G R Hughes

The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe.

The Euro-Phospholipid project started in 1999 with a multicentre, consecutive and prospective design. A total cohort of 1000 patients with antiphospholipid syndrome (APS), derived from 13 countries (Belgium, Bulgaria, Denmark, France, Germany, Greece, Hungary, Israel, Italy, the Netherlands, Portugal, Spain and United Kingdom), has been followed since then. This project allowed the identification of the prevalence and characteristics of the main clinical and immunological manifestations at the onset and during the evolution of APS and demonstrated that it is possible to recognize more homogeneous subsets of clinical significance. Patients with APS associated with systemic lupus erythematosus (SLE) had more episodes of arthritis, livedo reticularis and more frequently exhibited thrombocytopenia and leucopenia. Female patients had more episodes of arthritis and livedo reticularis – both connected with the higher prevalence of migraine and SLE-related APS in women, while male patients had more myocardial infarction, epilepsy and lower limb arterial thrombosis. Childhood onset patients presented more episodes of chorea and jugular vein thrombosis, whereas older onset patients were more frequently male and had more strokes and angina pectoris, but less frequently livedo reticularis.

Renal artery stenosis in the antiphospholipid (Hughes) syndrome and hypertension

Background: Hypertension is common in the antiphospholipid (Hughes) syndrome (APS) and its cause is poorly understood. Anecdotal evidence suggests that renal artery stenosis (RAS) may be a relevant and treatable cause of hypertension. Objective: To investigate the prevalence of RAS in patients with APS and hypertension. Patients and methods: Three groups of patients were evaluated: (1) 77 patients with positive antiphospholipid antibodies (aPL) (60 secondary APS, 11 primary APS, and 6 with aPL only) and uncontrolled hypertension who were receiving two or more antihypertensive drugs; (2) 91 patients (⩽50 years) attending hypertension clinics;(3) 92 normotensive healthy, potential renal transplant donors. Magnetic resonance renal angiography was used to image the renal arteries in all three groups. Results: Group 1: 20/77 (26%) patients had evidence of RAS (16 unilateral and 4 bilateral). Sixteen patients (80%) had smooth well defined stenoses in the proximal third of the renal artery. Three further patients had irregular arteries without distinct stenosis. Group 2: 7/91 (8%) hypertensive patients had RAS (χ2=10.3, p<0.001 v group 1). Group 3: 3/92 (3%) healthy donors had RAS (χ2=18.2, p<0.0001 v group 1). Conclusion: A significantly increased prevalence of RAS (26%) was found in patients with APS and hypertension, compared with relatively young (⩽50 years) hypertensive controls and healthy potential donors.

Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anticoagulant treatment

OBJECTIVE To study the demographic and clinical characteristics of patients with antiphospholipid syndrome (APS) with serious haemorrhagic complications of anticoagulant treatment in an attempt to establish risk factors for bleeding. METHODS Patients with APS who were attending our lupus unit and who presented with severe bleeding while receiving oral anticoagulation were studied retrospectively. Severe bleeding was defined by the need for admission to hospital. Demographic data, clinical features, concomitant diseases and drugs, warfarin doses, duration of anticoagulation, and International Normalised Ratios (INR) at the time of bleeding were collected. RESULTS Fifteen patients were included in the study (12 with systemic lupus erythematosus (SLE) plus APS and 3 with primary APS). The median age was 41.7 (range 27–66) and the median duration of the disease was 12.9 years (range 3–22). Duration of anticoagulation was between 10 days and 17 years. The INR at the time of bleeding was under 3 in 4 patients, between 3 and 4 in 5 patients and above 4 in 6 patients. There were 4 episodes of subdural haematoma, 4 episodes of renal haematoma (two after renal biopsy), 2 episodes of ovarian haemorrhage, 2 episodes of rectal haemorrhage, 1 episode of menorrhagia, 1 episode of haemarthrosis, and 1 episode of spinal haematoma. Concomitant drugs were aspirin in 9 patients, antibiotics in 2 patients, and azathioprine in 3 patients. In 6 patients hypertension was present as a concomitant disease. There were no deaths due to bleeding. Anticoagulant treatment was restarted in all patients and 3 of them had a new episode of bleeding. CONCLUSION No relation was established between age, duration of oral anticoagulant treatment, and bleeding. Concomitant drugs, mainly aspirin, and high blood pressure were present at the time of bleeding in a large number of patients.

