The impact of gastroesophageal reflux disease and its treatment on interstitial lung disease outcomes.

BACKGROUND: To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc). METHODS: SSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated. RESULTS: GORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively). CONCLUSION: GORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.

Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Drug-induced toxicity and patient reported outcomes in rheumatoid arthritis patients following intensive treated-to-target strategy: does ceasing therapy due to toxicity worsen outcomes in long term?

AIM: While the introduction of the treat-to-target (T2T) strategy has been an important advance in the management of rheumatoid arthritis (RA), the potential for increased toxicity due to use of concurrent drugs could adversely affect patient reported outcomes (PROs). The objective was to determine whether the cessation of therapy due to toxicity affects long-term improvement in PROs in patients treated according to T2T strategy. METHODS: A total of 149 patients from an inception cohort of early RA were included. The occurrence and severity of toxicity were monitored at each visit over 3 years. PROs studied were function (measured using health assessment questionnaire); pain, fatigue and patient global assessment (PtGA) all assessed using a 100 mm visual analogue scale; helplessness and health-related quality of life (HRQoL). For each PRO, effect of drug withdrawal was measured by comparing mean change in PROs among patients with no/temporary vs. permanent withdrawal. In addition, effects of frequency of drug withdrawals, weeks to withdrawal and number of drugs withdrawn were analysed using linear regression. RESULT: After 3 years, 56 (37.4%) patients ceased at least one drug permanently due to toxicity. Patients with no/temporary withdrawal (n = 93) achieved significantly greater improvement in function (mean change = -0.54 vs. -0.31, p = 0.033), pain (mean change = -39.82 vs. -5.02, p = 0.018), fatigue (mean change = -29.14 vs. -14.76, p = 0.015) and PtGA (mean change = -29.64 vs. -17.00, p = 0.018) compared with their counterparts. Higher frequency of withdrawals was associated with lesser improvements in function, pain, fatigue and PtGA, while the number of drugs withdrawn and the weeks to withdrawal had lesser effects. However, the cessation of the drugs due to their toxicity did not have a significant association with HRQoL and helplessness. CONCLUSION: Improvements in function, pain, fatigue and PtGA at 3 years were diminished for patients who ceased drugs due to toxicity while broader measures of HRQoL were not affected.

Cost savings with a new screening algorithm for pulmonary arterial hypertension in systemic sclerosis.

BACKGROUND: Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is now standard care in this disease. The existing Australian Scleroderma Interest Group algorithm (ASIGSTANDARD ) is based on transthoracic echocardiography (TTE) and pulmonary function tests (PFT). Recently, ASIG has derived and validated a new screening algorithm (ASIGPROPOSED ) that incorporates N-terminal pro-B-type natriuretic peptide level together with PFT in order to decrease reliance on TTE, which has some limitations. Right heart catheterisation (RHC) remains the gold standard for the diagnosis of PAH in patients who screen 'positive'. AIM: To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms. METHODS: We applied both ASIGSTANDARD and ASIGPROPOSED algorithms to 643 screen-naïve SSc patients from the Australian Scleroderma Cohort Study (ASCS), assuming a PAH prevalence of 10%. We compared the costs of screening, the number of TTE required and both the total number of RHC required and the number of RHC needed to diagnose one case of PAH, and costs, according to each algorithm. We then extrapolated the costs to the estimated total Australian SSc population. RESULTS: In screen-naïve patients from the ASCS, ASIGPROPOSED resulted in 64% fewer TTE and 10% fewer RHC compared with ASIGSTANDARD , with $1936 (15%) saved for each case of PAH diagnosed. When the costs were extrapolated to the entire Australian SSc population, there was an estimated screening cost saving of $946 000 per annum with ASIGPROPOSED , with a cost saving of $851 400 in each subsequent year of screening. CONCLUSIONS: ASIGPROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIGSTANDARD .

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients.

A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.

Prospects for improving outcomes in systemic sclerosis-related pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Approximately one in 10 will develop PAH during their lifetime. These patients have a worse prognosis than those with PAH due to other causes. The most common clinical feature of SSc-PAH in the early stages is non-specific exercise intolerance that can be erroneously attributed to other manifestations of SSc. Screening provides an opportunity for early identification of SSc-PAH and prompt initiation of therapies with the potential to improve quality of life and survival. International guidelines recommend annual transthoracic Doppler echocardiography (TTE), but TTE has limitations. The tricuspid regurgitant jet required for estimating the systolic pulmonary artery pressure is absent in up to 39% of patients, including a proportion with PAH. This has prompted a move to new screening algorithms that are less dependent on TTE. Not all pulmonary hypertension (PH) in patients with SSc is PAH. Other causes include PH secondary to left heart disease, interstitial lung disease-related PH, chronic thromboembolic PH and pulmonary veno-occlusive disease. With the advent of evidence-based therapies, including newer agents such as macitentan, riociguat and selexipag, the establishment of centres with expertise in PAH and the focus on early detection, there has been considerable improvement in survival. The role of anti-coagulation for SSc-PAH has been the subject of a recent meta-analysis of nine observational studies that suggests it may confer a survival benefit, but to date, there have been no randomised controlled trials to confirm this.

Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis?

The remarkable similarity in inflammatory response and pathology of periodontal disease and rheumatoid arthritis has been recognized for several decades. However, how these two disease may be interrelated has been less clear. During the pathogenesis of rheumatoid arthritis there is a preclinical immunological phase which precedes the clinical manifestation of rheumatoid arthritis. During this phase serum autoantibodies appear many years before the clinical signs and symptoms of rheumatoid arthritis become apparent. To date, the two best studied autoantibodies have been rheumatoid factor and anti-citrullinated protein antibodies (ACPA). Of these the production of ACPA has been considered very important due to their high predictive value in future manifestation of rheumatoid arthritis. Citrullination is a common post-translational modification of proteins based on the enzymatic conversion of arginine into citrulline. Extra-articular citrullination and production of ACPA, as a priming immunological experience, is well documented in many tissues including the inflamed gingival tissues associated with periodontal disease. More recently, carbamylation of proteins has also been implicated in the pathogenesis of rheumatoid arthritis in a manner similar to citrullination. Carbamylation is a post translational modification of proteins by an enzyme-independent modification of lysine residues against which autoantibodies are subsequently induced. In this article we hypothesise that, like citrullination, carbamylation of proteins and associated antibody production during the gingival inflammation associated with gingivitis and periodontitis may play a role in the pathogenesis of rheumatoid arthritis.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.

WHAT IS KNOWN AND OBJECTIVE: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. RESULTS AND DISCUSSION: A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. WHAT IS NEW AND CONCLUSION: This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.

The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis.

OBJECTIVES: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc). METHODS: Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA. RESULTS: One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations. CONCLUSIONS: The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.

Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis.

Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.

Decline in hand bone mineral density indicates increased risk of erosive change in early rheumatoid arthritis.

OBJECTIVE: Despite better disease suppression with combination disease-modifying antirheumatic drugs (DMARDs), some patients with rheumatoid arthritis (RA) have progressive erosive disease. The objective of this study was to determine whether hand bone mineral density (BMD) loss in the first 6 months of treatment indicates increased risk of erosions at 12 months. METHODS: Patients with DMARD-naive early RA receiving treat-to-target therapy were studied (n = 106). Hand BMD was measured at baseline and 6 months by dual x-ray absorptiometry. Hand and feet radiographs were performed at baseline and 12 months and scored using the van der Heijde modification of the Sharp method. A K-means clustering algorithm was used to divide patients into 2 groups: the BMD loss group or the no loss group, according to their absolute change in BMD from baseline to 6 months. Multiple regression analysis (hurdle model) was performed to determine the risk factors for both erosive disease and erosion scores. RESULTS: Hand BMD loss at 6 months was associated with erosion scores at 12 months (P = 0.021). In a multiple regression analysis, hand BMD loss (P = 0.046) and older age at onset (≥50 years; P = 0.014) were associated with erosive disease, whereas baseline erosion scores (P = 0.001) and anti-cyclic citrullinated peptide (P = 0.024) were correlated with erosion severity/progression. CONCLUSION: In RA patients receiving treat-to-target therapy, early hand BMD loss could identify patients who are at risk of developing erosive disease at 12 months, potentially allowing intensification of treatment to prevent erosive damage.

Should patients with systemic sclerosis-related pulmonary arterial hypertension be anticoagulated?

Pulmonary arterial hypertension (PAH) is a major cause of mortality in scleroderma and despite 'advanced' therapies confers a median survival of less than 5 years. Anticoagulation in systemic sclerosis-related PAH (SSc-PAH) is currently one of the most contentious issues in the management of patients with connective tissue disease. While some studies have shown a survival benefit with warfarin therapy in this disease, others have not. Accordingly, a state of clinical equipoise exists in relation to anticoagulation in SSc-PAH. With an over fivefold reduction in mortality demonstrated in some observational studies, the issue of anticoagulation in SSc-PAH demands resolution through a well-designed randomised controlled trial.

Scleroderma lung disease, variation in screening, diagnosis and treatment practices between rheumatologists and respiratory physicians.

BACKGROUND: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) represent the leading causes of death in systemic sclerosis (SSc). Screening for these complications has assumed greater importance, but is not universal. The aim of this study is to determine the self-reported screening, diagnosis and treatment practices of rheumatologists and respiratory physicians for SSc-related lung disease. METHODS: Email survey of 270 rheumatologists and 600 respiratory physicians. RESULTS: Responses were received from 42 (16%) rheumatologists and 68 (11%) respiratory physicians. Of SSc patients seen by rheumatologists, 17% had ILD and 7.5% had a diagnosis of PAH compared with 31% and 21% for respiratory physicians. Forty per cent of all physicians screened asymptomatic SSc patients without a known diagnosis of ILD or PAH less than annually or not at all. The most commonly used screening investigations were pulmonary function tests (PFT) (95%) and transthoracic echocardiogram (TTE) (78%). In suspected ILD, both groups used high-resolution computed tomography scans and PFT in >90% of patients. In suspected PAH, both used TTE and PFT (>90%); right heart catheterisation was used by only 50% of physicians. In treatment of ILD, rheumatologists used intravenous (IV) cyclophosphamide more often (CYC) (59% vs 28%, P= 0.003) and more respiratory physicians used oral CYC (44% vs 28%, P= 0.012). In PAH, more respiratory physicians used warfarin (68% vs 40%, P= 0.006). Only approximately 65% of physicians had used specific PAH therapy, which may reflect lack of access to a designated PAH treatment centre. CONCLUSION: The heterogeneity of responses revealed in this study raises the importance of screening, diagnosis and treatment algorithms in the management of this potentially life-threatening disease.

