Hughes syndrome: The discovery of the antiphospholipid syndrome.

In the 40 years since the original detailed description of antiphospholipid syndrome (APS), the condition has come to be regarded as one of the most common autoimmune diseases. The impact of the description has been enormous - for example, the recognition that some individuals with connective tissue diseases require anticoagulation rather than corticosteroids or anti-inflammatory treatment has bought about fundamental change in medical practice. In obstetrics, APS is now regarded as the most important prothrombotic cause of recurrent pregnancy loss - with pregnancy success improving from below 20% to current live birth rate over 80%. In neurology, APS may be associated with up to 20% of strokes in people under 40 - a striking figure not least in terms of medical economics, let alone in potentially preventable suffering. In vascular medicine, APS links immunology with thrombosis and vascular disease and may well provide insights into immunological factors in the pathogenesis of atherosclerosis.

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.

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.

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.

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.

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.

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.

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.

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.

Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus?

We retrospectively studied a large cohort of patients with primary antiphospholipid syndrome (APS) from 4 different referral centers to analyze the clinical and serologic features and, specifically, to determine the number of patients going on to develop systemic lupus erythematosus (SLE) or other autoimmune disease after long-term follow-up. The study included 128 unselected patients with primary APS who fulfilled the Sapporo International Criteria from 4 different tertiary hospitals in the United Kingdom, Mexico, and Spain. The patients had attended the referral centers between January 1987 and July 2001. We reviewed clinical and serologic characteristics according to a pre-established protocol. We used univariate analysis with the chi-squared or Fisher exact test and logistic regression to analyze possible factors related to the coexistence of SLE and APS. Ninety-seven female and 31 male patients fulfilled the criteria, with a median age of 42 +/- 12 years (range, 16-79 yr), and with a mean follow-up of 9 +/- 3 years (range, 2-15 yr). The main manifestations included deep vein thrombosis in 62 patients (48%), arterial thrombosis in 63 (49%) patients, pregnancy loss in 177/320 (55%) cases, and pulmonary embolism in 37 (30%) patients. Other clinical manifestations were migraine in 51 (40%) patients, thrombocytopenia in 48 (38%), livedo reticularis in 47 (37%), and valvular disease in 27 (21%). Serologic findings were anticardiolipin antibodies (aCL) IgG positive in 110 (86%) patients, aCL IgM in 36 (39%), lupus anticoagulant in 71 (65%), antinuclear antibodies in 47 (37%), and positive Coombs test in 5 (4%) patients. During the follow-up and after a median disease duration of 8.2 years (range, 1-14 yr), 11 (8%) patients developed SLE, 6 (5%) developed lupus-like disease, and 1 (1%) developed myasthenia gravis. The remaining 110 patients (86%) continued to have primary APS. After the univariate analysis, a family history of lupus, the presence of Raynaud phenomenon, migraine, psychiatric features, multiple sclerosis-like features, hemolytic anemia, low C3 and C4, and Coombs positivity conferred a statistically significant risk for the subsequent development of SLE (p < 0.05). Only the presence of Coombs positivity had statistical significance (odds ratio, 66.4; 95% confidence interval, 1.6-2714; p = 0.027) after the logistic regression evaluation. The current study confirms that progression from primary APS to SLE or lupus-like disease is unusual, even after a long follow-up. Only 3 patients developed anti-dsDNA antibodies. The presence of a positive Coombs test might be a marker for the development of SLE in patients with primary APS.

Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens.

