A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (ß = -2.5; [95% CI -4.7 to -0.4]), whereas negative symptoms were unaffected by treatment (ß = -0.39; [95% CI -2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

Cardiovascular MRI evidence of reduced systolic function and reduced LV mass in rheumatoid arthritis: impact of disease phenotype.

The accelerated risk of cardiovascular disease (CVD) in Rheumatoid Arthritis (RA) requires further study of the underlying pathophysiology and determination of the at-risk RA phenotype. Our objectives were to describe the cardiac structure and function and arterial stiffness, and association with disease phenotype in patients with established) RA, in comparison to healthy controls, as measured by cardiovascular magnetic resonance imaging (CMR). 76 patients with established RA and no history of CVD/diabetes mellitus were assessed for RA and cardiovascular profile and underwent a non-contrast 3T-CMR, and compared to 26 healthy controls. A univariable analysis and multivariable linear regression model determined associations between baseline variables and CMR-measures. Ten-year cardiovascular risk scores were increased in RA compared with controls. Adjusting for age, sex and traditional cardiovascular risk factors, patients with RA had reduced left ventricular ejection fraction (mean difference - 2.86% (- 5.17, - 0.55) p = 0.016), reduced absolute values of mid systolic strain rate (p < 0.001) and lower late/active diastolic strain rate (p < 0.001) compared to controls. There was evidence of reduced LV mass index (LVMI) (- 4.56 g/m2 (- 8.92, - 0.20), p = 0.041). CMR-measures predominantly associated with traditional cardiovascular risk factors; male sex and systolic blood pressure independently with increasing LVMI. Patients with established RA and no history of CVD have evidence of reduced LV systolic function and LVMI after adjustment for traditional cardiovascular risk factors; the latter suggesting cardiac pathology other than atherosclerosis in RA. Traditional cardiovascular risk factors, rather than RA disease phenotype, appear to be key determinants of subclinical CVD in RA potentially warranting more effective cardiovascular risk reduction programs.

Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis.

BACKGROUND: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at-risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA. METHODS: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti-cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non-progressors. RESULTS: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals. CONCLUSIONS: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker.

What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort.

OBJECTIVE: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA). METHODS: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept. RESULTS: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77 IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status. CONCLUSIONS: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.

A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial.

OBJECTIVE: To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis. METHODS: In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52. RESULTS: No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026). CONCLUSIONS: In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy. TRIAL REGISTRATION NUMBER: The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 (http://www.controlled-trials.com/ISRCTN55428162/EMPIRE). The full trial protocol can be obtained from the corresponding author.

Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study).

OBJECTIVES: In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. METHODS: In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. RESULTS: The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. CONCLUSIONS: In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients.

Anti-tumour necrosis factor (TNF) biologics have revolutionized therapy of rheumatoid arthritis (RA). We compared the effects of infliximab on numbers of circulating leucocyte subsets in early RA (disease/symptom duration of ≤1 year) and late RA patients (>1 year). A control group consisted of early RA patients treated with a combination of methotrexate (MTX) and methylprednisolone. Blood samples were obtained at baseline (pre-therapy) from all RA patients, divided into three groups: (i) late RA receiving infliximab/MTX, (ii) early RA-infliximab/MTX, (iii) early RA-steroid/MTX, and also from follow-up patients at 2 and 14 weeks. Significant differences in absolute counts of monocytes and granulocytes were observed between healthy controls and RA patients. At baseline CD14(bright) monocytes and CD16(+) granulocytes were increased in both early RA and late RA patients. CD4(+) T cells, CD8(+) T cells and B cells were all increased at baseline in early RA, but not in late RA. At 2 weeks following infliximab treatment decreased granulocytes were observed in both early and late RA and decreased natural killer (NK) cells in late RA. CD16(+) granulocytes and NK cells were also decreased at 14 weeks post-infliximab in early RA. Biotinylated infliximab was used to detect membrane-associated TNF (mTNF)-expressing leucocytes in RA patients. CD16(+) granulocytes, NK cells and CD14(dim) monocytes all expressed higher levels of mTNF in RA patients. In summary infliximab is associated with decreased CD16(+) granulocyte and NK cell counts, possibly through binding of mTNF. Differential effects of infliximab between early and late RA suggest that pathogenic mechanisms change as disease progresses.

Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA.