Treatment-induced stable, moderate reduction in blood cell counts correlate to disease control in early rheumatoid arthritis.

BACKGROUND: Treatment of rheumatoid arthritis (RA) has become more intensive, thereby raising concerns regarding toxicities, including leucopenia. The objective was to analyse cell counts obtained as routine surveillance for adverse effects to assess the effect of intensive treatment and treatment dosage and to examine correlations to disease activity scores. METHODS: Patients with early RA were treated with combinations of disease-modifying anti-inflammatory drugs according to pre-defined rules, with dose adjustments contingent on residual disease activity and tolerance. RESULTS: Mean leucocyte, neutrophil and platelet counts fell with levels that correlated to disease activity scores. The strongest correlation was between platelets and disease activity scores. There was a modest, inverse correlation between methotrexate dose and monocyte and lymphocyte counts. No serious toxicity associated with the therapy was seen. CONCLUSION: Moderate reductions in cell counts are well tolerated in RA and appear to contribute to disease control.

Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment.

Pulmonary arterial hypertension (PAH) is an important cause of mortality in systemic sclerosis (SSc). The symptoms are non-specific and can be ascribed to other features of the disease, so it is often underrecognized until the late stages. Earlier treatment with new agents is associated with better treatment outcomes. The aim of this article is to develop evidence-based guidelines for screening for PAH and interstitial lung disease (ILD) in SSc. PAH occurs in up to 27% of patients with SSc. Abnormal pulmonary function, particularly a disproportionate fall in carbon monoxide diffusing capacity (DLCO), can identify patients in the early stages of PAH, prompting further investigation in high-risk patients (limited SSc of >10 years' duration, symptoms and/or signs of PAH, DLCO <50% predicted, a rapid or large fall in DLCO without evidence of ILD and/or estimated systolic pulmonary artery pressure >45 mmHg on echocardiography). Right heart catheter remains the diagnostic gold standard. An algorithm for screening with regular pulmonary function tests for the early detection of PAH and ILD in SSc is proposed.

Dietary n-3 fats as adjunctive therapy in a prototypic inflammatory disease: issues and obstacles for use in rheumatoid arthritis.

Eicosanoids derived from the n-6 fatty acid, arachidonic acid, and the cytokines interleukin-1beta and tumour necrosis factor-alpha are involved in the signs and symptoms of inflammatory joint disease, as well as the cartilage degradation seen in established rheumatoid arthritis (RA). Then n-3 fatty acids in fish and fish oil can inhibit production of both eicosanoid and cytokine inflammatory mediators and therefore, have the potential to modify RA pathology. Epidemiological studies suggest that fish intake may be preventive for RA and double-blind placebo-controlled studies demonstrate that dietary fish oil can alleviate the signs and symptoms of RA. The implementation of these findings will require among other things, a range of n-3 fat enriched foods, as well as physician awareness of the possibilities for dietary n-3 fat increases to be used as adjunctive therapy in RA.

Recruitment of mononuclear leucocytes to osteoarthritic human synovial xenografts in the ears of SCID mice.

A system has been established to assess the recruitment of 99mTc-hexamethylpropylene amine oxamine (99mTc-HMPAO)-labelled PBMC and [125I]iododeoxyuridine-labelled Con A stimulated lymphoblasts to allogeneic human synovial xenografts in the ears of SCID mice. Successful engraftment of osteoarthritic synovium was achieved in approximately 90% of cases and a connection between the human microvasculature of the xenograft and the circulation of the mouse was shown. Cells were delivered to the xenograft by a system of regional vascular perfusion, thus avoiding the major murine vascular beds. The accumulation of 99mTc-HMPAO-labelled PBMC in mouse ears was monitored in real time. Direct injection of xenograft-bearing ears with recombinant human TNF-alpha, 7 h prior to perfusion, increased the accumulation of both PBMC and lymphoblasts in cytokine-injected ears compared to contralateral control-injected ears. Autoradiography revealed the presence of [125I]iododeoxyuridine-labelled lymphoblasts associated with human microvasculature within the xenograft. However, the increased accumulation of lymphoblasts in cytokine-injected ears occurred in the tissues surrounding the xenograft, where lymphoblasts were associated more often with murine than human vessels. Although the system described offers advantages over similar models, the propensity for mouse endothelium to interact with human leucocytes is likely to be a generic disadvantage for models of human leucocyte recruitment to xenografts in immunodeficient mice.

Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone.

OBJECTIVE: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ). METHODS: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks. RESULTS: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm. CONCLUSION: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset.