Increased risk of vascular complications in Takayasu's arteritis patients with positive lupus anticoagulant.

OBJECTIVES: Previous studies have shown antiphospholipid antibodies (aPL) to be prevalent in primary systemic vasculitides; however, the possible clinical impact of aPL positivity in such patients has not been explored in depth. The aims of this study were to determine the prevalence of aPL in patients with Takayasu's arteritis (TA) and to ascertain whether aPL positivity was predictive of a worse clinical outcome in TA. METHOD: Clinical data were collected retrospectively on 22 TA patients over an 11-year period. Data collected included the presence of lupus anticoagulant (LA) and immunoglobulin (Ig)G and IgM anticardiolipin antibody (aCL) titres. Adverse clinical outcomes included cerebrovascular accident (CVA), transient ischaemic attack (TIA), loss of vision, vascular lesions (carotid, femoral, renal, coronary, or other vessels) requiring stenting, angioplasty, or other surgical intervention, aortic valve replacement, end-stage renal failure or death. RESULTS: Persistently positive aPL or a concurrent diagnosis of antiphospholipid syndrome (APS) was found in 45% (n = 10) of TA patients while 55% (n = 12) had TA alone. LA was present in a significant proportion of TA patients with aPL (p = 0.002). Vascular complications occurred in 70% (n = 7) of TA patients with aPL and in 25% (n = 3) of TA patients without aPL (p = 0.035). LA was associated with a higher prevalence of vascular complications. CONCLUSIONS: Persistently positive aPL are present in a significant proportion of TA patients. This study shows that vascular complications and need for intervention are more prevalent in TA patients with aPL, particularly those with LA. Prospective studies are needed to determine the long term prognosis in such patients.

Morbidity and mortality associated with subglottic laryngotracheal stenosis in granulomatosis with polyangiitis (Wegener's granulomatosis): a single-centre experience in the United Kingdom.

OBJECTIVES: We aimed to determine the prevalence of symptomatic subglottic laryngotracheal stenosis in patients with granulomatosis with polyangiitis (Wegener's granulomatosis); we also wanted to characterise the clinical outcomes and surgical interventions required, and the relapse rate in our cohort. METHODS: We undertook a retrospective clinical review of all granulomatosis with polyangiitis patients with symptomatic subglottic laryngotracheal stenosis attending St Thomas' Hospital, London, United Kingdom. RESULTS: Symptomatic subglottic laryngotracheal stenosis developed in 16 per cent of granulomatosis with polyangiitis patients attending our clinic. The median age of patients at diagnosis was 44 years (range: 34-81 years); 78 per cent of those presenting with subglottic laryngotracheal stenosis were women and 22 per cent were men. All patients were white; 67 per cent of patients were proteinase 3-antineutrophil cytoplasmic antibody-positive and 67 per cent developed relapsing disease requiring repeated surgical intervention. Subglottic laryngotracheal stenosis relapse was not associated with active systemic vasculitis elsewhere. CONCLUSION: Subglottic laryngotracheal stenosis is an uncommon but significant complication of granulomatosis with polyangiitis. Management of subglottic laryngotracheal stenosis requires a multi-disciplinary approach, with both rheumatological and otolaryngological expertise involved, given the relapsing nature of the disease.

Cardiac complications of Behcet's disease.

We describe two patients with Behcet's disease (BD) with cardiac complications and their response to treatment. This report adds to the evidence that cardiac involvement can be a feature of Behcet's disease and may be more common than previously thought.

Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis.

OBJECTIVE: The objective of this paper is to report the clinical outcome of B cell depletion therapy in 18 patients with refractory lupus nephritis (LN). METHODS: Eighteen patients received rituximab on an open-label basis with prospective evaluations. All patients had renal disease refractory to conventional immunosuppressive therapy, including intravenous cyclophosphamide (CyC). All patients fulfilled the revised ACR classification criteria for SLE. Rituximab was given as 2 × 1 g infusions with 500 mg iv CyC and 500 mg iv methylprednisolone, two weeks apart. Complete remission (CR) of nephritis at six months was defined as normal serum creatinine and serum albumin levels, inactive urine sediment, and proteinuria < 0.5 g/day; partial remission (PR) was defined as a ≥50% improvement in all renal parameters that were abnormal at baseline. Clinical response was assessed by the British Isles Lupus Assessment Group (BILAG) score pre- and post-rituximab treatment, and efficacy was recorded by extent and duration of B lymphocyte depletion (normal range 0.100-0.500 × 10(9)/l). Follow-up data were collected at six months, one year post-treatment and at the most recent clinic visit. RESULTS: At six months, 11/18 patients reached renal CR and two of 18 PR. The mean global BILAG scores for responders decreased from 15 (SD 10) to 5 (SD 3), and a total of ten A scores disappeared. Five patients failed to show complete or partial renal response despite peripheral B lymphocyte count depletion, and progressed to end-stage renal failure (ESRF) and dialysis. Four of these patients had severe proliferative, crescentic nephritis, of whom three had Class IV-G, one Class III and one late membranous glomerulonephritis. One patient died six years after rituximab therapy from overwhelming sepsis while on long-term haemodialysis. CONCLUSION: Rituximab therapy achieved a response in 13/18 patients with refractory LN. However, in patients with rapidly progressive crescentic LN, when there is already evidence of significant renal impairment, rituximab therapy may not prevent progression to ESRF and dialysis. Our data also suggest that severe Class IV-G LN may be associated with a poor response to therapy.

