Antiphospholipid syndrome (APS) revisited: Would migraine headaches be included in future classification criteria?

Headaches have been extensively reported in Antiphospholipid syndrome (APS)/Antiphospholipid antibodies (aPL)-positive patients. The aim of this study was to highlight the prevalence of headaches among APS/aPL-positive patients and discuss its association with laboratory, clinical and imaging findings. We searched the literature through Google Scholar and PubMed for publications on the epidemiology, pathogenesis, laboratory, imaging and clinical findings, and management of headaches in APS/aPL-positive patients. The following keywords were used: Antiphospholipid, Hughes syndrome, anticardiolipin, lupus anticoagulant, anti-ß2 glycoprotein I, headache, migraine, tension, and cluster. All reports published between 1969 and 2015 were included. Migraine is the most commonly reported type of headache in APS/aPL-positive patients. Thrombotic and platelet dysfunction hypotheses have been studied to uncover the pathogenic role of aPL in the development of headaches. Several studies are reporting higher levels of aPL in primary and secondary APS migraineurs, but only few reached statistical significance. Migraine patients without clinical signs/symptoms of cerebral infarction rarely show positive imaging findings. Digital subtraction angiography shows promise in demonstrating small vascular lesions otherwise not detected on computed tomography, magnetic resonance imaging, or cerebral angiograms. Although it may be solitary and harmless in many cases, the deleterious effect of migraine on the quality of life of APS patients prompts rapid diagnosis and proper management. An anticoagulation trial is advisable in APS patients with migraine as many cases of severe, refractory migraine resolved with anticoagulation therapy. The profile of migraine headaches discussed in this study permits its candidacy for inclusion in future APS classification criteria.

Hughes syndrome (the antiphospholipid syndrome): a disease of our time.

A pro-thrombotic condition was described in 1983 which was characterised by the presence of circulating antiphospholipid antibodies, as well as peripheral thrombosis (e.g. DVT), a tendency to internal organ involvement, repeated miscarriage, and, occasionally, thrombocytopenia (aPL) (Hughes, Br Med J 287:1088-1089, 1983). Previously, there had been a number of observations, mainly in patients with lupus having "false positive" tests for syphilis, miscarriage and circulating lupus anticoagulants. The description in 1983 had three notable features (a) a detailed comprehensive clinical picture of the syndrome; (b) this description differed from other coagulopathies in showing a propensity for arterial thrombosis (e.g. stroke and heart attack); and (c) this was a syndrome quite independent from lupus. There are indications that the primary antiphospholipid syndrome will turn out to be more common than lupus, though this could still be a reflection of referral practice.

Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis, recurrent abortions, and antiphospholipid antibodies (aPL). However, it is possible to find patients with clinical signs of APS who persistently test negative for aPL (seronegative APS, or SN-APS). The aim of this study was to identify new antigenic target(s) of autoantibodies in APS patients, which may also be recognized in SN-APS. We tested sera from patients with SN-APS with a proteomic approach by analyzing endothelial cell-surface membrane proteins. Sera from SN-APS patients revealed 2 reactive spots corresponding to vimentin, a protein that is shown to bind cardiolipin in vitro. Antivimentin/cardiolipin antibodies were tested in 29 SN-APS patients, 40 APS patients, 30 patients with systemic lupus erythematosus, 30 with rheumatoid arthritis, 30 with venous or arterial thrombosis, and 32 healthy control patients. We observed that not only a large proportion of SN-APS patients but also almost all the APS patients displayed the presence of antivimentin/cardiolipin antibodies. To verify the possible pathogenic role of these autoantibodies, we demonstrated that affinity-purified antivimentin/cardiolipin antibodies induced interleukin receptor-associated kinase phosphorylation and nuclear factor-κB activation in endothelial cells. Our results prompt to identify vimentin as a "new" cofactor for aPL, which may represent a useful tool mainly in SN-APS patients.

Oxidation of LDL and its clinical implication.

Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis. Oxidized LDL (oxLDL) represents a variety of modification of both lipid and apolipoprotein B (apoB) components by lipid peroxidation. This promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. Recent findings also suggest that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) within atherosclerotic lesions and that these complexes appear in the circulation. Autoantibodies (auto-Abs) against oxLDL/beta(2)GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). These autoantibodies significantly correlate with arterial thrombosis. IgG auto-Abs having similar specificity emerge spontaneously in NZWxBXSB F1 mice, which generally are considered to be an animal model of APS, and these mice produce a monoclonal IgG auto-Ab (WB-CAL-1) against oxLDL/beta(2)GPI complexes. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages, which suggests that such IgG auto-Abs are pro-atherogenic. In contrast, IgM anti-oxLDL natural Abs found in the atherosclerosis-prone mice have been proposed to be protective. The presence of such Abs in humans has been documented in many publications but their exact pathophysiological significance remains unclear. In this article, we review recent progress in our understanding of the clinical significance of oxidation of LDL, formation of oxLDL complexes, and Abs in atherosclerotic and/or autoimmune disease.

Hughes Syndrome (the antiphospholipid syndrome): ten clinical lessons.

The APS was described 25 years ago as a triad of manifestations (GRV Hughes). During the last 3 decades the disease became more systemic than systemic lupus erythematosus (SLE). The paper entails many of the old clinical findings as well as novel ones which are still not well documented in large series. The authors also refer to the second hit theory of infectious origin of APS. How to treat and indications for self monitoring the INR are detailed. The question of whether specific IVIG (directed against anti cardiolipin) or anti CD 20 be incorporated into the therapeutic armamentarium employed in APS will be answered in the near future.

Systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune connective-tissue disorder with a wide range of clinical features, which predominantly affects women, especially from certain ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. Treatments range from antimalarial agents to corticosteroids and immunosuppressive agents. This Seminar draws attention to advances in the epidemiology, genetics, cardiovascular risks, lupus nephritis, CNS disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related and quality of life issues. New therapeutic approaches, such as biological agents and mycophenolate mofetil, will also be discussed.

Intravenous immunoglobulin in the treatment of resistant subacute cutaneous lupus erythematosus: a possible alternative.

Subacute cutaneous lupus erythematosus (SCLE) is a common manifestation of systemic lupus erythematosus. In many cases it appears to be resistant to various systemic or topical treatments. Three cases of resistant SCLE with good response to intravenous immunoglobulin (IVIG) are described here suggesting that IVIG could be an alternative treatment in these patients.

Factor XII autoantibodies as a novel marker for thrombosis and adverse obstetric history in patients with systemic lupus erythematosus.

AIM: To investigate the clinical significance of anti-factor XII (FXII) in a large cohort of patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: This study comprised 127 patients with SLE. IgG and IgM anti-FXII were tested by an in-house ELISA. 123 healthy donors comprised the control group. RESULTS: 51 (40%) patients with SLE and 9 (7%) healthy controls were positive for anti-FXII. IgG and IgM anti-FXII were frequently found in patients with thrombosis (28% and 13%, respectively). Levels of IgG and IgM anti-FXII were higher in patients with thrombosis than in the control group (p<0.001 and p=0.005, respectively). Anti-FXII was more frequent in patients with arterial thrombosis (31% vs 4% for IgG and 14% vs 3% for IgM, respectively) and venous thrombosis than in controls (37% vs 4% for IgG). IgG anti-FXII were more frequent in patients with miscarriages and fetal death (35% and 40% vs 4% for IgM). The prevalence of IgM anti-FXII was not different between groups. CONCLUSION: Anti-FXII are frequent in patients with SLE. Their presence is associated with thrombosis and adverse obstetric history, making these antibodies a novel marker for the antiphospholipid syndrome.

Antiphospholipid antibody testing: which are most useful for diagnosis?

Laboratory diagnosis of APS relies on the demonstration of a positive test for aPL. In clinical practice, the gold standard tests are those that detect beta2GPI-dependent aCL or LA. The question on the use of anti-beta2GPI asa routine diagnostic test remains unanswered, and testing for these antibodies should be only performed in very selected cases and not as an alternative to aCL or LA testing. Clinical utility and standardization are still lacking for other aPL specificities; therefore, their application as routine diagnostic tools is not recommended.

Hughes syndrome, the antiphospholipid syndrome: a new chapter in neurology.

The importance of cerebral disease in patients with the antiphospholipid (Hughes) syndrome (APS) is now becoming more widely recognized. The range of neuropsychiatric manifestations of APS is comprehensive and includes focal symptoms attributable to lesions in a specific area of the brain as well as diffuse or global dysfunction. Patients with APS frequently present with strokes and transient ischemic attacks, but a wide spectrum of other neurologic features, also including nonthrombotic neurological syndromes, has been described in association with the presence of antiphospholipid antibodies. In this review, we attempt to highlight the large variety of the neurological features of APS.