Value of IgA anticardiolipin and anti-beta2-glycoprotein I antibody testing in patients with pregnancy morbidity.

Objective: To study the prevalence of IgA antiphospholipid antibodies, particularly anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I (aβ2GPI), in a cohort of patients with pregnancy morbidity. Patients and methods: Serum samples from four groups of patients were studied by an in house enzyme linked immunosorbent assay (ELISA). Group I: 28 patients with primary antiphospholipid syndrome (PAPS) (median age 32.5 years, range 25–34). Twelve patients had a history of thrombosis. All were positive for IgG/M aCL or lupus anticoagulant (LA), or both. Group II: 28 patients with unexplained pregnancy morbidity (median age 35 years, range 23–48). Seven had history of thrombosis. Nine patients were positive for IgG/M aCL. None from this group fulfilled Sapporo criteria for APS. Group III: 28 patients with systemic lupus erythematosus (SLE) (median age 34 years, range 25–52). Eleven had a history of thrombosis. Twenty one patients had IgG/M aCL and/or LA, but only 19 fulfilled Sapporo criteria for APS. Results: IgA aCL were found in 12, 6, and 14 patients from the groups with PAPS, unexplained pregnancy morbidity, and SLE, respectively. Most patients had these antibodies together with IgG/IgM aCL. Three patients from the group with unexplained pregnancy morbidity and two with SLE had IgA aCL alone. IgA aβ2GPI was present in one patient from each group. All IgA aβ2GPI were present together with IgG and/or IgM aβ2GPI. Conclusions: The prevalence of IgA aCL is high in patients with pregnancy morbidity, although IgA aCL are usually present together with IgG and/or IgM aCL. IgA aβ2GPI are not useful in identifying additional women with APS and pregnancy morbidity.

Atherosclerosis and autoimmunity

Novel risk factors for the progression of atherosclerosis such as C-reactive protein (CRP) and adhesion molecules have stimulated much recent interest in the role of inflammation in athero-sclerotic disease. There is also evidence emerging that autoimmunity may have a role in the pathogenesis of atherosclerosis. In this article we explore the evidence for the role of autoimmunity in human atherosclerosis, both in the general population and in the context of the antiphospholipid syndrome. In particular we will focus on several autoantigens, review the evidence for their role in the process of atherosclerosis and the nature of the immune responses.

Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes

OBJECTIVEnTo investigate the associations between HLA class II genes and antiphosphatidylserine/prothrombin antibodies (aPS/PT) in a group of British caucasoid patients with antiphospholipid antibodies (aPL).nnnMETHODSnThis study included 82 patients with aPL. IgG aPS/PT were detected in sera using enzyme-linked immunosorbent assays. HLA-DQB1, DQA1, and DRB1 genotypes were determined by polymerase chain reaction using sequence-specific primers. All results were compared with 177 matched healthy control subjects.nnnRESULTSnIgG aPS/PT were present in 41 of 82 patients (50%). The frequencies of DQB1*0301/4, DQB1*0604/5/6/7/9, and DRB1*1302 alleles were increased in patients with aPS/PT compared with controls. To minimize the interference of the association between anti-beta2-glycoprotein I (anti-beta2GPI) and HLA, patients with anti-beta2GPI were excluded from further analyses, and only HLA-DQB1*0301/4 remained significant compared with controls (odds ratio [OR] 2.75, 95% confidence interval [95% CI] 1.2-6.5, P < 0.03). In the haplotype analysis, HLA-DQB1*0301/4;DQA1* 0301/2;DRB1*04 was significantly increased in patients with IgG aPS/PT compared with controls (OR 4.75, 95% CI 1.72-13.10, P = 0.0063).nnnCONCLUSIONnThe HLA-DQB1*0301/4;DQA1*0301/ 2;DRB1*04 haplotype and its components may influence the production of aPS/PT in the antiphospholipid syndrome, which partly explains the correlation between the lupus anticoagulant and DQB1*03.