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) may require prolonged periods of corticosteroid therapy which lead to excessive weight gain and increased cardiovascular risk. OBJECTIVE: To assess the utility of a low glycaemic index diet in patients with corticosteroid dependent SLE in achieving weight loss and improving glycaemic control. DESIGN: A total of 23 women were enrolled in a 6 week study. All had mild, stable SLE, were receiving corticosteroids and had a body mass index > 25 kg/m(2). Subjects were randomly assigned to a low glycaemic index (Low GI) diet or a calorie restricted (Low Cal) diet. The primary end point was weight loss. Secondary end points included tolerability of diet, bio-markers of cardiovascular risk, disease activity, fatigue and sleep quality. RESULTS: Weight loss in both treatment groups was significant (mean ± SD: Low GI diet 3.9 ± 0.9 kg; Low Cal diet 2.4 ± 2.2 kg, p < 0.01 from baseline in each group). There were also significant improvements in waist and hip measurements. However, the difference in weight loss and waist and hip measurements between the two diet groups was not statistically significant. There was a statistically significant reduction in Fatigue Severity Scale in both diet groups, (p < 0.03). Both Low GI and Low Cal diets were well tolerated, resulting in no serious adverse effects or increase in disease activity. CONCLUSION: Significant weight loss is achievable over 6 weeks in a diet-specific trial in subjects with stable SLE, who are on low dose prednisolone. Both diets were equally tolerable, and did not cause flares in disease activity. Our results suggest that dietary manipulation may significantly improve fatigue in subjects with SLE.

Correlation of 24-hour urinary protein quantification with spot urine protein:creatinine ratio in lupus nephritis.

OBJECTIVES: Twenty-four hour urine collection has been the foundation for monitoring patients with lupus nephritis. However, the use of protein to creatinine ratios in spot urine samples is now widely used. We aimed to evaluate the validity of this method cross-sectionally and longitudinally. METHODS: A cross-sectional retrospective study was conducted. Records of 486 lupus nephritis patients were searched for paired results of 24-h quantification of urinary protein and a random spot urine protein to creatinine ratio and were examined over a three-year period. RESULTS AND CONCLUSIONS: Ninety-five lupus nephritis patients had paired results and were included in the final analysis, male/female 14/81, mean age 36.5 years. Over a three-year period there were a total of 137 samples from 95 patients. For the entire dataset, there was a significant correlation between protein:creatinine ratio and 24-h urine collection protein (mg), Spearman Rho correlation coefficient was 0.869, p < 0.0001 with (R (2 )= 0.504). There was also a strong correlation for longitudinal data, n = 14 at two-years Rho 0.910, p < 0.0001 with (R (2 )= 0.878), n = 8 at three-years Rho 0.909, p < 0.0001 and (R (2 )= 0.73). We have shown for the first time in a UK population of lupus nephritis patients, well trained in producing 24-h collection, that the spot protein:creatinine ratio correlates well with 24-h urinary total protein excretion. Having a simple, reliable, reproducible and cost-effective test such as the spot urine protein:creatinine ratio is therefore a valuable tool with which to monitor disease progression.

Mathematical analysis of antigen selection in somatically mutated immunoglobulin genes associated with autoimmunity.

Affinity maturation is a process by which low-affinity antibodies are transformed into highly specific antibodies in germinal centres. This process occurs by hypermutation of immunoglobulin heavy chain variable (IgH V) region genes followed by selection for high-affinity variants. It has been proposed that statistical tests can identify affinity maturation and antigen selection by analysing the frequency of replacement and silent mutations in the complementarity determining regions (CDRs) that contact antigen and the framework regions (FRs) that encode structural integrity. In this study three different methods that have been proposed for detecting selection: the binomial test, the multinomial test and the focused binomial test, have been assessed for their reliability and ability to detect selection in human IgH V genes. We observe first that no statistical test is able to identify selection in the CDR antigen-binding sites, second that tests can reliably detect selection in the FR and third that antibodies from nasal biopsies from patients with Wegener's granulomatosis and pathogenic antibodies from systemic lupus erythematosus do not appear to be as stringently selected for structural integrity as other groups of functional sequences.

