only two Aborigines with low titre anticentromere antibody (despite frequent occurrence of ANA with other specificities). Neither of these Aborigines had features of scleroderma. In conclusion, scleroderma does occur in indigenous Australians but further studies are needed to confirm the apparent infrequency of centromere-associated limited scleroderma (which is the commonest form of scleroderma in our Caucasian population).

Genomic instability in scleroderma.

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p < 0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p < 0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.

Suprascapular nerve block in chronic shoulder pain: are the radiologists better?

BACKGROUND: Suprascapular nerve block is a safe and effective treatment for chronic shoulder pain in arthritis, which can be performed either by direct imaging (CT guided) or in the clinic using anatomical landmarks to determine needle placement. OBJECTIVE: To compare a CT guided versus an anatomical landmark approach in a randomised, single blind trial examining the efficacy of suprascapular nerve block for shoulder pain in patients with degenerative joint/rotator cuff disease. METHODS: 67 patients with chronic shoulder pain from degenerative disease participated in the trial. 77 shoulders were randomised. The group randomised to receive the block through the anatomical landmark approach received a single suprascapular nerve block. Those in the CT guided group received an injection of methylprednisolone acetate and a smaller volume of bupivacaine around the suprascapular nerve. The patients were followed up for 12 weeks by a "blinded" observer and reviewed at weeks 1, 4, and 12 after the injection. RESULTS: Significant improvements were seen in all pain scores and disability in the shoulders receiving both types of nerve block, with no significant differences in the improvement in pain and disability between the two approaches at any time. Improvements in pain and disability scores were clinically and statistically significant. No significant adverse effects occurred in either group. Patient satisfaction scores for pain relief using either approach were high. CONCLUSION: The CT guided control and landmark approaches to performing suprascapular nerve blocks result in similar significant and prolonged pain and disability reductions; both approaches are safe.

T cells, fibroblast-like synoviocytes, and granzyme B+ cytotoxic cells are associated with joint damage in patients with recent onset rheumatoid arthritis.

OBJECTIVE: To determine immunohistological markers in synovial tissue of patients with early rheumatoid arthritis (RA) which are associated with unfavourable disease outcome. METHODS: Synovial tissue was obtained from 36 patients with RA within 1 year after the initial symptoms and before starting disease modifying antirheumatic drug treatment. Clinical, laboratory, and radiological assessments (Larsen score) were performed at the time of the biopsy and at the end of follow up (mean 58 months, range 38-72). Immunohistological analysis was performed to detect T cells, B cells, plasma cells, fibroblast-like synoviocytes (FLS), macrophages, and granzyme B+ cytotoxic cells. The sections were evaluated by digital image analysis. RESULTS: Patients were divided into two groups based upon the radiological progression per year of follow up: group I with mild progression (n = 20; Larsen <2 points/year); group II with more severe progression (n = 16; Larsen > or =2 points/year). Regression analysis with a univariate model showed that the numbers of granzyme B+ cytotoxic cells (relative risk (RR) = 12, p = 0.003), T cells (RR = 11, p = 0.013), and FLS (RR = 10, p = 0.020) discriminated between groups I and II. A multivariate model demonstrated that the numbers of T cells (RR = 1.2, p = 0.015) and FLS (RR = 1.4, p = 0.013) were independent discriminators between groups I and II. CONCLUSION: The numbers of granzyme B+ cytotoxic cells, T cells, and FLS in synovial tissue of patients with RA are related to the severity of joint damage. The data suggest a pathogenetic role for these cells in the process of joint damage.