SERONEGATIVE Hughes Syndrome - by popular demand, some papers to read for further information

This post/section will be added to over time, but for now will contain a few papers, as often as Administrators we are asked for this information either out on the forum or by private message. I myself am so grateful as a seronegative patient to have been treated correctly through three pregnancies from 1989 through to 2001. I was lucky enough to have lived in central London and to have been a patient at St Thomas' Hospital. There are many other papers out there to be read, but they involve quite a fee to read, unless in a medical setting with access to an account. I am sure this section will grow over time.

DIRECT LINK to Hughes Syndrome Foundation charity web pages on this subject:

hughes-syndrome.org/about-h... ALSO further reading below:

1. jautoimdis.com/content/6/1/3

2. Patient's Day Transcript 2013 - available from HSF with section from Professor Anisur Rahman talking about Seronegative Hughes Syndrome: hughes-syndrome.org/get-inv...

3. ard.bmj.com/content/62/12/1...

4. ncbi.nlm.nih.gov/pubmed/219...

5. lgfellowship.org/index/Rese...

6. unboundmedicine.com/harriet...'seronegative_APS'__

7. ncbi.nlm.nih.gov/pubmed/235...

omicsonline.org/focal-segme...

8. link.springer.com/chapter/1...

9. asheducationbook.hematology...

10. orpha.net/data/patho/Pro/en...

11, pediatriainp.com/Nefroserve...

12. Several people including a couple of us ADMINS get regular updates from Pubmed, it is about getting time to wade through it all, so these came in via three separate sources other than myself: ncbi.nlm.nih.gov/pubmed/244...

13. ncbi.nlm.nih.gov/pubmed/220...

14: pubfacts.com/detail/2474159...

15. From Professor Hughes' Sero-negative Hughes syndrome

Introduction

Two important lessons which trainee doctors must learn are ‘listen to the patient’, for he/she is telling you the diagnosis and ‘remember, the tests can let you down’. There is a history of unexpected negative tests in other diseases, including rheumatoid arthritis and lupus.

Rheumatoid arthritis

Early in the 1940s, blood tests such as ‘rheumatoid factor’ were introduced in the diagnosis of rheumatoid arthritis (RA). They proved extremely useful, but little by little, observant physicians (notably the late Professor Verna Wright of Leeds) recognised that a number of patients with widespread inflammatory arthritis had negative RA tests. The concept of ‘sero-negative RA’ – doubted by many doctors at the time – stuck, and indeed became clinically very useful. It allowed the recognition of different important conditions such as psoriatic arthritis, ankylosing arthritis and others.

Lupus

In the mid-1900s, a number of blood tests were developed for lupus, culminating in the description of the anti–DNA test in the late 1960s – the gold standard.

But, again a number of patients with all the clinical features of lupus – including, in some cases, a ‘butterfly’ rash, had negative antibody tests.

The concept of ‘sero-negative’ lupus was floated, often by dermatologists, who saw classical lupus rashes, but with negative lupus tests.

It proved a useful concept, contributing later to the development of newer tests (including the important ‘anti-Ro’ antibody) which proved absolutely invaluable in the

definition of some subsets of lupus which had, for example, less of a tendency to kidney involvement.

Hughes syndrome

In 1983, my team described what we initially called the ‘anti-cardiolipin syndrome’. Cardiolipin belongs to a group of molecules called phospholipids – we could have used other phospholipids as test material, so changed the name to ‘anti-phospholipid syndrome’.

We soon began to see patients in our clinic who had many of the clinical features of Hughes syndrome but in whom the two commonly used tests aCL (the anti-cardiolipin test) and LA (the inappropriately named ‘lupus anticoagulant’) were negative. In many cases, the patients only reached our clinic because they had a relative with the diagnosis, or because they had ‘done their homework’ on the internet.

And, of course, many such patients had remained untreated

So, in 2003, together with my colleague, Professor Munther Khamashta, we published the article entitled ‘Sero-negative anti-phospholipid syndrome’ in the Annals of the Rheumatic Diseases (Dec 2003, vol. 62, p1127).

