Systemic lupus erythematosus (SLE) ... PRESENTATIONS... Epidemiology of Systemic Lupus Erythematosus. Based on a presentation by Susan Manzi, MD, MPH

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1 ... PRESENTATIONS... Epidemiology of Systemic Lupus Erythematosus Based on a presentation by Susan Manzi, MD, MPH Presentation Summary Tracking the epidemiology of systemic lupus erythematosus is problematic because the diagnosis can be elusive. Systematic review of cases is also difficult because of the varying paths these patients take through the medical provider system. In general, 7 women are stricken with the disease for every man, with an 11:1 female-tomale ratio during the childbearing years. African- Americans are disproportionately afflicted, and evidence is at least suggesting a higher prevalence among other ethnic groups including Hispanics, Asians, and native Americans. Difficulties with defining the patient population, along with minimal education for physicians, may contribute to suboptimal treatment, especially in the critical early stages of disease. Systemic lupus erythematosus (SLE) is a complex, chronic, multisystem disease that targets young women and men. Its natural course involves sporadic bursts of activity that cumulatively can cause irreversible damage, via the vasculature, to the organs of the body. The true incidence of SLE is difficult to estimate, because of the complexity of the diagnosis and the challenges posed by tracking patients who may be diagnosed and treated by any of a wide range of specialists. What is clear is that women are much more commonly affected than are men, and African-Americans, along with other minorities, more often than Caucasians. One recent examination of epidemiologic reports found incidence rates of 0.3 to 0.9 (per 100,000 people per year) in Caucasian men; 0.7 to 2.5 in African- American men; 2.5 to 3.9 in Caucasian women; and 8.1 to 11.4 in African- American women. 1 There is also disparity among prevalence rates reported by various sources. These rates ranged from 3 to 19 (per 100,000) in Caucasian men; 3 to 53 in African-American men; 17 to 71 in Caucasian women; and 56 to 283 in African- American women. 1 Some researchers question the upper limits of these prevalence ranges. In a random telephone screening study, respondents were asked whether they had ever been diagnosed with SLE by a physician; the calculated prevalence based on their responses was 372 per 100, One in approximately every 250 African-American women in this study reported being diagnosed with SLE. 2 Although not a highly reliable epidemiologic finding, the result tends to support the widespread suspicion that the prevalence of this disease is consistently underestimated. The etiology of SLE likewise remains a mystery. A possible clue, however, may lie in the demographics of the afflicted population. Women are 7 times as likely as men to be affected. Furthermore, women of childbearing age are 11 times as likely to be stricken as men, compared with a 2:1 female-to-male ratio in prepubertal girls and postmenopausal women. This raises the question of a potential role for hormones as either a causative or exacerbating factor in SLE. Diagnostic Issues The elusiveness of a definitive epidemiology for this condition begins with diag- S474 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2001

2 Epidemiology of Systemic Lupus Erythematosus nosis. Patient presentation is highly variable, and some of the most common symptoms of SLE are not specific for the disease. Constitutional symptoms such as fatigue, malaise, fever in the absence of infection, and weight loss are common in all types of chronic conditions. Organ-specific signs and symptoms, as well, often mimic those of other diseases. The American College of Rheumatology (ACR) criteria for SLE classification go a long way in helping primary-care physicians and various specialists arrive at a more confident diagnosis, but they are unavoidably fallible, especially in light of the fact that determining the presence or relevance of the criteria often requires interpretation. An examiner applying liberal standards or a low threshold for determining presence of the signs and symptoms could easily identify the required 4 of 11 ACR criteria for positive diagnosis in a patient who does not in fact have the disease. Thus, physicians need to be judicious in accepting the presence of criteria such as photosensitivity, malar rash, and oral ulcers (Table). 3 Cutaneous Signs. The skin is a major target of SLE activity. Aside from the typical butterfly rash whence lupus gets its name, a wide variety of cutaneous manifestations are possible. A common characteristic of lupus presentations is photosensitivity very commonly appearing in sun-exposed areas such as the forehead, cheeks, neck, arms, and hands. Discoid lesions, scarring rashes, urticaria, hives, and bullous rashes are all seen in these patients. Oral ulcers, usually on the soft or hard palate, are common and typically painless. Alopecia in SLE can take various forms, sometimes in conjunction with discoid rashes but more often appearing as a diffuse hair loss that is reversed after the acute flare is resolved. Referral to a dermatologist is often indicated. Other Criteria. Arthritic effects are seen in more than 95% of SLE patients. Generally symmetric in distribution, they can be debilitating but tend to be Table. American College of Rheumatology Criteria (Revised in 1982 for Classification of SLE) Criterion Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibody Definition Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds Erythematosus raised patches with adherent keratotic scaling and follicular plugging. Atrophic scarring may occur in older lesions. History of or observed skin rash resulting from unusual reaction to sunlight Oral or nasopharyngeal ulceration, usually painless Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion Pleuritis: history of pleuritic pain, rub, or evidence of pleural effusion OR Pericarditis documented by ECG, rub, or evidence of pericardial effusion Persistent proteinuria >0.5 g/day or >3+ if quantitation not performed OR Cellular casts that may be red cell, hemoglobin, granular, tubular, or mixed Seizures OR Psychosis in the absence of offending drugs or known metabolic derangements Hemolytic anemia with reticulocytosis OR Leukopenia less than 4000/mm 3 total on 2 or more occasions OR Lymphopenia less than 1500/mm 3 on 2 or more occasions OR Thrombocytopenia less than 100,000/mm 3 in the absence of offending drugs Positive SLE cell preparation OR Anti-DNA: antibody to native DNA in abnormal titer OR Anti-Sm: presence of antibody to Sm nuclear antigen OR False-positive serologic test for syphilis known to be positive for a least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test Abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug- ANA = antinuclear antibody; Anti-Sm = anti-smith; DNA = deoxyribonucleic acid; ECG = electrocardiogram; SLE = systemic lupus erythematosus. For the purpose of identifying patients in clinical studies, a person shall be said to have SLE if any 4 or more of the 11 criteria are present serially or simultaneously during any interval of observation. Source: Reference 3. VOL. 7, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S475

3 PRESENTATIONS nonerosive. Pericarditis and pleuritis are typical among heart and lung manifestations, which can also include fluid buildup and pain. Renal involvement is ubiquitous and is responsible for a great deal of the lupus-associated morbidity and mortality. Neurologic afflictions (the ACR criteria name seizures and psychoses) may result from hypercoagulation or, less often, from vasculitis. Hematologic disorders to watch for include anemia, leukopenia, lymphopenia, and thrombocytopenia. Several tests are recommended to identify SLE-related immunologic disorders, and an antinuclear antibody (ANA) titer can identify ANA, which is present in 90% to 95% of cases but is not specific to lupus. Criteria Limitations. All the above signs are included in the ACR criteria for classification of SLE. These criteria were originally developed to aid in uniformity of clinical research trials, and they serve as useful reminders of clinical and laboratory features of systemic lupus. It has been stated that diagnoses made on the basis of 4 or more of the 11 criteria have 95% specificity and 85% sensitivity rates. 3 However, an understanding of the disease is helpful in determining which manifestations should be deemed related to a potential diagnosis of SLE. Clinicians must remember that the ACR criteria do not cover the gamut of SLE manifestations. For instance, patients often develop constitutional effects, myositis, vasculitis, lymphadenopathy, various central nervous system disorders, and a broad spectrum of other signs. It is worth noting that in patients with the systemic disease, no blood vessel is safe. Ischemia may afflict the extremities and the eyes; an array of related ocular problems commonly afflict these patients. To further complicate a difficult diagnosis, symptoms of SLE continually evolve in scope and severity. Patients can develop new manifestations and involvement of previously unaffected organs throughout the course of their disease. Also, the activity and severity of the same clinical manifestation may vary from patient to patient. Differential Diagnoses. Other diseases, especially autoimmune conditions such as Sjögren s syndrome, mimic lupus in various ways. Fibromyalgia with totalbody involvement and a positive ANA test is not uncommonly mistaken for SLE. Rheumatoid arthritis in its early stages, before it is manifested completely, can cause confusion. Patients with thrombocytopenia, primary antiphospholipid syndrome, or clotting problems need to be differentiated from SLE sufferers as well. A variety of undifferentiated connective tissue diseases can overlap symptoms of SLE, and certain drugs can cause temporary lupus-like illness during their course of therapy. Thus, in addition to history, physical examination, and laboratory testing, well-informed clinical judgment is an essential factor in making an SLE diagnosis. Natural History The course of SLE consists of silent periods punctuated periodically by disease flares, which tend to be reversible inflammatory processes. Over time, however, these flares begin to inflict irreversible damage to organ systems. For example, disease activity targeted to the kidneys may be managed with the steroid prednisone and the agent cyclophosphamide but despite treatment, renal scarring may result. In addition, the use of prednisone can lead to osteoporosis, and the use of cyclophosphamide can cause toxicity to the ovaries and premature menopause in women and gonadal failure in men. Adequate disease monitoring requires the clinician to watch for fever and fatigue, chest pain, new cutaneous manifestations such as oral ulcers and alopecia, as well as joint pain or swelling and headaches. Physical examinations should also include monitoring for signs of leg edema, which may represent early kidney disease. Monitoring should also include appropriate laboratory testing: hematology, chemistry, urinalysis for kidney failure, radiology, and serology (C3, C4, double-stranded deoxyribonucleic acid). S476 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2001