A case of mistaken identity: subacute bacterial endocarditis associated with p-antineutrophil cytoplasmic antibody.

Seventeen cases of subacute bacterial endocarditis (SBE) associated with antineutrophil cytoplasmic antibody (ANCA) have been reported. Fifteen such cases have been associated with c-ANCA postivity and two with dual p-ANCA and c-ANCA antibodies. The authors describe a 61-year-old man with sole p-ANCA positive autoantibodies on immunofluorescence presenting with Staphylococcus aureus SBE of the aortic valve. To the best of our knowledge this is the only reported case of sole p-ANCA positive SBE. Full recovery was achieved with antibiotic treatment. ANCAs are known to be associated with infection and their characterisation in acute illness is key in differentiating a true vasculitis from an infection. Unnecessary immunosuppression can be prevented with full investigation of such patients, including both immunofluorescence and ELISA.

The Euro-Lupus Nephritis Trial: the development of the sequential treatment protocol.

The treatment of lupus nephritis has evolved over many decades and cyclophosphamide has become the standard of care for proliferative lupus nephritis. This article describes the development of a protocol that utilises fixed low doses of cyclophosphamide followed sequentially by azathioprine as a maintenance agent, which has stood the test of time. As novel therapies and biologic agents are more widely used, it is likely that cyclophosphamide use will decline. In particular the prolonged high-dose regimen pioneered by the National Institutes of Health studies will no longer be used on account of its toxicity.

Ankle-brachial pressure index: a simple tool for assessing cardiovascular risk in patients with systemic vasculitis.

OBJECTIVE: Cardiovascular disease may be increased in patients with systemic vasculitides (SV). The Ankle-Brachial Pressure Index (ABPI) is a non-invasive tool for the assessment of cardiovascular risk (CV). Our aim was to determine the prevalence of an abnormal ABPI in patients with SV and healthy controls and to correlate with clinical and serological parameters. METHODS: We studied 54 consecutive vasculitis patients (20 males) attending the vasculitis clinic and 49 healthy subjects. Patients were classified according to the ACR 1990 criteria and the Chapel Hill Consensus definitions. There were 18 patients with Wegener's granulomatosis, eight with Behcet's disease, seven with Churg-Strauss Syndrome, three with Henoch-Schonlein purpura, three with polyarteritis nodosa, three with Takayasu's disease, three with p-ANCA associated vasculitis, three with urticarial vasculitis, two with cutaneous leucocytoclastic angiitis, one with microscopic polyangiitis, one with primary central nervous system angiitis, one giant cell arteritis and one with cutaneous vasculitis secondary to Sjogren's syndrome. Traditional risk factors as well as glucose, lipid profile, CRP, hsCRP, ANCA and aPL were assessed. ABPI was measured according to a consensus statement on the methodology. RESULTS: The ABPI was abnormal in 11/54 (20.4%) of SV patients and 2/49 (4%) of the control group (chi(2) with Yates correction = 4.8, P

Microangiopathic haemolytic anaemia secondary to lupus nephritis: an important differential diagnosis of thrombotic thrombocytopenic purpura.

Systemic lupus erythematosus (SLE) has been described as a cause of microangiopathic haemolytic anaemia (MAHA), however there is little literature to support this assertion. We report on three patients presenting with SLE and MAHA with a clinical picture indistinguishable from thrombotic thrombocytopenic purpura (TTP), who had underlying lupus nephritis. They all had significant proteinuria and normal Von Willebrand Factor cleaving protease (vWF-CP) levels. Their MAHA fitted better for haemolytic syndrome (HUS) and their cerebral signs were explained either by malignant hypertension or cerebral lupus. Their MAHA only improved when the appropriate treatment for lupus nephritis was given. We propose that the previously described association between SLE and MAHA, in actuality relates to the underlying presence of lupus nephritis causing haemolytic uraemic syndrome, not TTP. Significant proteinuria was present in all cases of MAHA due to lupus nephritis, so may be a useful discriminatory sign. Furthermore the demonstration of a normal vWF-CP assay aided in the distinction between TTP and MAHA due to lupus nephritis. All our patients responded to mycophenolate mofetil suggesting this may be useful in other cases of lupus nephritis causing HUS.