OBJECTIVES: To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. METHODS: Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) published between 1962 and February 2009; published abstracts from the 2007-2008 American College of Rheumatology (ACR) and EULAR conference were obtained. RESULTS: 87 articles and 40 abstracts were identified. In methotrexate (MTX) naïve patients, biological therapy with IFX, ETN, ADA, GLM or ABT has been shown to improve clinical outcomes (level of evidence 1B). In MTX/other synthetic disease-modifying antirheumatic drug (DMARD) failures all nine biological agents confer benefit (1B), with lower efficacy noted for ANA. RTX, ABT, TCZ and GLM demonstrate efficacy in tumour necrosis factor inhibitor (TNFi) failures (1B). Less evidence exists for switching between IFX, ETN and ADA (3B). Biological and MTX combination therapy is more efficacious than a biological agent alone (1B). A safety review shows no increased malignancy risk compared with conventional DMARDs (3B). TNFi are generally associated with an increased risk of serious bacterial infection, particularly within the first 6 months of treatment initiation; increased tuberculosis (TB) rates with TNFi are highest with the monoclonal antibodies (3B). CONCLUSIONS: There is good evidence for the efficacy of biological agents in patients with RA. Safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.

Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment.

OBJECTIVE: A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle. METHODS: Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 x 10(9) cells/liter. RESULTS: At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response. CONCLUSION: RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses.

Mesenchymal stem cells in rheumatoid synovium: enumeration and functional assessment in relation to synovial inflammation level.

OBJECTIVE: Achieving joint regeneration in rheumatoid arthritis (RA) represents a future challenge. Autologous synovial mesenchymal stem cells (MSCs) could be therapeutically exploited. However, the inflammatory milieu in the RA synovium could adversely affect endogenous MSC function. To test this hypothesis, the frequency and multipotency of RA synovial MSCs was evaluated in relation to existing synovial inflammation. METHODS: Synovial inflammation was measured using the arthroscopic visual analogue score (VAS) and further validated using immunohistochemistry and flow cytometry. Highly proliferative clonogenic in vivo MSCs were enumerated following fluorescence-activated cell sorting and expansion for 20 population doublings. MSC multipotency was quantified following standard in vitro culture expansion and trilineage differentiation assays. Real-time PCR, flow cytometry and ELISA were used to evaluate pro- and anti-chondrogenic molecules in standard polyclonal synovial MSCs. RESULTS: The arthroscopic VAS significantly correlated with synovial macrophage infiltration. In RA, synovial MSC chondrogenesis was inhibited in direct relation to VAS (r = -0.777, p<0.05) and reduced compared with control osteoarthritis (OA)-MSCs (p<0.05). In vivo, MSCs resided in the synovial fibroblastic/stromal fraction (CD45(-)CD31(-)) and were reduced in frequency in relation to VAS (r = -0.695, p<0.05). In RA-MSCs, CD44 levels correlated negatively with inflammation and positively with chondrogenesis (r = -0.830 and r = 0.865, respectively). Cytokine production and Sox9 expression was similar in RA-MSCs and OA-MSCs. CONCLUSIONS: There is a negative relationship between synovial MSC chondrogenic and clonogenic capacities and the magnitude of synovitis in RA. Effective suppression of joint inflammation is therefore necessary for the development of autologous MSC treatments aimed at cartilage regeneration in RA.

Evaluation of an existing screening tool for psoriatic arthritis in people with psoriasis and the development of a new instrument: the Psoriasis Epidemiology Screening Tool (PEST) questionnaire.

OBJECTIVE: To evaluate an existing tool (the Swedish modification of the Psoriasis Assessment Questionnaire) and to develop a new instrument to screen for psoriatic arthritis in people with psoriasis. DESIGN: The starting point was a community-based survey of people with psoriasis using questionnaires developed from the literature. Selected respondents were examined and additional known cases of psoriatic arthritis were included in the analysis. The new instrument was developed using univariate statistics and a logistic regression model, comparing people with and without psoriatic arthritis. The instruments were compared using receiver operating curve (ROC) curve analysis. RESULTS: 168 questionnaires were returned (response rate 27%) and 93 people attended for examination (55% of questionnaire respondents). Of these 93, twelve were newly diagnosed with psoriatic arthritis during this study. These 12 were supplemented by 21 people with known psoriatic arthritis. Just 5 questions were found to be significant predictors of psoriatic arthritis in this population. Figures for sensitivity and specificity were 0.92 and 0.78 respectively, an improvement on the Alenius tool (sensitivity and specificity, 0.63 and 0.72 respectively). CONCLUSIONS: A new screening tool for identifying people with psoriatic arthritis has been developed. Five simple questions demonstrated good sensitivity and specificity in this population but further validation is required.

Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study.

OBJECTIVES: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFalpha) blocking therapy. METHODS: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. RESULTS: Sixteen patients (13 women) were studied; all had previously failed TNFalpha-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNgamma of -52% (95% CI -73 to -15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters. CONCLUSION: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

The value of synovial cytokine expression in predicting the clinical response to TNF antagonist therapy (infliximab).

OBJECTIVES: Clinical response to TNF-alpha blockade in the treatment of RA is heterogeneous. The study aims were to determine whether pre-treatment synovial cytokine expression predicted infliximab response and whether synovial changes after therapy correlated with response. METHODS: Fifty-one patients had arthroscopic biopsies of the knee joint prior to infliximab (3 mg/kg) treatment. Synovial tissue cell numbers (CD68 and CD3 positive) and cytokine expression (TNF-alpha, lymphotoxin-alpha, IL-1alpha, -beta and receptor antagonist, and IL-6) pre-treatment was assessed using semi-quantitative immunohistochemistry. Changes in these parameters were assessed 16 weeks after infliximab in 32 patients who underwent repeat arthroscopic biopsy. RESULTS: Of the total patients, 47% (n = 24) achieved an ACR20 response; 53% (n = 27) did not. Baseline synovial TNF-alpha, IL-1alpha and -beta expression did not differ between the two groups. No differences in baseline TNF-alpha levels were observed with ACR levels of response (ACR20 and ACR50/70 groups). Post-treatment biopsies (17 ACR responders, 15 ACR non-responders) revealed significant reductions in sub-lining layer TNF-alpha expression in both response and non-response groups with significant reduction in vascularity and membrane proliferation scores. The worst ACR non-responders (<20% CRP suppression) demonstrated no reduction in any of the parameters. CONCLUSION: Pre-treatment synovial TNF-alpha or IL-1 expression does not predict TNF blockade response. Both ACR response and non-response was associated with reduction in synovial TNF-alpha-level expression. Suppression in TNF-alpha levels was not observed in the worst non-responders. The improvements (including in vascularity), independent of ACR clinical response, are compatible with the reduced structural damage documented in all groups of patients independent of response.

Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders.

OBJECTIVE: Patients may cease therapy with anti-tumour necrosis factor (TNF) agents due to inefficacy at 12 weeks (termed primary non-response) or later. Until now, the extent of this later secondary non-response has not been clearly defined. We followed-up a substantial single-centre cohort to determine kinetics of this secondary loss of response. The licensed dose of 3 mg/kg was used throughout. METHODS: Prospective data collection since anti-TNF therapy introduction in 1999 formed the basis of the analysis. Patients with rheumatoid arthritis who received infliximab as their first biologic agent, with at least 2 yrs follow-up were included. All relevant clinical data to calculate DAS-28 score and EULAR response were collected at 3, 6, 9, 12, 18 and 24 months. Reasons for cessation in those patients achieving a EULAR response at 3 months (secondary failures) were determined. RESULTS: Of a total of 309 patients commenced on infliximab, 290 received this as their first biologic agent.; 195 commenced > or = 2 yrs ago. Efficacy data to identify EULAR responders at 3 months was available in 174 patients. Sixty-seven per cent achieved a 'moderate' or 'good' EULAR response; 25% failed to achieve a response, 8% developed toxicity within the first 12 weeks. Of the primary responders, over 55% subsequently ceased therapy in the first year, the predominant reason was a secondary loss of response; other reasons included high disease activity despite achieving a definable response, toxicity, and intercurrent illness. Subsequent loss of response in the second year was less pronounced. CONCLUSIONS: This study of patients treated in clinical practice with infliximab demonstrated that secondary non-response occurred in around half the patients in the first year. The data highlight the need to continue development of other therapies as well as investigation of the underlying causes of this loss of response.

Submaximal exercise testing in the assessment of interstitial lung disease secondary to systemic sclerosis: reproducibility and correlations of the 6-min walk test.

BACKGROUND: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD). AIM: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters. METHODS: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT. RESULTS: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity. CONCLUSION: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.