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Lupus

Lupus is a multi-system autoimmune disease. Although there is some overlap, some more than others, with all these other organ-specific autoimmune diseases like hemolytic anemia, even RA, polymyositis, pulmonary fibrosis, thyroiditis, you can see all these different diseases that sort of encircle lupus in overlap with lupus. There is sort of a continuum between patients that are diagnosed with lupus and patients that are diagnosed with these organ-specific diseases, as an example, multiple sclerosis. Sometimes that may be the first manifestation of lupus or these patients may have a positive ANA or they may also have arthralgias or RA nodes. I think it’s a little difficult sometimes for medical students to realize that patients don’t always fit into the nice little categories that physicians have made for them.

I wouldn’t say it’s an extremely common disease but it’s not rare. Probably the overall incidence is 1:2,000, maybe higher than that. There is some variability depending on which study you read, and I think over the last 30 years - especially with the use of the ANA test and using the HEp-2 substrate, that’s much more sensitive and maybe picking up more patients. Also awareness by physicians in general has probably helped to diagnose milder cases.

Obviously it is much more common in women, probably about 9:1. If I have 5% male patients I would be surprised. It’s, just in my experience, it’s even less so but the literature would suggest about a 9:1 female to male ratio. It’s much more common in women of childbearing age. As the age of the patient goes to the young end or the old end of the spectrum, that female to male ratio is not quite as dramatic.

Now the etiology is still unknown. There is quite a bit known about the pathophysiology. What actually causes lupus is not clear, and again lupus is probably better described as a syndrome. Lupus, like many diseases in rheumatology - and in medicine in general - does not fulfill Koch’s postulate. We can’t really produce it by any known agent. Therefore, by definition, it is really a syndrome. When you look at these patients it’s hard to imagine that doctors thought that all these patients have the same disease because the manifestations are so variable. But using clinical criteria - and this is one disease where the criteria …actually rheumatologists use it in their everyday practice - but using those criteria we group these patients together. Genetic factors are obviously important. Immune response genes, certain complement deficiency syndromes, or genotypes.

Infection, viral infection, is the main focus of research. Still nothing has been found. Possibly retroviruses, Rubella is thought to be a possibility, and I’ve seen a couple of studies, Polyomavirus which I’m not really sure what kind of a virus that is. I think it’s a big DNA virus. But these types of infections have been suggested, but again there’s no direct proof. Environmental factors, toxins, may relate to metabolic defects.

Just looking at some of the genetic factors real quickly. Obviously, HLA genes, DR-2 and DR-3 are the most strongly associated. Also MHC class III genes, some of the complement components, are located in this region, and C-2 deficiency, C-4 deficiency or C-4A deletion, sometimes called C4 annul, are also associated with lupus. There has been a question that tumor necrosis factor gene is located in this region and there is a question whether variations in this gene may be related to expression of lupus.

This is livedo reticularis, which again is not very specific. It almost depends on how cold you keep your room temperature. If you have a real nice cold office you are going to see a lot more livedo than if it’s like a sauna, which sometimes our office is like. But you can see this lacy, venous pattern due to vascular instability in the arm, and it’s generally best found in the arms, the forearms and the legs.

These are hives around the knee of a patient who was diagnosed with lupus a couple of years ago and she called saying that she had this rash, and of course I had to see it. So she came in and she said, "It’s itchy, it’s driving me crazy. I think it’s due to a medication I started."

Oral ulcers; this is a young girl with lupus. You can see this little ulcer, erythematous based ulcer on the hard palate. Oral ulcers and nasal ulcers can occur commonly. They are often painless so that means you have to look for them, especially in the nose. I’ve seen patients with large septal perforations that you never knew they had a problem. If you see that and someone wasn’t a cocaine user or they didn’t have their nose fractured ten times, then that’s likely to be due to some sort of vasculitis, of which lupus is one of the ones that can cause that.

Moving on to musculoskeletal manifestations. Arthritis is very common, probably about 90%. Almost all the patients have arthralgias but as part of the criteria, you’d like to see some evidence of inflammation. And the distribution of joints is similar to the rheumatoid pattern. In general, the patients have at least their hands, wrists and knees. That seems to be the classic areas that are involved. It’s less common for them to have shoulder or neck or other involvement. Again, this synovitis of lupus is not usually destructive and usually responds very well to treatment of the rest.

Now, going on to the kidneys. This is one of the most serious organ manifestations and about 50% of adult lupus patients will have clinical evidence of renal disease, even more so in children. If you do biopsies of every patient that has lupus, probably 100% of patients will have at least evidence of immune complex deposition, and maybe some mild light microscopy changes. These are categories, histologically, into several different classifications. Sometimes people refer to the World Health Organization I, II, III, IV and V. I just call them by the appearance on light microscopy.

Mesangial is very very mild. As you can see, it is often there without any clinical manifestations. Occasionally patients will have a little proteinuria and some hematuria. We will end up getting a kidney biopsy if their protein excretion seems to be increasing or is enough to be of concern. But this is not something, in my clinical practice, that I find on biopsy. Maybe only every couple of years I’ll have a patient because their manifestations are so mild you really don’t worry about it.

Focal proliferative is a little bit more severe renal lesion, with some proteinuria and some hematuria but the renal function is usually well preserved. The patients often have serologic findings of anti-DNA and complement changes. A lot of extrarenal manifestations like arthritis, rash, and these patients do fairly well. Usually they require steroids but the kidneys do fairly well in response to that.

The most common renal lesion is diffuse proliferative, also the most serious one. Probably more than 50% of all lupus nephritis is diffuse proliferative, and you can see heavy proteinuria, hematuria and casts. I don’t do my own urinalysis so I have to depend on the nephrologist to do the urinalysis because the lab never finds casts. They find hyaline casts but not cellular casts, for whatever reason. You can see that renal insufficiency is fairly common. It’s not unusual for these patients to come in with creatinines with 2 or 3 initially.

Moving on to neurologic manifestations. This is probably the next most serious organ involvement. I’m not saying that to have a stroke or a major CNS problem isn’t serious, it just isn’t quite as common. You have your diffuse manifestations with things like organic brain syndromes, psychosis, and others. People will have headaches, migraine-like headaches are very common. Aseptic meningitis, particularly in response to certain NSAID’s, may occur, pseudotumor cerebri can occur just because of lupus, not just because of the steroids. These are some … especially organic brain syndrome can be a little difficult to be sure of what it is. Sometimes neuropsychiatric testing can pick up patients with a very mild organic manifestations. So that’s why you’ll see different reports of central nervous system manifestations can be 10% to 70%, because this particular item is very nebulous when it is very mild.