Hughes' Syndrome: The antiphospholipid syndrome.

A historical view

Dr. Graham R.V. Hughes, MD FRCP
The Rayne Institute
St. Thomas' Hospital, London, UK.


(First printed in Lupus: An International Journal, Volume 7 Supplement 2: 8th International Symposium on Antiphospholipid Antibodies. Sapporo, Japan, 6-9 October 1998.)

(Full references have been omitted and the reader should refer to the above journal or to Stockton Press).

Introduction

In 1983 we described a complex clinical syndrome, characterised by thrombosis, recurrent abortion, neurological disease and anti-phospholipid antibodies. In the 1983 "Prosser-White Oration" to the British Society of Dermatology, the following passages still seem clinically appropriate 15 years later: "Although many of these patients fall under the general heading of lupus, or lupus-like disease, I believe that the group is sufficiently homogenous and in some ways (such as the frequently negative ANA serology) sufficiently different from typical systemic lupus erythematosus (SLE) to warrant separate consideration. the manifestations of this syndrome are thrombosis (often multiple) and frequently, spontaneous abortions (often multiple), neurological disease, thrombocytopenia and livedo reticularis. The livedo reticularis is often florid on the knees. This may or may not be associated with mild to moderate Raynaud's phenomenon.

These patients' blood pressures often fluctuate, apparently correlating with the severity of the livedo, suggesting a possible reno-vascular aetiology. However, this group of patients rarely has primary renal disease.

The cerebral features are prominent and of three varieties: headaches - often migrainous and intractable. Epilepsy (or abnormal EEGs) - often going back to early teenage. Fortunately, severe or difficult-to-control epilepsy is infrequent. Some patients have chorea. Cerebro-vascular accidents - sometimes transient and seemingly attributable to migraine, are frequently progressive . . . The patients may develop transient cerebral ischaemic attacks or visual field defects, or more significantly, progressive cerebral ischaemia.

Two other features of the syndrome are a tendency to multiple spontaneous abortions and peripheral thrombosis, often with multiple leg and arm vein thrombosis. We have also seen Budd-Chiari syndrome and renal vein thrombosis in some of these patients.

We have, of course, tended to group these patients under the diagnostic umbrella of systemic lupus, through an alternative label of "primary" Sjgren's syndrome covers other patients, and characteristic dry Schirmer's tests and lymphocytic infiltration of the minor salivary glands have been found in a number (though not all) of this group of patients.

To my mind, however, the most striking, and often the most serious feature of this disease is the tendency to thrombosis, particularly cerebral thrombosis. So prominent has this feature been that we have some patients in their 40s and 50s who had been diagnosed as primary cerebrovascular disease or - when the labile hypertension has been observed - as hypertensive cerebrovascular disease. The finding that many of these patients may have high titres of circulating anti-cardiolipin antibodies leads us to believe that a new line of investigation may be possible in such patients."

The clinical description

During the late 1970s and early 1980s, our team collected and documented large numbers of patients with what we called the "anticardiolipin syndrome" - or primary anticardiolipin syndrome - in view of the absence of "classical" lupus features.

My early research fellows, including Margaret Byron, Helen Englert (who used to refer to the syndrome as the "GRVH syndrome"), Bernie Colaco, Genevieve Derue, Mee Ling Boey and Aziz Gharavi, were later joined by Nigel Harris, Charles Mackworth-Young, Sozos Loizou, Bupendra Patel, John Chan and Ron Asherton, and later Munther Khamashta, who has done so much to characterise the mechanisms of the syndrome.

We presented our findings at a number of meetings, including the British Society for Rheumatology, American Rheumatism Association and, subsequently, the ILAR meeting in Sydney.

In 1982 I gave the "Heberden Round" to the British Society for Rheumatology, and first presented a patient with full primary anti-phospholipid syndrome. (Interestingly, this patient, 16 years later, is still anti-cardiolipin antibody positive and still has no clinical and serological features of lupus.) In 1996 at the 7th International Symposium of Anti-phospholipid Antibodies, held at New Orleans, a comprehensive review of the syndrome was published by the congress organisers, Aziz Gharavi and Wendell Wilson. The ramifications spread even further with the work of Vaarala, linking the anti-phospholipid antibodies, lupus and atheroma.

Between 1983 and 1987, we published detailed series and description of the associations with recurrent miscarriage, livedo, renal thrombosis, strokes, liver thrombosis, pulmonary hypertension, myleopathy, chorea, large-bowel infarction, thrombocytopenia and dementia.

The primary anti-phospholipid syndrome (Hughes' syndrome)

We published similar features seen in patients without systemic lupus, including Behet's disease, Degos disease, transverse mylepathy, and "idiopathic" thrombocytopenia. Subsequent reports included migraine, epilepsy, heart valve disease and Addison's disease.

