David Carruthers

Modification and validation of the Birmingham Vasculitis Activity Score (version 3)

Background: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. Objective: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. Methods: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. Results: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman’s rsu200a=u200a0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (rsu200a=u200a0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (rsu200a=u200a0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (rsu200a=u200a0.43, 95% CI 0.31 to 0.54), physician’s global assessment (rsu200a=u200a0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (rsu200a=u200a0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). Conclusion: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Epidemiology of Systemic Vasculitis: Changing Incidence or Definition?

The epidemiology of the systemic vasculitides is poorly documented. Many studies have been conducted from tertiary referral centers, with resulting problems of referral bias and uncertainty of denominator population, or have involved small populations. We have estimated the incidence of the major forms of systemic vasculitis in a stable, ethnically homogeneous population of 414,000 adults from 1988 to 1994. The overall annual incidence of systemic vasculitis (excluding giant cell arteritis) is 39/million (95% confidence intervals; ranging from 31 to 47). The annual incidence of Wegeners granulomatosis is 8.5/million (range, 5.2 to 12.9), Churg-Strauss syndrome 2.4/million (0.9 to 5.3), microscopic polyangiitis 2.4/million (0.9 to 5.3), adult Henoch-Schonlein purpura 1.2/million (0.3 to 3.5), and systemic rheumatoid vasculitis 12.5/million (8.5 to 17.7). These data suggest that the overall incidence of systemic vasculitis is greater than previously thought (10/million) with Wegeners granulomatosis and systemic rheumatoid vasculitis being the most common. Whether this represents a genuine increase in incidence or increased physician awareness is uncertain.

Inflammation and Microvascular and Macrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Effect of Treatment

Objective. To determine whether abnormalities in microvascular and macrovascular function in rheumatoid arthritis (RA) are associated with plasma markers [von Willebrand factor (VWF)] of endothelial dysfunction and inflammation [C-reactive protein (CRP)] and whether the abnormalities would be altered by treatment. Endothelial dysfunction and inflammation in RA may contribute to adverse cardiovascular events. Although endothelial dysfunction in RA has been demonstrated by altered plasma markers, the relationships with macrovascular and microvascular function are relatively unexplored. Methods. We recruited 66 patients with chronic RA, 48 community controls (CC), and 25 patients with diabetes and hypertension as a disease control group (DC). Subjects had venous blood sampled for plasma markers, and underwent laser Doppler perfusion imaging of forearm skin (to assess microvascular circulation) following acetylcholine and sodium nitroprusside iontophoresis, to assess endothelium-dependent and endothelium-independent responses, respectively. Brachial artery flow-mediated dilatation assessed endothelial dysfunction in a macrovascular bed. A subgroup of 29 patients with RA were assessed pretherapy and after 2–4 weeks of antirheumatic therapy. Results. As expected, patients with RA had higher CRP, erythrocyte sedimentation rate (ESR), and VWF. Endothelium-independent vasoreactivity was abnormal in RA, and this correlated negatively with CRP. All aspects of microvascular function were abnormal in the DC compared to the CC. Macrovascular function was preserved in RA but was abnormal in the DC group. Four weeks of antiinflammatory therapy reduced CRP and ESR but had no effect on any vascular function index in the patients with RA. Conclusion. Patients with RA have abnormal endothelium-independent microvascular function that correlates with inflammation but is not altered by short-term antiinflammatory therapy.

Isolated nail fold vasculitis in rheumatoid arthritis.

OBJECTIVES--To establish the clinical significance of isolated nail fold vasculitis in patients with rheumatoid arthritis (RA). METHODS--Patients attending hospital with established RA were assessed by a single observer using unaided vision. Isolated nail fold vasculitis (NFV) was diagnosed as small nail edge or nail fold lesions without any evidence of other extra-articular or systemic vasculitis. Patients were followed prospectively. RESULTS--Thirty patients with isolated NFV were identified and followed for a median interval of 22 months. Three patients died within three months of diagnosis and six developed complications possibly indicative of extra-articular disease: xerostomia (three), pericarditis (one), pleural effusion and empyaema (one), pulmonary fibrosis (one). No patient developed systemic vasculitis. CONCLUSION--Isolated NFV has a favourable prognosis compared with systemic vasculitis. There is a low risk of developing systemic or extra-articular disease.