PURPOSE: Thalidomide is effective for the treatment of severe cutaneous lupus. Our aim was to study the safety and efficacy of different doses of thalidomide in this condition. METHODS: We studied patients with severe cutaneous lupus that was unresponsive to antimalarials, prednisolone, methotrexate, azathioprine, and cyclosporin A. Starting doses of 100 mg daily (n = 16 patients), 50 mg daily (n = 17), or 50 mg on alternate days (n = 15) were compared. The response to thalidomide was categorized as complete remission, partial remission, or no visible improvement. All patients received a baseline electromyogram (EMG) followed by repeat EMG every 3 to 6 months, or sooner if neuropathic symptoms developed. RESULTS: Forty-eight patients (46 female; mean [+/- SD] age, 44 +/- 12 years; range, 22 to 71 years) with discoid lupus (n = 18), subacute cutaneous lupus (n = 6), or systemic lupus erythematosus with skin involvement (n = 24) were included. The response rate was 81%, including 29 patients (60%) in complete remission and 10 (21%) in partial remission. Nine patients (19%) failed to respond. Thirteen patients (27%) developed peripheral neuropathy, which was EMG-proven in 11, including 4 patients in the 50-mg alternate-day group. Other side effects included drowsiness, constipation or abdominal pain, and amenorrhea. The relapse rate after stopping thalidomide was 67% (26/39). There was no association between a positive response to the drug and either starting doses or cumulative dose. Similarly, no association was found between peripheral neuropathy and the starting or cumulative dose. CONCLUSION: Thalidomide is effective for the treatment of severe cutaneous lupus. There were no clear dose-dependent effects. However, the high incidence of neurotoxicity, even at low doses, suggests that it may be most useful as a remission-inducing drug.

Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus.

We evaluated the clinical significance of aPT and aPS-PT by testing for the presence of these antibodies in 212 SLE patients and in 100 healthy individuals. Results show that anti-prothrombin antibodies were found in 47% of the patients (aPT in 31% and aPS-PT in 31%). Their presence did not correlate with that of aCL, anti-beta2GPI, LA and/or anti-protein S. IgG but not IgM aPT were more frequently found in patients with thrombosis than in those without. IgG and IgM aPS-PT were also more frequent in patients with thrombosis (venous and/or arterial) than in those without. Levels of IgG aPT and IgG and IgM aPS-PT were higher in patients with thrombosis than in those without. Although aPT and aPS-PT were more frequently found in women with adverse obstetric history than in those without, the differences were not statistically significant. More significantly, 48% of the patients with aPL-related clinical features who were negative for standard tests had antiprothrombin antibodies. We can conclude that aPT and aPS-PT are frequently found in SLE. Their presence is associated with thrombosis, making these antibodies potential markers for the APS. Testing for these antibodies could be of clinical benefit in patients who are negative for the routinely used tests.

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.

Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5.

BACKGROUND: Prolonged anticoagulation is the treatment of choice for patients with thrombosis and the antiphospholipid syndrome. However, there is still debate about the optimum intensity of anticoagulation. METHODS: The study included 66 patients with antiphospholipid syndrome (Sapporo criteria) and previous thrombosis. All were receiving oral anticoagulation to a target international normalized ratio of 3.5. Every patient was individually interviewed to recall major bleeding and thrombotic episodes during the previous 12 months. RESULTS: Patients were mainly women and white. The rate of major bleeding was 6 cases per 100 patient-years (95% confidence interval [CI] 1.6-15.0). The rate of intracranial bleed was 1.5 per 100 patient-years (95% CI, 0.04-8.4). None of the bleeding episodes was fatal. The rate of thrombotic recurrences was 9.1 cases per 100 patient-years (95% CI, 3.3-19.6). Most recurrences took place in the same vascular bed as the original thrombosis. Age, time receiving anticoagulant therapy, primary vs secondary antiphospholipid syndrome, positivity for anticardiolipin antibodies, positivity for lupus anticoagulant, previous arterial thrombosis, previous stroke, previous venous thrombosis, and previous thrombocytopenia were not predictive of bleeding events. However, the risk of thrombotic recurrences was independently higher in patients who were receiving anticoagulation for longer periods. CONCLUSIONS: The risk of intracranial and fatal bleeding in patients with definite antiphospholipid syndrome and previous thrombosis treated with oral anticoagulation to a target international normalized ratio of 3.5 is similar than in groups of patients treated to lower target ratios. The risk of thrombotic recurrences, even during anticoagulation, was high. Most recurrences took place in the same territory as original thromboses.