4 Epidemiology of Systemic Lupus Erythematosus Conclusion After diagnosis supported by ACR criteria, patients should be seen every 3 to 6 months for monitoring of disease activity, treatment toxicity, and organ damage. During flares, much more frequent visits may be indicated. In addition to the primary care physician and rheumatologist, the SLE management team may grow over the course of a patient s disease to include specialists in nephrology, hematology, cardiology, pulmonary disease, neurology, high-risk obstetrics/gynecology, dermatology, and gastroenterology. Cooperation among the various physicians is essential. During periods of moderate-to-severe activity, close monitoring by a lupus specialist is recommended.... DISCUSSION HIGHLIGHTS... Incidence and Prevalence Dr. Wallace: Regarding prevalence, the study showing that only 1 person in 3 who has been told by a doctor that he or she has lupus in fact fulfills the criteria and has the disease was published with an accompanying article indicating there are up to 2.5 million Americans with the disease. 2,4 Extrapolation suggests that the figure is probably about 800,000. I also believe that in studying lupus prevalence, investigation into environmental and genetic factors is necessary. I believe many people diagnosed with lupus have undifferentiated connective tissue disease, and this nosologic category has not been well explored. Also, many ANA-positive fibromyalgia patients are given false diagnoses of lupus, which is complicated by the fact that approximately 25% of lupus patients do in fact develop fibromyalgia. Dr. Petri: A research group at the Mayo Clinic compared the incidence and prevalence of lupus several decades ago with the modern era, using a population-based database in the area of Rochester, Minnesota. 5 Using very strict classification criteria and controlling for variables, they were able to determine that in this Caucasian, middle-class population, lupus had tripled since My own observations and history of lupus in the Baltimore community support the notion of a substantial rise in lupus cases since the early part of the century. One factor may be changing demographics, especially increases among the African-American and Hispanic populations. The population of Rochester, Minnesota, however, is heavily Caucasian. We need to be concerned about a possible increase in environmental triggers. In light of Dr. Manzi s comments concerning ultraviolet light, photosensitivity, and lupus rashes, I would note the damage that has been done to the ozone layer; in addition, we know that many children and teenagers do not believe in using sunscreen. We also need to consider drugs and nutraceuticals that might trigger lupus in genetically susceptible individuals, including sulfonamide antibiotics, which have been shown to induce flares of SLE. Regarding nutraceuticals, we don t know much about their safety. We do know we have had a series of major problems in our lupus center with young women who decided to take echinacea on a daily basis. Serious nephritis flares appeared in cases of clinically quiescent disease in these women taking echinacea. Dr. Manzi: The paradox is that this very population of patients who should not be using these unregulated alternative medications is the same patient group for whom no new drug has been developed in 40 years. This points to the need for better therapies that are regulated. Diagnosis and Follow-Up Dr. Walker: I would like to emphasize the importance of allowing appropriate consultation in establishing the diagnosis. We know that rheumatologists are less likely to misdiagnose lupus and direct those patients to proper therapy, which can be very cost effective in the long run. In addition, it is important to allow laboratory tests that rheumatologists need to do their work. VOL. 7, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S477

5 PRESENTATIONS Dr. Petri: A misdiagnosis of SLE has serious economic impact. Such patients usually cannot get life insurance or long-term disability insurance, which is part of the tragedy of women who are misdiagnosed with lupus. These patients also may be treated with prednisone long term, resulting in further medical complications. Dr. Clarke: In regard to allowing rheumatologist consultations and serology tests, the scenario is different in Canada because of our national healthcare system. Patients usually can have a rheumatologist visit paid for by the system, although they may have to wait several months for the visit. For obtaining serology results, the situation is similar. Dr. Petri: There is frustration in the United States regarding our patients in managed care. In my case, I am rarely allowed to perform the laboratory tests at my institution. Quality control is also an issue because there is no standardization across laboratories on many of these tests. For example, with the lupus anticoagulant tests: If fresh plasma is not spun down within 4 hours, we can miss the diagnosis of this blood-clotting antibody. Many rheumatologists are very unhappy about new restrictive rules. Our knowledge base is rapidly improving as we identify new antibodies and refine old assays. Dr. Manzi: I echo Dr. Petri s comments. I would add that the diagnosis very often cannot be done in one visit for reasons we have discussed. This disease is frequently underdiagnosed and frequently overdiagnosed. I agree with Dr. Petri that physicians not having the full armamentarium of laboratory tests at their disposal is also part of the problem. Primary Care Versus Rheumatologist Dr. Wallace: The average family practice physician has had 1 to 2 weeks of rheumatology in the 3-year training program, and the average internist has had 1 month out of 3 years. The family practitioners, therefore, often do not know what tests to order or how to interpret the results. Partly for these reasons, nonorgan-threatening lupus is commonly not diagnosed promptly, and there is