Headache and memory loss: rapid response to heparin in the antiphospholipid syndrome

Headache and memory impairment are prominent features of the antiphospholipid (Hughes) syndrome (APS). We have reported that anticoagulation, given, for example, for DVT in patients with this pro-thrombotic disorder, results in a rapid, sometimes overnight, improvement in these symptoms. Clearly, the use of warfarin for patients who have not suffered overt thrombosis is hard to justify, especially when, as is so often the case, the brain MRI is inconclusive. For this reason we have suggested a clinically practicable 2-week ‘therapeutic trial’ of heparin, given to assess possible response to anti-coagulation. We have over the past three months treated 21 APS patients using this therapeutic trial. All patients had a history of severe recurrent headaches – often daily – some migrainous. In all, there was a strong history of memory impairment. Three patients had had dysarthria and in four there had been visual disturbances. Fifteen had had brain MRI’s performed, all of which were normal. Nine patients had previously experienced some improvement on low dose aspirin, but in no patient had there been a satisfactory response. All patients were treated with a 2-week trial of selfadministered low-molecular weight (LMW) heparin. We chose dalteparin (Fragmin) 10 000 units s.c. daily (though other LMW preparations would presumably be equally effective). Patients were reviewed at 7 and 14 days. In all 21 patients, there was a clear clinical response. Headaches were abolished in 19, and in two were partially improved. Memory function was clinically felt to be improved in all 21 patients. An interesting clinical observation was that in four patients (all ANA negative), arthralgia was markedly improved. Clearly, the placebo value of treatment in subjective symptoms is likely to be important. Moreover, a response to heparin may not necessarily predict a future response to warfarin: the improvement in arthralgia, for example, might point to other therapeutic effects of heparin. However, anecdotally, in six patients started on warfarin following a successful ‘heparin trial’ there has been sustained clinical improvement. Our preliminary clinical experience leads us to believe that a ‘therapeutic trial’ of heparin may be a safe and useful clinical tool in what is a common and important clinical situation. We are currently conducting a prospective doubleblind placebo versus LMW heparin trial, with detailed psychometric testing, in patients with Hughes syndrome whose main symptoms are memory loss and headache.

Heparin and osteoporosis during pregnancy: 2002 update

Althoughsignificant bone mass loss is rare duringpregnancy,some situationsmay increasethe risk of symptomaticosteoporosis.Heparin may be necessaryfor a number of pregnantwomen with systemic lupus erythematosus and antiphospholipid syndrome. The osteopenic effect of heparin is low even during pregnancy, and recent data point to a more favourable profile of low-molecular-weight heparins as compared with unfractionated heparin. Lactation results in a significant increase of calcium demands and may be a higher risk period for women at risk for osteoporosis.

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

OBJECTIVEnCardiovascular 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.nnnMETHODSnWe 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 Wegeners granulomatosis, eight with Behcets disease, seven with Churg-Strauss Syndrome, three with Henoch-Schonlein purpura, three with polyarteritis nodosa, three with Takayasus 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 Sjogrens 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.nnnRESULTSnThe 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 <or= 0.03). CV events were more prevalent in the SV patients with abnormal ABPI (45.5% vs 11.6%, P <or= 0.01).nnnCONCLUSIONSnThere is an increased prevalence of an abnormal ABPI in patients with systemic vasculitides implying an increased risk of cardiovascular disease. This simple tool may be clinically useful in identifying systemic vasculitis patients at risk of accelerated atherosclerosis.

Clinical and therapeutic aspects of the antiphospholipid syndrome.

After the original description of the anticardiolipin syndrome I, it became clear that antibodies from affected patients could bind to phospholipids other than cardiolipin; therefore the term antiphospholipid syndrome (APS) seemed more appropriate. The recent demonstration that patients may have phospholipid independent binding antibodies to beta-2-glycoprotein 12, together with the description of few cases of a complete APS in the absence of antiphospholipid antibodies (aPLS)3.4, has led to the unusual term seronegative APS. Initially described as the association of anticardiolipin antibodies and/or lupus anticoagulant with arterial and venous thrombosis, recurrent fetal losses and thrombocytopenia, the APS includes a spectrum of predominantly vascular manifestations, ranging from deep vein thrombosis to the so called catastrophic APS with multiorgan failure and thrombotic thrombocytopenic purpura. Initially the APS was closely associated with systemic lupus erythematosus (SLE), but subsequently the same syndrome could be found in subjects who had no disease other than the presence of the aPLs, allowing the definition of a primary APS. Although a set of exclusion criteria has been proposed to distinguish primary APS from APS secondary to SLE6, an international multicentre study has recently shown that primary and secondary APS share most clinical and laboratory features apart from autoimmune haemolytic anaemia, endocardial valve disease, neutropenia and C4 levels, which are more common in the secondary form? However, APS-related features such as arterial thrombosis, thrombocytopenia and haemolytic anaemia may have an adverse influence on survival when present in patients with SLE8.