We included immunoassays and standards for antiphospholipid antibodies (aPL), work led largely by Aziz Gharavi and Nigel Harris.

It was clear from the beginning that, while the syndrome was associated with classical lupus, it was separable from it:

"for distinct syndrome it most certainly is . . . occurs in ANA-negative LE patients, atypical lupus patients and, as expected, individuals with no lupus at all" . . . the origin of the primary anti-cardiolipin syndrome.

The antibodies also reacted with other phospholipids, so we changed the name from primary "anticardiolipin syndrome" to primary "anti-phospholipid syndrome."

Two years later, in 1989, our group, led by Ron Asherton and Donato Alarcon-Segovia and his colleagues, published detailed series which confirmed the clinical features described in our earlier papers.

However, Gharavi, among others, had always maintained that nature abhors antibodies and react with phospholipids. It mistrusts antibodies which bind to anything other than proteins. Thus the discovery of the "co-factor" provided a major impetus in the study of the syndrome.

The co-factor

In 1990, three groups, Takao Koike and colleagues, Monica Galli and colleagues and Steven Krilis and his team, reported that the aCL associated with clinical thrombosis required a plasma protein "co-factor" to bind cardiolipin in ELISA plates. This co-factor was identified as ߲- glycoprotein 1 (߲GP1), a naturally occurring anticoagulant. There are probably a number of phospholipid-binding "co-factor" proteins, including prothrombin.

Such is the importance of these co-factors, both to clinical testing and to investigate clotting mechanisms that much of recent APS conferences has focussed on them.

Some workers have suggested the cumbersome title "anti-phospholipid co-factor syndrome". recent studies have suggested that even this title may be wrong: for example, monoclonals have, in some studies, been shown to bind to a trimolecular complex of phospholipid protein C and co-factor.

The interactions between aPL, phospholipid and protein(s) are still under debate. In 1994 a group of my colleagues at the Louvain meeting suggested the name "Hughes' syndrome", as being more scientifically honest at this stage. I am honoured and touched by those of you who felt fit to use this eponym.

Background

The history of the APS can, with a little poetic licence, be traced back (as can almost all lupus-related syndromes) to William Osler, who described strokes as a feature of lupus. Following that time, dozens of papers on lupus have included the observations of a tendency to thrombosis, to miscarriage, and to all the features of the APS. None of these papers put together the constellation of features of the syndrome. For example, one of our own papers in the early 1970s described an association between a false positive VDRL and thrombosis on the oral contraceptive pill, but without really grasping the full significance of the association.

Historically, the oldest "immunological" test related to lupus is the Wasserman reaction. Moore and Mohr in 1952 recognised that biologically false positive serological 9BFP-STS) tests for syphilis could occur, especially in lupus.

In 1957, Laurell and Nilsson found that the so-called lupus inhibitor (or "lupus anticoagulant") was frequently associated with BFP-STS, and Lee and Saunders showed that these were aPL, an observation confirmed by later studies using monoclonal antibodies.

Harris and Gharavi, in my laboratory, set up anti-cardiolipin assays that proved to be 400 times more sensitive than VDRL agglutination test and, even more importantly, instituted international standardisation workshops.

In clinical lupus studies, Bowie et al. (1963), reported a paradoxical occurrence of thrombotic lesions in patients with a circulating LA, a finding confirmed by Lechner (1969) and Mueh et al. (1980), Beaumont et al. (1954) described a patient with circulating anticoagulant and seven previous abortions and this was followed by similar observations by Nillson et al. (1975), Soulier and Boffa (1980) and Carreras et al. (1981), who also undertook important studies suggesting a link between LA and vascular prostacycline formation. The vascular link has been strengthened by the interesting associations between aPL family of antibodies, accelerated atheroma and vascular disease, work pioneered by Outi Vaarala.

Conferences and workshops

In 1984, we held the first international workshop on APL, followed two years later, after our move of the lupus research unit to St Thomas' Hospital, by the second. Again, we rather grandly gave it the title "World Symposium on Anti-phospholipid Antibodies". Since then, there have been a further five conferences. these conferences have produced a tightly knit group of clinicians and researchers; certainly in my own clinical experience this is the most collaborative grouping of units with whom I have ever worked.

from the very beginning, under the leadership of colleagues such as Aziz Gharavi, Nigel Harris, Munther Khamashta, Marie Claire Boffa, Angela Tincani, Luigi Meroni, Yehuda Shoenfeld, Ron Derksen, Jean Claude Piette, Takao Koike and others, there has been a spirit of standardisation, of scientific and clinical sharing. . . . . Takao Koike . . . . His contributions to this field are outstanding.

[Picture]