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Systemic Lupus Erythematosus 

Lupus may present in a variety of manifestations. You may think the patient has a fever of unknown origin or you may think that the basis of the problem is an infectious disorder, perhaps neoplastic or lymphoma-like state, only to see with the evolution of time that it turns out to be lupus. So they can come into the office and simply have a rash and a little bit of fatigue. A little bit of nondescript arthralgia or frank arthritis. That is with joint effusions. Other times it presents only as a nephrologic disorder. Proteinuria, seizures, psychoses sometimes also can occur very early on. Inflammation of serosal surfaces and on occasion a diminution in red blood cell elements suggesting perhaps that it is just another hematologic disorder systemic lupus erythematosus, lupus, lupis.

Now we still think that quintessentially lupus is an autogram body mediated disorder. And over the last 10 or even 20 years there certainly has been some very clinically relevant clinical manifestations of lupus represented by these specific autoantibodies. Perhaps most persuasively, listed at the top, is the close correlation of antismith reactivity with irrefutable lupus. But on the downside only about 10 or 15% of lupus patients have this so-called pathognomonic autoantibody. Anti-DNA antibodies donít associated themselves quite as exquisitely with lupus nephritis. Again, the laboratory

But on the other hand, the only way we really can look, even in 1999, at what pathophysiologically is trying to explain lupus is to look at the kidney disease. Because thatís the place where elegant studies have been and continue to be performed. Currently there has been some modification of the mind set regarding lupus nephritis, and by inference, other inflammatory events in lupus outside of the kidney. They can be distilled down into one of three possibilities. Waning immune complexes may still be the pathophysiologic hallmark of the disease. On the other hand, though, our perception has shifted away from the anti-native DNA antibody in specificityís towards a broadening in terms of thinking that they do display more exquisitely specific anti-chromatin positively. So chromatin, another broader nucleosome, histone nuclear constituent may be the hallmark attack autoantigens in

Arising as a replacement strategy however, is the currently popular notion that the planted antigen pathway may be pivotal, at least in lupus nephritis. Here we have histones and nucleosomes binding avidly to major post-constituents of the glomerular basement membrane. That is so-called basement membrane type 4 collagen and heparin sulfated. So perhaps these nuclear particles break off from the cell, or as the cell dies or empytosis ensues, they get out into the blood stream and then they plant themselves on the basement membrane and then the autoantibody generated in the lymphatic system elsewhere comes along, sees the target antigen and fixes itself quite permanently at the site of subsequent compliment-mediated injury. Now going back to the clinical side of the equation for a second, fortunately as we have been able to take better care of lupus patients over the last two to three decades, I think it is now possible to divide this disease into two stages. A very early conceptual phase that is highly inflammatory and almost

Now, turning to neuropsychiatric manifestations of lupus, because I think in terms of overall seriousness, after the kidney lesion, patients that have serious lupus tend to be around our hospital networks neuropsychiatric problems can become quite dominant in the past few years. They can be as nondescript as headache. On the other hand sometimes they can be varying forms of psychoneurosis, organic brain syndromes, diminution in mental acuity. Sometimes quite seriously, seizures can come up. How do you approach them therapeutically? Is it with steroids? Is it with anti-seizure medications? Still problematic many times. Other times itís far outside of the brain, either peripheral low grade neuropathy or a mononeuritis multiplex as seen in rheumatoid arthritis. Strokes can occur and isolated cranial neuropathies can be attributable to lupus.

Going over more to the psychiatric or subjective problems, again, Iíve alluded to that fact that many times thereís an emotional or affective problem. Letís say, manic/depressive symptoms. Emotional mobility leading to poor drug compliance and appearance with patient physician interactions. Many times also major problems, lupus patients tend to frequently be young. They still may be in their schooling years or early in the job environment, any aspect of cognitive impairment or decline in mental acuity can be major problems in terms of lifestyle for these patients. They also can fluctuate and absolutely confound attempts of employers or teachers to deal with such patients. Sometimes very serious dementia can occur simulating Alzheimerís disease. And last but not least, hallucinations, delirium, confusion and even coma can be part and parcel of lupus. Unfortunately, whether these problems respond to the newer quite effective anti-psychotropic agents remains to be determined. Certainly Prozac can be used, but there havenít been carefully conducted prospective trials to identify whether you should attack these problems with an antiinflammatory or immunosuppressant approach, or can you get by with your anti-inflammatories coupled with psychotropic drugs.

Now diagnostic measures to try to objectify this highly subjective sphere remains problematic, unfortunately I think. No question about the fact that anti-ribosomal-P protein antibodies can correlate with neuropsychiatric dysfunction. But on the other hand, their capabilities still resides largely in tertiary care, academic centers, very hard to standardize this antibody assay and thus make it immediately applicable to the larger lupus population. For reasons that largely reflect further difficulties in antibody standardization, anti-neuronal antibodies have fallen down the road. None are widely used. But as a visual replacement CT or MRI, MRI angio etc. certainly are quite sensitive. Unfortunately they may be too sensitive for diagnostic discrimination in a patient with lupus. Sometimes lupus patients that have mental aberrations, they are quite likely to have an abnormal MRI but you donít know the degree to which the visual image is playing on the clinically meaningful or lacking in meaning. Finally, CNS angiography certainly would be the gold standard but extremely expensive and complex, and even hazardous to the patient.

Under-recognized problems in lupus: again, because of the longevity of the disease, we are having to deal with it more and more. Perhaps the findings seven years ago, a very large cohort of lupus deaths were reported from the Johns-Hopkins investigators and the leading cause of mortality actually turned out to be mesenteric vasculitis that has an unexplained predilection to involve the right side of the colon and lead to serious intestinal perforation and many times demised because of the diagnostic and the lack of surgical intervention. These patients will come in, they will have a history of multiple, repetitive episodes of abdominal serositis, so you think itís just their serositis flaring up again. They are often on prednisone and this may mask the febrile response, it may make the belly less tender. It may account for what you think, or you may think it is the explanation for the moderate elevation in the white count. So this serious lesion may be missed. The shrinking-lung syndrome: recognized radiographically by symmetric elevations of the diaphragm, looking on PHS films like it was a poor inspiratory effort on the part of the patient, actually turns out to be a very puzzling localized myositis or myopathy of the diaphragm that can further impair breathing, leading to additional shortness of breath but not meaning that there are problems with the pulmonary parenchyma. Other times the myositis, the myopathies were widespread. The diagnostic dilemma about whether the peripheral weakness is an attribute of steroid administration or active muscle inflammation, many times occurs. Itís the same situation as polymyositis. You may have to treat it more aggressively. You may have to undertreat. Sometimes you have to do a muscle biopsy to demarcate these problems.

Interstitial lung disease can occur. Pulmonary hemorrhage simulating Goodpastureís syndrome, but sometimes observed in the absence of anti-glomerular basement membrane reactivity, can be a further problem. Not infrequently, patients with late-stage, otherwise quiescent lupus, can have a little bit of depression, little bit of affect change, multiple trigger points and look all the world like prototypic fibromyalgia. How do you treat them? Is it with amitriptyline nocturnally, or do they require a more specific drug intervention? We need to know more about this problem. I got a call just yesterday from a physician in another locale wanting to discuss a case of a patient with lupus. It was on azathioprine, had hemolytic anemia that was positive, typical of lupus and developed pancreatitis. Whatís the culprit? An unrecognized hemolysis-induced degenerative gallstone. Was it the azathioprine or was it lupus per se? Very difficult to distinguish.

Now the treatment of lupus certainly has not had the exciting advances of rheumatoid arthritis. But on the other hand, there has been some evolution towards a more effective - at least in terms of risk - benefit profile. To review quickly some of the manifestations and how generically they can be dealt with today, letís start with a common problem. Iíve emphasized the major morbid elements of lupus, but in actuality in the community lupus, fortunately, tends to be a mild even self-limited or fluctuant disease that you can display that attitude of optimism to the patient. Donít let them go out and abandon their job, their career plans. Say to them that maybe they will improve with therapy over a few years time. And you can certainly treat most of the mild symptoms by either conventional nonsteroidal antiinflammatory drugs, trying to avoid steroids because of the co-morbidity they produce, and thereís actually - even though there is no clinical experience to my knowledge - no reason why one of the newer COX-2 inhibitors couldnít be tried. Recognizing that you may not get third party payment, but if you have a history of upper GI bleeds in the past, you might indeed want to go with some of them. Weíll know more about this possibility in the next few years Iím sure. Photosensitivity: donít overplay it. Itís not ubiquitously a problem in lupus, not even in very fair skinned patients. But if there is recognizable photosensitivity leading to malar skin rashes or serositis, arthritis, avoidance is intuitively obvious. Sunscreens, the higher the numerical value lots can be helpful and should be pursued with avidity. Arthritis and rash: still the drug hydroxychloroquine, Plaquenil, has an acceptable track record. It is slow in action but it allows you to get something

