Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010).

OBJECTIVES: There are no valid instruments to measure disease activity in Takayasu arteritis (TA). We aim to provide a valid measure to assess clinical disease activity with or without incorporating acute phase reactants. METHODS: The Indian Takayasu Clinical Activity Score (ITAS) was initially derived from disease manifestations scored in the Disease Extent Index (DEI.Tak). The ITAS was validated by a group of physicians scoring both live and paper cases for inter-rater reliability (IRR), convergence with BVAS, correlation with the Physician's Global Assessment (PGA) and ESR/CRP. It was further validated at a single centre in 177 patients for its ability to discriminate between active and inactive disease state at first visit and sensitivity to change in 132 active patients measured serially at two follow-up visits. ITAS-A also included graded scores for ESR/CRP. RESULTS: The final ITAS2010 contains 44 items with 33 features arising from the cardiovascular system. Seven key items are weighted to score 2 and all others score 1 only. Inter-observer variability was highly satisfactory (IRR 0.97). The ITAS showed superior inter-rater agreement compared with the BVAS (IRR 0.9) and PGA (IRR 0.82). In the single-centre study, median ITAS scores at first visit were significantly higher in active disease (5.62 ± 3.14) compared with grumbling (3.36 ± 1.96) and inactive disease (1.27 ± 1.26, P < 0.0001). The therapy induced a significant decrease in the ITAS2010 but the higher ITAS-A scores remained elevated. CONCLUSION: The ITAS2010, validated in over 300 TA patients and sensitive to change, is a useful measure of clinical disease activity for patient monitoring. Higher ITAS-A scores suggest poor control of active disease by current therapy.

Breaking communication barriers for RA patients of South Asian origin: the use of a bilingual educational audio CD and linguistically appropriate peer support and education.

BACKGROUND: People from the Indian subcontinent represent one of the largest ethnic groups in the UK. Patient education resources are required to address language barriers, poor literacy and (potentially discordant) cultural beliefs. We have investigated a novel strategy to meet this need. METHODS: Rheumatoid arthritis (RA) patients of South Asian origin who prefer to communicate in a South Asian language were invited to a face-to-face interaction with a trained patient volunteer to provide linguistically appropriate peer support and education, and given a bilingual educational audio CD. Qualitative methods were used to assess this approach; three focus groups were held and 15 patients participated in total. RESULTS: Four important themes were identified: (1) The need for information about RA; all patients agreed that this was vital to learn how to live with their chronic disease. (2) Currently available approaches to education; particular concerns related to a lack of time in clinic, language barriers, difficulties in communicating via interpreters and that most written information was available only in English. (3) Support provided by a trained patient volunteer; patients appreciated that they were listened to, and were motivated by the volunteers' positive attitude. (4) The usefulness of the audio CD; patients appreciated that information was presented in a language they could understand, via a convenient medium and which offered a helpful perspective on their illness. CONCLUSIONS: This approach is a successful way of delivering information and encouraged patients from a difficult-to-reach community to become more involved in their disease management.

Vasculitis integrated clinical assessment database: a data management system to support studies into systemic vasculitis.

BACKGROUND: The systemic vasculitides are characterized by immune inflammation affecting blood vessels, which can lead to organ and tissue damage. Treatment has improved but optimum long-term management still remains unsatisfactory, requiring ongoing therapeutic studies. These often base their measures of efficacy on the outcome of clinical assessments which include the Birmingham Vasculitis Activity Score and the Vasculitis Damage Index. OBJECTIVES: Efficient management of assessment data is complex and often hampered by working with time-consuming paper-based systems. The Vasculitis Integrated Clinical Assessment Database (VICAD) was created to improve the process. METHODS: VICAD was developed using Microsoft Access. Visual Basic for Applications and the Data Access Objects Application Programming Interface provide the functionality to assist with scoring, calculation of results, and storing of data. RESULTS: VICAD is an efficient system for managing data. Evaluation of its use showed an improvement in the completeness of patient assessments from 77% (paper based: n = 44) to 98% (computer based: n = 30). During development clinicians (n = 4) rated it at 8/10 for its layout and visual presentation and 8/10 for easy to use (intuitiveness and navigability). CONCLUSIONS: The development of an integrated and standardized system of data collection (VICAD) helps to support clinical decision making processes and report findings in a more timely manner. It is available free for use and modification under the GNU General Public License. The open source nature of VICAD could help to inform the design of other databases where management of complex information into important multisystem diseases is needed.

Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV. METHODS: Patients with newly diagnosed AASV, with serum creatinine levels <150 mumoles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing). RESULTS: One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036). CONCLUSION: MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.

TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx.

Tumor necrosis factor alpha (TNF-alpha) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF-alpha alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca(2+)](i)) signal in Jurkat T cells after just 30 min exposure to TNF-alpha, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca(2+)](i) was also observed in human CD4+ T lymphocytes. The change in Ca(2+) signal was related to a decrease in the plasma membrane Ca(2+) influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca(2+) influx. The role of TNF-alpha-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-alpha led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca(2+) response to phytohemagglutinin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca(2+) responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF-alpha-induced inhibition of the Ca(2+) influx in an ASM-deficient murine T cell line (OT-II(+/+)ASM(-/-)). This potent ability of TNF-alpha to rapidly modulate the TCR Ca(2+) signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.

Persistent TNF-alpha exposure impairs store operated calcium influx in CD4+ T lymphocytes.

Persistent tumour necrosis factor alpha (TNF-alpha) exposure uncouples proximal T-cell receptor (TCR)-signalling events. Here, we demonstrate that chronic TNF-alpha exposure also attenuates signalling distal to the TCR, by specifically inhibiting Ca2+ influx evoked by thapsigargin in CD4+ T-cells. Mitogen-induced Ca2+ responses were impaired in a dose dependent manner, and TCR-induced Ca2+ responses were also significantly reduced. The impairment of Ca2+ influx strongly correlated with poor function as proliferative responses to both mitogen and anti-CD3/CD28 stimulation were suppressed. Our findings show that persistent TNF-alpha exposure of T-cells specifically inhibits store operated Ca2+ influx. This may affect gene activation and contribute to the poor T-cell function in chronic inflammatory disease.

Assessment of disease activity and damage for clinical decision making in vasculitis

The progress in many aspects of vasculitis has emphasised the need for detailed assessment to dissect the components of each individual case as it progresses and to use this to determine progressive therapeutic regimes tailored to the current disease status. Assessment of the extent of organ involvement and the degree of disease activity have obvious value in determining the need for initial therapy at disease presentation. The control of acute mortality has revealed a persistent morbidity, most clearly documented in patient self-assessment of their functional status. The high tendency to relapse also stresses the need for continuing assessment during long-term follow-up. Newer drugs may allow specific control of ongoing activity to be achieved at lower risk of toxicity. The problem of accumulating disease scars has not yet been solved although the detailed description of organ damage has revealed the important contribution which damage makes to later mortality. Finally, there are new techniques to look at the function of the endothelium itself the important target tissue in vasculitis. These will hopefully provide opportunities to assess non invasively the state of blood vessels and their potential to respond to further therapy