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Complicated Systemic Lupus Erythematosus

Lupus is a clinical syndrome, the cause of which remains uncertain. It is a member of the family of autoimmune rheumatic diseases. Lupus is more common in women, and certainly more common amongst the black and Chinese population. It’s clinical diversity is at least apparently matched by its serological diversity.

Lupus is far from confined to the skin. Indeed, we now recognize lupus in all its many systemic forms, much of the work being done in this century in various parts of the United States. At least 10% of the patients in my cohort who have been misdiagnoses as suffering from lymphomas or other malignant diseases. Virtually all lupus patients of course have musculoskeletal involvement, substantial number have dermatologic involvement, and a large number of patients also have gastrointestinal disease.

I want to make a few general comments about the treatment of lupus before I come back to some more specific problems a little later on. Clearly, fatigue is a major problem for lupus patients. I’ll be discussing that in some detain. Therefore it is avoidance and the avoidance of stress, where that is feasible, is important.

Now it’s clearly not practical to suggest to a lupus patient that the best holiday that they could have would be perhaps two weeks in Greenland in December. But nevertheless you have to persuade them to be a little bit sensible. Ultra-violet light can lead to an increase in apoptosis. And it’s apoptosis that leads to the production of the surface expression of nuclear proteins and thus gives us a mechanism for the production of many autoantibodies in patients with lupus. Many patients with lupus ask me about dietary manipulation. If you put laboratory mice - these mice are the mice which are destined to get a form of lupus - onto diets that are low in saturated fats and have fish oils, these mice will.

They will live longer, they will have lower DNA antibody levels and less kidney disease as well. Clearly, given the vast number of patients with lupus being female, questions of hormonal manipulation must be considered. And although we wait for this out of the SLE-dye study which is due in a couple of years time which will tell us definitively about the issue of postmenopausal hormone replacement. From preliminary evidence it appears that about one patient in seven, given hormones after the menopause, will develop a flare of the disease.

It’s also important to ask, is it safe to immunize patients with lupus? Because they have a highly disorganized immune system. The British Society of Rheumatology considered this question relatively recently and concluded that it would be safe - or it is safe - to immunize patients with lupus if the dose of steroids is less than 10 mg and if they are not on azathioprine or cyclophosphamide. I would certainly concur with that view. Live viral modified vaccines are more of a problem, especially for patients on Imuran or Cytoxan and are not recommended.

The problems with pregnancy would be a whole other lecture in itself. Suffice it to say that pregnancy represents a far greater threat to the fetus than it does to the mother. Approximately one pregnancy in four in a lupus patient will end prematurely.

When the going is not too bad when there is lethargy and fatigue, arthralgia, myalgia, rash, most patients can be treated very successfully with non-steroidal antiinflammatories and antimalarials. In the presence of frank arthritis, pleuritis, pericarditis.

Treatment of cerebral disease is more controversial. In North America during the years that I have been going around, it seemed to me that CNS lupus was treated more aggressively, in the sense of higher doses of steroids being used.

Now in terms of lupus survival we have clearly moved ahead very dramatically in the last 50 years. We now anticipate that 95% of lupus patients will live five years. We know also that the 10-year survival approaches 90%.

In terms of the causes of death - and I’m showing you figures from my own years - this is what we’ve found over the last 20-years. These were 265 patients that I personally followed over this 20-year period; 30 of the patients have died, so a little under 10%. The causes of death fall into four groups. Either infection, or cancer, vascular problems, or miscellaneous group. The problem of infection obviously relates to the use of immunosuppressive therapy and the sort of problems.

Then we come to the more thorny issue of fibromyalgia. Here’s some very interesting differences that have appeared in the medical press. In the United States the generally accepted figure seems to be something in the region of 20%. So 20% of lupus patients appear to meet the criteria for fibromyalgia. In contrast to the United Kingdom, both in the study by Caroline Golden of 99 patients in her cohort with lupus and in my cohort, we have found much smaller numbers; well under 10%. I had at first surmised that this might be due to some increased stoicism amongst British patients, but I’m not sure that is really true. But the fact that it probably isn’t true was also brought home to me by a member of the Lumina group who was chatting with me over a poster this week, and who emphasized that in Alabama their figure is also only 8%. So whether there are differences in the patients or there are perhaps differences in the methodologies remains uncertain. But perhaps the most important point to make is that even if the figures of 20% are correct, it still means that the majority of patients with lupus complaining of fatigue will not have fibromyalgia.