History repeats itself. As in the cases of ‘sero-negative RA’ and ‘sero-negative lupus’, the concept attracted a lot of debate. One reasonable objection was that the term ‘anti-phospholipid-test negative anti-phospholipid syndrome’ was an oxymoron and made no sense – perhaps ‘sero-negative Hughes syndrome’, based more on clinical criteria, was better.

Reasons for ‘sero-negative’ tests

There are three main possibilities. Firstly that the diagnosis is wrong. Secondly, that the tests had been positive years previously but had now become negative (we do see this occasionally). Thirdly, our current tests don’t provide the whole answer. Over the past decade many laboratories, including our own, have been studying other blood tests for the syndrome. To date, some progress has been made. There are some samples which only appear positive on an exhaustive battery of tests, but these are still a minority.

Professor Munther Khamashta and the team at St Thomas’ hospital are actively involved in this research and Munther has recently updated their observations. (Rodriguez-Garcia JL et al. Annals of the Rheumatic Diseases. 2012. Vol 71. P242-244).

What is our experience so far?

Every week, I see at least half a dozen people who fit the clinical picture of Hughes syndrome, but with negative aPL results. There are sometimes clues such as other positive antibody tests (thyroid or ANA for example) or borderline low platelet counts.

But the proof of the pudding lies in the response to treatment (either aspirin/clopidogrel/heparin or warfarin) once the decision is made to treat.

Of course it can be argued that yes, other diagnoses might sometimes respond similarly, but a good physician can usually differentiate.

But – and it is a very big but – many of our patients do not get swift treatment – or even worse are diagnosed as ‘fibromyalgia’ or migraine or even worse, as ‘nerves’.

Another observation, as in the case of Mrs O.L., is that the patient has finally arrived in our clinic because of a positive family history – leaving the obvious question – how many more cases are there out there?

How many cases are we missing?

The numbers could be huge. Take the following medical scenarios – migraine clinics, women with unexpected still birth, unusual teenage epilepsy, unexplained bone fracture, under 40-year olds with angina and no other obvious risk factors, young strokes, abdominal pain after meals. All of these can be seen in Hughes syndrome – all potentially treatable or preventable if the diagnosis is made.

The future

For these reasons, I believe that the study of sero-negative cases of Hughes syndrome (and the need for newer more sensitive or specific tests) is perhaps THE most important of all the current clinical research projects in this disease.

Further studies

Mass blood screening might prove too expensive for many groups, but questionnaires can still provide some clues. For example, we could consider a detailed family history on all of our patients, before widening the net.

And think of the life-changing health benefits and the cost savings to the country if we could teach the medical world to think of the diagnosis – even when the current tests are less than perfect.

Graham Hughes

The London Lupus Centre

London Bridge Hospital

Last edited by

16 Replies

oldestnewest
  • Thanks Mary - you'll be pleased to know that I have managed to persuade Professor Rahman to speak again this year's Patient Day :) However, we have yet to discuss the content of his talk.

  • Yes this issue is not going to go away, the questionnaire for the Sero Negative Hughes Syndrome Book is being compiled now in Europe, and a hard hitting book will be written. The patient histories flowing in and the evidence is very compelling. I do hope that the content of any talk will also cover this subject as we do live in a democratic society! MaryF

  • Er - I think that will be up to him and him alone. We are very fortunate to have professors of his calibre speaking for FREE at our Patients' Day, so I wouldn't dream of dictating the content!

  • Well the feedback after these patient's days is always good, on all the subject matter covered, I have been to three so far and enjoyed them immensely and found the content of the lectures very very good, and they have definitely informed intelligent medical care around myself and children! I look forward to the next one. MaryF

  • Thanks Mary - and also for bringing your useful contacts to the Patients' Day. Yes, we had very positive feedback last year - I am hoping to find a neurologist to speak this year too. I've already nabbed Profs Hughes, Hunt, Rahman and Khamashta...