A major therapeutic advance, and Iíll allude to more, is taking the old drug, cyclophosphamide and recognizing - based largely on experience in Wegenerís granulomatosis - that itís much better tolerated and probably less toxic long term if it is given intravenously periodic monthly pulses, almost like the Remicade story, it will be capable of capturing and even reversing - even in most serious stages - of diffuse proliferative

Most of the drugs Iíve talked about may cause serious side effects. You have to be constantly vigilant in this regard. I havenít even put up glucocortical way to treat these problems because of their obviousness to this group. On the other hand, sometimes there is some peculiar predilections that you have to be aware of. I certainly tend to believe the old clinical saw that for inapparent reasons lupus patients may be idiosyncratically susceptible to ibuprofen but not other NSAID drugs. And the problem that can arise is aseptic meningitis that looks like a viral meningitis but is a repetitive, reproducible event. So I certainly do not provide ibuprofen in pharmacologic doses nor do I countenance the use of Advil in OTC lower doses for that potential problem. Other NSAIDís can be used but they do have the capability of the decreasing the GFR,

Weíve talked about cyclophosphamide. You are quite aware of what it can do cosmetically. Itís been quite a problem in the young woman, young womanís disease many times. Infection, lymphoma, cancer of the bladder are serious sequelae. Hydroxychloroquine, retinal toxicity is quite rare. Probably has been overplayed but mandate every six months or so a careful funduscopic examination by an ophthalmologist. And if nothing else that is going to have a major additive cost superimposed on all of the other medical problems that they should face this. Sometimes third party payers will

New treatments for rheumatoid arthritis. Iíve already alluded to IV cyclophosphamide. Now let me refer to perhaps a much more utilitarian, beneficial steroid-sparing drug than azathioprine and that is methotrexate. Over the past decade or so Iíve tended to prefer more and more giving methotrexate, particularly for joint manifestations, skin problems, to decrease the prednisone requirement. Why do I prefer it more than

More and more I think itís becoming rational, and fashionable and scientifically valid to use less toxic therapy for a disease that actually spans decades the majority of the time. Dietary manipulations such as lithic restriction, just as they appear at atherosclerosis, and any type of patient situation can be quite invaluable. More and more aggressive use of the better tolerated, newer lipid lowering drugs and antihypertensive agents I think have a rightful place in patients with low grade mild lupus nephritis, regardless of the form. It clearly works, for example, in the membranous glomerulonephritis problems. Being vigorous and even getting the blood pressure to a little bit lower nadir than we might have thought optimally required ten years ago may be really true. The issue of fish oil, mega 3 fatty acids that have putative antiinflammatory value perhaps in arthritis, perhaps in asthma, perhaps in anti-platelet effects, benefits on the vasculature. Well itís certainly fashionable in the lupus sphere. I donít condemn it to a patient who wants to try it. Itís not too cost prohibitive. It gives a little bit of halitosis, attracts cats for example, like it would in any of us. But I donít dissuade the patient if they want to try it for a short period of time and see whether or not it might benefit their overall health status. Even though that is very hard to identify on an individual patient basis.