a perception even among good internists that it can be treated with a nonsteroidal anti-inflammatory and perhaps low doses of prednisone. They don t understand the use of antimalarials, methotrexate, or investigative treatment of prasterone. They often don t see the need for a referral. Also, the plea to be made is that rheumatology consultants be able to either use their university-based laboratory, or the 3 or 4 very good rheumatology diagnostic laboratories in the country that could subcontract with laboratories used by health maintenance organizations (HMOs). Dr. Petri: The ACR practice guidelines clearly state that it is important for patients to be able to visit a rheumatologist for follow up. One example of why this is so is the high incidence of renal involvement, which requires appropriate monitoring and laboratory tests for early detection, and early detection is critical in reducing morbidity and cost. This is very difficult to do for a busy family practitioner. Dr. Manzi: I would point out that if there is extra expense in rheumatologists being given more of a free hand in handling laboratory testing, this is offset by much of the inappropriate testing done by those not well versed in monitoring patients. Rheumatologists know how to focus on what is important, and do not, for example, continually retest for ANA, which is a very common practice. Dr. Wallace: Another way to help resolve this problem would be through physician education. There are really no efforts to put rheumatologists in front of community physicians and explain to them how to order tests, when to make referrals, and so on. Economic Realities Mr. Hardesty: One of the challenges is maintaining an affordable benefit for our HMO members and not forget our respon- S478 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2001

6 Epidemiology of Systemic Lupus Erythematosus sibilities for other serious conditions that affect a much larger percentage of the population, such as heart failure and diabetes. I agree that there needs to be an educational effort with regard to primary care practitioners. We do have designated laboratory vendors, but they also subcontract with specialty laboratories to run more complex tests. So we feel we re meeting the need, but I m hearing today about discrepancies in lab results. To respond effectively, we would need some good data on lab discrepancies in this patient population. Dr. Petri: At Johns Hopkins University, the lupus patients who come to see us have a referral from their primary care doctor, who usually only checks off the box for the visit itself no laboratory or radiology referrals. So the patient has to go back to the primary care doctor and is referred to the contracting laboratory. For some of these super-specialized assays, that s almost a guarantee of a poor quality test. What are your experiences in other regions? Dr. Walker: I have heard rheumatologists complain bitterly about not being able to do the tests needed. I am very fortunate in my personal situation that I do not have these restrictions. Our tests are done on site, and I have access to results within 1 or 2 days. Dr. Abu-Samrah: We in managed care need some kind of evidence-based statements that will justify that a particular test is only done accurately with quality control in certain facilities. Until we have that evidence, we are going to be hard pressed to justify repeating those tests that are available in the service area. Dr. Petri: I think some of the problems are because rheumatology has not been high on the list of priorities in managed care. For antiphospholipid antibodies there are international committees that have published guidelines on how to do lupus anticoagulant testing, for example. How do we keep rheumatology from being forgotten? Dr. Wallace: The numbers of patients we are talking about is relatively very small. Also, when a well-trained physician can rule out the diagnosis, which as we have heard may be in 2 of 3 cases, there are cost savings. Some of the laboratories are adapting to the economic realities and offering patients a complete ANA 12 or a panel, which usually is sufficient, for a modest fee when the patient brings a managed care membership card. Dr. Petri: Can there be more give-andtake in cases where the best laboratory testing available is at a university center? Some patients are sent to us specifically because of these laboratory resources. It s very difficult currently to have those exceptions made. We need to have those mechanisms made very clear, because primary care practitioners are telling rheumatologists who call them that they lack authority to work outside the procedures prescribed by the plan. On the referral note there could be a telephone number to call. Dr. Abu-Samrah: I think this discussion is beneficial and will help managed care directors understand some of the needs and problems of rheumatologists in these regards. Almost all managed care plans now have a system for direct specialty access without a referral. There is a difference in copayments, but for those patients who cannot wait, this is an option.... REFERENCES Systemic lupus erythematosus. In: Goldman and Hatch, eds. San Diego, CA: Academic Press. Women and Health; 2000: Hochberg MC, Perlmutter DL, Medsger TA, et al. Prevalence of self-reported physician-diagnosed systemic lupus erythematosus in the USA. Lupus 1995;6: Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;11: Lahita RG. Special Report: Adjusted lupus prevalence-results of a marketing study by the Lupus Foundation of America. Lupus 1995;6: Uramoto KM, Michet CJJ, Thumboo J, et al. Trends in the incidence and mortality of systemic lupus erythematosus; Arthritis Rheum 1999;42: VOL. 7, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S479