  • Good stuff... a full house as they say! MaryF

  • Thank you for highlighting Sero Negative Hughes Mary. I believe it to be very poorly understood, and for that matter, very little documented research is in fact available to educate both doctor´s and patients alike. I am very fortunate as I am not seronegative, however, I can only imagine the struggle for patients who are. I know how many hoops I had to jump through to get a diagnosis, and that was even after testing positive for Lupus Anticoagulant 8 times and having 2 DVT´s one of which very nearly killed me. It is a well documented fact that Idiopathic illnesses exist and there is no reason in the 21st century why Antiphospholipid Syndrome shouldn´t be included too. xxx

  • Yes, well I/we are directly responding to what members have asked for. It has been known for years regarding sero negative RA and also Seronegative Lupus, which of course I was also until recently! It is never pleasant for anybody being seriously chronically unwell and if medically sidelined also, even worse. So we aim to help where we can. MaryF x

  • I agree with everything that is said above and of course suffered myself as a result of misdiagnosis because of seronegativity after a PE and a Stroke! Thankfully now I am dx and under the care of both Prof's Khamashta and Hughes and even Prof D'Cruz as well as another respected Consultant Immunologist has confirmed my Hughes Syndrome and declared I am not seronegative!

    I am pleased to say however after talking to Prof Hughes on this subject that he will be talking to Kate at the Charity about updating the HSF website with information on sero-negative Hughes Syndrome. He feels its terribly important to have more information about it as so many people do come looking for help, so I really hope that is forthcoming soon so we can direct people from this site to the HSF site for more clarity and understanding.

  • It just goes to show with a case like yours, how you can be Seronegative for so long, only for it show up and confirm what was suspected in the first place! MaryF x

  • Hi

    Excellent input once again, MaryF. Many thanks.

    My recent antibody test came back "weakly positive" but I see that there are some caveats (please see below):

    I'm scheduled to see a GP to sort out my referral to St Thomas' at the moment. I'm sure I will take a copy of the above articles. Thanks,

    mayomedicallaboratories.com...

    "Cautions

    The immunoassay for phospholipid (cardiolipin) antibodies does not distinguish between autoantibodies and antibodies produced in response to infectious agents or as epiphenomena following thrombosis. For this reason, a single positive test result is not sufficient to meet accepted serologic criteria for the diagnosis of antiphospholipid syndrome (APS).

    Comparative studies and interlaboratory proficiency surveys indicate that results of phospholipid antibody tests can be highly variable and results obtained with different commercial immunoassays may yield substantially different results.(5,6)"

  • Thank you, yes we as ADMINS are reacting to a common question we are asked and also a strong call to have more information available, the patient transcript from the last patient's day contains content from Professor Hughes, also responses to questions and of course another professor clearly answering valid questions. If we not respond and give the public, whether paid up members of the charity or just members on here, what they are asking for then we would not be doing our job. We receive much feedback and input behind the scenes and there will soon be far more information in this section. MaryF x

  • Thank you very much, I will look into the patient transcript.

  • Its seems extremely strange to me that probably the most common question or subject matter that we get asked about on here on a Post or question will concern sero-negative "Hughes Syndrome", and I use that name specifically!

    We want to support all the people that come for information no matter where it is and given that so many people do pass tests eventually it seems idiotic that things are not explained in more detail by more Doctors. There is going to be a big push from us to get this information out there so that we can stop people from suffering anymore than they need to. There are no hidden agenda's and the medical world if they want to help patients should not be sticking to rigid criteria that was designed for research purposes.

    Patients that fall into Doctors surgeries are not research subjects! They want to know what is wrong with them and get treatment to stop them from getting worse...thats it. Its not much to ask for really, is it?

  • If anyone wants to access last years Patients day audio they can do so by going to the bottom of the "pinned posts" list on the top right of this page and click on the the title next to my picture.

  • Thanks You very much

You may also like...