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Lupis

Lupis 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, lupis, erythematosis. There is sort of a continuum between patients that are diagnosed with lupis 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 itís a little difficult sometimes for medical students to realize that patients donít always fit into the nice little categories that physicians have made for them, and that they sometimes fall in lupus, lupis, erythematosis

I wouldnít say itís an extremely common disease but itís 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, thatís much more sensitive and maybe picking up more patients. Also awareness by physicians in general has probably helped to diagnose milder cases. So the incidence in studies is a

Obviously it is much more common in women, probably about 9:1. If I have 5% male patients I would be surprised. Itís, just in my experience, itís even less so but the literature would suggest about a 9:1 female to male ratio. Itís 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. It is more common in blacks and

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 Kochís postulate. We canít really produce it by any known agent. Therefore, by definition, it is really a syndrome. When you look at these patients itís 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 Öactually 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 are

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

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. In mice, it appears to be so, and some people have thought that part of the

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 itís 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 itís generally best found in the arms, the forearms and the legs. Much easier to see in a fair

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, "Itís itchy, itís driving me crazy. I think itís due to a medication I started." Of course she hadnít

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. Iíve seen patients with large septal perforations that you never knew they had a problem. If you see that and someone wasnít a cocaine user or they didnít have their nose fractured ten times, then thatís likely to be due to some sort of vasculitis, of which lupus is one of the ones that can cause that. You can also see it in other types

Moving on to musculoskeletal manifestations. Arthritis is very common, probably about 90%. Almost all the patients have arthralgias but as part of the criteria, youíd 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. Itís 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 of the

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 Iíll have a patient because their manifestations are so mild you really donít 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 donít 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. Itís not unusual for these patients to come in with creatinines with 2 or 3 initially. Significant serologic abnormalities, anti-DNA

Moving on to neurologic manifestations. This is probably the next most serious organ involvement. Iím not saying that to have a stroke or a major CNS problem isnít serious, it just isnít 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 NSAIDís, may occur, pseudotumor cerebri can occur just because of lupus, not just because of the steroids. These are some Ö 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 thatís why youíll 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. Is it just that the patients are tired and they canít go through the testing? Is it an effect of the medication? So

Of course seizures, which can be of any type, most commonly the tonic, chronic or generalized seizures or possibly temporal lobe seizures. What do they call it? Complex partial seizures, which can be very difficult to diagnose in some patients. I had one patient who was diagnosed by a psychiatrist as chronic hallucinosis. She hallucinated but she knew she was hallucinating. It was frightening, but really there was no other evidence of

Also focal manifestations; cerebrovascular transverse myelitis, which is really bad news. Movement disorders, even peripheral neuropathy. Some of these things are associated with antiphospholipid antibodies. In fact, cerebrovascular accident may be more of just a vasculopathy than really a true

Cardiopulmonary manifestations are common, particularly the pericarditis pleuritis, which are included in the diagnostic criteria. You can have a whole host of other abnormalities, myocarditis. I had a patient who died last Christmas of myocarditis. She had had recurrent chest pain and had been evaluated. We never really found anything and I think over a period of a few weeks she had a rather acute myocarditis and she was already on a ton of steroids, and maybe an immunosuppressive could have helped. But this wasnít recognized until autopsy.

Acute pneumonitis. Thatís a real tough one because it looks pretty much like a bacterial pneumonia. The patients are febrile, may have some chest pain, coughing - it can even be productive, although it tends to be white sputum rather than the purulent sputum. Often these patients end up getting admitted and started on antibiotics until it looks like nothing is working, unless you start to increase their steroids. So itís usually a

This is a picture of some pleural fluid. This is a woman with pleuritis. When it occurs for the first time, especially if the patient is febrile, you probably should tap the fluid just to make sure itís not infectious, but these patients may have recurrent episodes. Again, if you are missing an infection you are going to treat the patient with steroids. That could be a bad situation.

Hematologic manifestations. Various types of anemia, hemolytic anemia like a Coombs positive hemolytic anemia is only found in about 10%. Also, lymphopenia or leukopenia. Remember, when you have a patient who is febrile, acutely ill, a finding of leukopenia is very helpful because in the vasculitides, other rheumatic diseases and most infections, usually the white count goes up. Except for certain viral infections, particularly in children, and also - this is like a Board question - Salmonellosis can be associated with a low white count. Thrombocytopenia, and this can be quite severe. The patient can essentially have ITP associated with lupus. Also coagulopathies with antiphospholipid antibodies, which is really a separate

Vascular involvement. Raynaudís phenomenon is fairly common in lupus. Itís usually not so severe, and sometimes if you have to start steroids, that seems to improve the symptoms. In my experience itís not a major problem. Usually a little calcium channel blocker will help that if the patient canít just avoid cold, and thatís not enough. Other vascular manifestations can occur. As I mentioned, these thrombotic events, which can occur associated with antiphospholipid antibodies, or even without them. There may be other antibodies that induce a hypercoagulable state, but any

Pregnancy, again this is rather a broad topic, but this disease is found, for the most part, in young women of reproductive age, so pregnancy is going to be an issue. Lupus does not generally affect fertility or increase the incidence of congenital malformations. The disease does have a genetic component, so there is an increased incidence of lupus in the offspring of a patient with lupus, but not so much so that I would tell a woman, "Oh, you shouldnít have children" because itís maybe a five to tenfold increase over the general population so it is increased - or maybe itís 20, I forget the exact number - but it doesnít mean that half their kids are going to have lupus. So itís still less likely than they would expect. Severe disease, particularly end-stage renal disease or high dose steroids, obviously may affect fertility. Basically just because they wonít be menstruating.

The therapy, particularly using cyclophosphamide, may affect fertility, may make a woman infertile or more likely, a man infertile. And if they are getting these treatments during pregnancy, thatís not a good thing, so you have counsel the patients, especially if you are treating a young woman -

Treatment of lupus basically is individualized for each patient. Patients with non-major organ involvement, you treat these symptomatically. If you have arthritis, you might use a non-steroidal antiinflammatory drug. A serositis, the same. A Raynaudís phenomenon, you might use a calcium channel blocker. A patient with severe headaches, you might use a calcium channel blocker, a tricyclic antidepressant, whatever. Major organ involvement, renal, CNS, pulmonary, cardiac and hematologic are the main ones, generally require high dose steroids, and in some instances depending on the organ involvement, immunosuppressives. Taking renal disease as an example; if a patient has renal disease and a biopsy shows diffuse proliferative nephritis, that patient should probably get IV monthly cyclophosphamide. For these other organ involvements, maybe azathioprine would be helpful. For hematologic manifestations, maybe intravenous gamma globulin would be helpful, but usually steroids in

These are some of the drugs that we use. Again, it really depends on the patient. The NSAIDís and the anti-malarial agents are good for less ill patients with non-major organ involvement. Corticosteroids are still sort of the workhorse, and almost every patient with lupus is going to be on these at one time or another. The immunosuppressive agents, particularly cyclophosphamide for severe disease, particularly renal disease, but you can see azathioprine and methotrexate have been used. Some people have studied cyclosporine. I have been a little reluctant to use it because of its