I want to turn now to the question in the dermatological system of alopecia. Now alopecia for patients represents sort of a further and a real genuine disaster. These sorts of lesions that you see over here and here are permanent. Indeed they have been present on this patient for some 10 years. Now in my own group - we’ve just looked at the figures recently - and 18% of our patients appear to have alopecia. Most of the published is a little higher, up to 40%. In 9% of these 49 patients the alopecia was severe and scarring. Now since alopecia is perhaps not something which we spend a lot of time thinking about, I’ve highlighted its pathological features. It’s the sebaceous glands that seem to be the first victim early in the course of the disease, and indeed they seem to be destroyed before the hair follicle is destroyed. There is an intense inflammatory cellular reaction around the hair follicle. But eventually the hair forming epithelium is destroyed. The mechanism of action appears from the dermatological literature to be somewhat uncertain, but certainly appears to be lymphocyte mediated. The best treatment of alopecia, certainly scarring alopecia, is to treat the lupus flare quickly because it often will respond to the treatment with immunosuppression. In addition, in the literature - although frankly, the evidence base for this is, I think, rather thin - there has been the description of intralesional cortical steroids, oral thalidomide and interferon 2 alpha. But as I said, prevention is the best treatment for scarring alopecia. And short of actually going to a wig-maker, some patients have also tried cosmetic surgery and carbon dioxide laser. But scarring alopecia remains a particularly difficult problem to manage.

Turning now to the musculoskeletal system. About 5% of lupus patients have an erosive arthritis and clearly there is an overlap with rheumatoid arthritis. And some of these patients are referred to as "Rhupus" patients. There have been some very interesting developments in the serology of patients with rheumatoid arthritis and number of what I call new autoantibodies have been identified in the last ten years or so. Joe Smullen and colleagues in Vienna have identified antibodies to what was called RA-33 and the antigen is actually the 18^th protein of the heterogeneous nuclear ribonucleic complex. In addition, Walter Valderois and colleagues have identified antibodies binding to a cyclic cytidine synthetic peptide. Both of these antibodies were claimed originally to be specific for rheumatoid arthritis. Bearing this in mind, I in collaboration with these other workers, have looked at some of our lupus patients who have either erosions or a deforming arthropathy but lacking erosions, or as a control, non-deforming, non-erosive patients. In six of these ten patients we found evidence of rheumatoid factor, in six of these ten

Central nervous system lupus has always been a problem, and it’s been a problem for a number of reasons. Not the least of which of course is the fact that whereas we can biopsy the kidney and we can biopsy the skin and we can biopsy the lung and the muscle with great ease in patients with lupus, we cannot go biopsy-ing the brain with quite that degree of alacrity. There has also been the question that in the ACR criteria for CNS lupus only seizures and psychosis are mentioned, yet every doctor looking after a lupus patient will know there are a whole wide variety of other clinical features. In order to try to resolve this

I want to turn now to the question of kidneys and lupus and I want to acknowledge the considerable amount of work that has been done by studies at the National Institute of Health. Again, as many of you in the audience will know, for many years they have been treating patients in a randomized fashion with combinations of drugs. Either steroids alone or steroids and azathioprine, steroids and oral cyclophosphamide, steroids and low dose azathioprine and cyclo, or steroids and IV cyclo. Many of you will

But the other bigger problem for me is, what do you do with the patients with lupus nephritis who have been through the NIH regime. That regime is again, as many of you know, is six months of monthly infusions of intravenous cyclophosphamide followed by three monthly infusions for two years. Once you have been through this two-and-a-half year period what do you do next? Do you go back to azathioprine? Do you try microphenylate, which has become a little more popular? Will the new biological agents help us; antibodies to CD-40, LJP-394? There are a number of ongoing studies at the moment. The answer is, we just don’t know. For me this remains the black hole, if you like, of research in lupus nephritis.

I want to turn now to a slightly happier story and that is the issue in the cardiovascular system of pulmonary hypertension. Uncommon, but there have been some very exciting developments in the last ten years. Pulmonary hypertension occurring in lupus is a harbinger of a fatal outcome within months or a few years. Undoubtedly true at the time that was written ten years ago. It is a relatively uncommon complication compared to its prevalence in patients with scleroderma or overlap syndromes. Earlier studies reported the prevalence of around 1%-9% but more recent studies have utilized echocardiography and it showed a

Let’s turn now to vasculitis, and in particular to abdominal pain lupus, because this is a considerable difficulty. GI manifestations, quite recently but it was William Osler over 100 years ago who was the first to emphasize that GI manifestations may overshadow other aspect of this disease and indeed may mimic any kind of abdominal condition. We have always had the difficult problem that they can be difficult to distinguish the processes or side effect of medication. As I’ve said, the acute

For the final clinical conundrum, I’d like to draw your attention to thrombocytopenia. I’d like to persuade you, at least to my mind, that there are at least three sorts of thrombocytopenia in patients with lupus. There are a group of patients who present with what is generally regarded as idiopathic disease, idiopathic thrombocytopenia, until other features of lupus turn up some