Now lets deal topically for just a second with drug induced lupus. Offending agents in the past, some have been largely discarded from clinical frequent usage. Sure we still use hydralazine, isoniazid, Thorazine from time to time and they are capable of producing the problem. But possibly the most common offending agent, currently, is the use of minocycline for long periods of time in the treatment of severe acne. There have been some

Anti-phospholipid antibody syndrome, kind of a peripheral topic for lupus but I think one very very important for general medical audience to review. Itís defined clinically as either recurrent thrombotic events coupled with fetal loss if the requisite conditions are met. Thatís obviously a young woman seeking children. If you have unexplained spontaneous abortions occurring at any point during the pregnancy, one has to consider anti-phospholipid antibody generated problem is the culprit. It exists in two forms: primary, which is an independent type of problem, or secondary,

Now its treatment. Fortunately itís been much more refined, even codified, in the past few years and quintessentially it boils down to prolonged, vigorous, sustained Coumadin administration. No, itís not trivial in amounts. It has to be protracted. How long? Itís still a little bit up in the air but if the patient has had a major problem it usually mandates therapy for at least a year. Itís more apt to be three years, perhaps even a lifetime. Obviously Coumadin is teratogenic so in setting a pregnancy you have to shift to heparin and aspirin, even though this is a little osteopenic producing agent and aspirin can get you into problems. Clearly, despite early anecdotal reports, there is no problem for either steroids or any immunosuppressant recognized today in the management of this disorder.

Now lets shift over and finish with the other problem. That is scleroderma. Rare but it means the world to a patient whether itís rare or common. You get a rare disease on your hands, you have to treat it by the same modus operandi that you have to otherwise. Usually it presents inceptually Ö the onset of scleroderma usually presents solely as Raynaudís phenomenon. It can occur at any stage in life. Very common abnormality. At least 80% of the time it is so low grade or trivial that the patient doesnít go into the doctor to seek an explanation. They just kind of self-modify it themselves and say, "Well, Iíve always had cold hands, cold feet" even though in actuality there is a change. Most of the time itís isolated but on the

Sometimes I think we overplay the "how your diagnose scleroderma". Quintessentially it boils down to simply the state at which you can define tight tied down skin involving the back of the hand, proximal to the metacarpal row, bilaterally or unilaterally, that patient has some form of scleroderma. Prior to that time, even when there is massive so-called sclerodactyly, puffiness, itís premature to scare that patient with a diagnosis of scleroderma. So you have to be cautionary, vigilant but not premature in the diagnosis. Now fortunately if you go mainly to the laboratory these days there are two demarcatable forms of scleroderma that you should try to do once the disease has sufficiently established itself. There is a diffuse variety and now I think we are truthfully, semantically saying, a limited variety. This limited variety is an evolution of the so-called CREST syndrome; calcinosis, Raynaudís, sclerodactyly, telangiectasia. The autoantibody correlates I alluded to, if they are positive, are fairly predictive. If they are negative, they donít tell you anything. Because 50% or so of patients with diffuse scleroderma wonít have SEL-70 or the anti-tocolysoerase reactivity and likewise about half of the limited patients are not going to have anti-citrovir reactivity. But nonetheless, if they have it itís pretty good evidence as to how the disease is going to evolve and thereís also some clinical patterns which are pretty specific in individual patients. For example, joint contractures are much more difficult in the acute disease. Telangiectases, those little freckle-like deformities on the face, around the mouth, periorbital are much more frequently seen in limited. Tendon friction rubs, again, when you apply a stethoscope over a knee or wrist and you hear a friction-like noise, that usually means you have diffuse disease. Note at the bottom, esophageal dysmotility and pulmonary fibrosis occur with equal frequency of disorders. But again in importance, prognostically speaking, is independent of therapy, survivorship in the diffuse form obviously is much more shortened than in the limited form. I really donít like these figures. I think they are a little out of date. They are too pessimistic, but nonetheless they are the best we have today based on the literature and careful prospective appraisals.

Serious complications of scleroderma: just as in lupus, you can have - for example - isolated pulmonary hypertension, which is almost always treatment refractory. You can have admixtures of inflammation, alveolitis of the lung coupled with scarring, fibrosis. Itís not treatment possible.

Renal hypertensive crisis is probably one of the early major events in scleroderma, but for reasons unknown, it tends to have a predilection for older men, and occurring in the first three or four years of disease. Now tracking blood pressure frequently really is not capable of picking up the problem because of itís abrupt onset. You can see a patient one day, everything will be okay. The very next day there is an onset of a headache, blurred