An observational study of endothelial function in early arthritis

Eur J Clin Invest 2012; 42 (5): 510–516

Circulating endothelial cells and rheumatoid arthritis: relationship with plasma markers of endothelial damage/dysfunction

OBJECTIVESnRA is associated with endothelial cell dysfunction (ECD) and increased cardiovascular mortality and morbidity. Circulating endothelial cells (CECs) are a novel marker of severe endothelial damage. We hypothesized altered CECs in patients with RA compared with community controls (CCs) and hospital controls (HCs, with diabetes and hypertension) correlate with established plasma markers of inflammation and of ECD.nnnMETHODSnCECs (CD146-immunobeads), von Willebrand factor, soluble E-selectin, soluble intercellular adhesion molecule-1, soluble vascular endothelial adhesion molecule-1 (sVCAM, all ELISA) and C-reactive protein (CRP, immunonephelometry) were measured in 57 patients with RA, 45 CC and 23 HC patients.nnnRESULTSnCECs in RA [median/interquartile range 8 (5-13.5) cells/ml] were elevated compared with either CC [4 (2-8.5) cells/ml] or HC [4 (1-8) cells/ml] (both P < 0.001). Levels of CECs did not correlate with other markers of ECD or of inflammation but did correlate inversely with sVCAM.nnnCONCLUSIONnEvidence of endothelial damage in the form of mildly increased numbers of CECs is present in RA and is independent of plasma markers of inflammation and of ECD.

Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment

Tumour necrosis factor alpha (TNF-α) and interlekin-6 (IL-6) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA), a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules. As relationships between these processes and molecules are unclear, we tested the hypotheses (a) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules, and (b) that intensive anti-inflammatory treatment improves levels of these indices. We recruited 66 patients with RA, 48 community controls (CC), and 25 disease controls (DC). Plasma TNF-α and IL-6 were compared to markers of vascular biology (vWF, sE-sel), soluble adhesion molecules (sICAM, sVCAM) and routine inflammatory markers (CRP and ESR). Blood was obtained at baseline and at 1xa0week and again 4xa0weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA. With the exception of sE-selectin, RA patients had increased levels of all plasma markers compared to the HCs, whilst levels in the DCs were largely intermediate between RA and the CCs. Within the RA group, sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM (all rxa0>xa00.32, Pxa0<xa00.01). After 1xa0week of combined anti-inflammatory therapy, only CRP, ESR, sEsel and sVCAM were significantly reduced (all Pxa0<xa00.05). In RA, endothelial activation (as sEsel) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications.

Refractory multisystem sarcoidosis responding to infliximab therapy

Chronic progressive multisystem granulomatous disease is seen in 10–30% of patients with sarcoidosis and can result in end organ damage. Corticosteroids are the mainstay of treatment with the addition of cytotoxic agents in severe cases. Some patients are refractory to such treatment and, therefore, management is a challenge. There is currently limited evidence for biological agents such as infliximab, a monoclonal anti-tumor necrosis factor-α antibody in the treatment of multisystem sarcoidosis. We report outcomes of three patients with extensive multisystem sarcoidosis refractory to conventional treatment and treated at our center. Clinical assessment and radiographic imaging were used to assess the response to infliximab treatment. Infliximab therapy induced clinical remission in all three patients, and this clinical response correlated with radiographic evidence of the resolution of granulomatous disease. Serum ACE level was reduced in all cases, and daily steroid dosage was reduced. We propose that infliximab can be an effective treatment in patients with multisystem complex sarcoidosis refractory to conventional drug therapy and can result in sustained clinical remission. Our experience supports the urgent need for randomized controlled clinical trials of anti-TNF therapy in refractory systemic sarcoidosis.

Infliximab leads to a rapid but transient improvement in endothelial function in patients with primary systemic vasculitis

Objective: To assess the immediate effects of tumour necrosis factor α (TNFα) blockade on endothelial function in systemic vasculitis. Methods: Endothelial function was assessed by laser Doppler flowmetry in patients with active vasculitis after 10 infusions of infliximab. For comparison endothelial responses were assessed after five infusions of cyclophosphamide plus methylprednisolone. Results: Endothelial dependent vasodilatation (EDV) improved significantly within 24 hours of infliximab infusion. The median change in red blood cell flux (interquartile range) was 5.7 (4.3–8.2) before infusion v 8.4 (7.5–10.9) at 24 hours; pu200a=u200a0.027. This was not maintained at day 14. No improvement was seen in EDV after cyclophosphamide plus methylprednisolone infusion. Conclusion: The rapid but transient improvement in EDV after TNFα inhibition suggests that TNFα may have a direct role in the impairment of endothelial function.

Relationships between endothelial, inflammatory and angiogenesis markers in rheumatoid arthritis: implications for cardiovascular pathophysiology.

Rheumatoid arthritis (RA), an inflammatory condition with approximately 1% prevalence in the UK population, is the most common seropositive arthritis. Over 50 years ago, epidemiological data demonstrated that patients with RA died younger than those free of RA, an increase in cardiovascular deathswas shown in studies RA of death certificates, and case reports of patients with RA also suggested an increase in thrombotic vascular complications [1–3]. Thus RA is an additional risk factor for cardiovascular disease,