[Reprinted from ARTHRITIS & RHEUMATISM Lippincont Raven Publishers Vol 42, No.9, September 599 Copyright © 1999, bythe American Collegeof Rheumatology Printed inUS.A. GUIDELINES FOR REFERRAL AND MANAGEMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS IN ADULTS AMERICAN COLLEGE OF RHEUMATOLOGY AD HOC COMMITTEE ON SYSTEMIC LUPUS ERYTHEMATOSUS GUIDELINES Introduction Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown etiology, ‘with protean manifestations and a variable course and prognosis. SLE is a complex disorder that affects pri- sarily women in their childbearing years. It is charac terized hy periods of relative quiescence and periods of exacerbations, which may involve any organ or ssstem ia various combinations (1-10) (Tables | and 2), Patients ‘with SLE develop distinct immunologic abnosmalities, in particular, antinuclear, anticytoplasmic, and antiphos- pholipid antibodies. Genetic, immunologic, hormonal, and environmental factors are involved in its pathogen= esis (1-10). The prevalence of SLE is £:1,000; thus, most primary care physicians and general internists will not hhave sufficient experience in the management of mod- erate or severe life-threatening disease Members of the Ad Hac Comaiitee on Systemic Lopus ‘Enythematoous Gnidelines ace 2¢Joligws. Dafna D. Gladman, MD {elisi), Murray B. Uromit, MD: The Toronto Hospital a¢ University ‘of Toronto, Toeoain, Stari, Canada: Joha M. Esdsle, MD, MPH: Mary Pack Artheis Centre and. Vancouver Hospital, Vancouves, Britkh Columbia, Canad; Bovea H, Haba, MD: University of Cale fornia, Los Angeles John Klippel, MD: Nationa Istitle of Arhatis snd Musculosteletal aad Skin Diseeses, NIE, Bethesda, Marys0d; Robert Latta, MD, PhD: Saint Vinents Mesicel Ceates, New York, ‘New York: Mattie H. Liang, MD, MPH, Pater Schur, MD. Begharb and Womea's Hospital, Boston, Massachostts, Michelle Petr, MD, [MPH Jobns Hepcins Hospital, Baltimore, Maryland: Daniel Wallace, MD: Cedars. Sitai Medical Cente/Univity of Caforia, Los Aw oles, School of Medicine ‘The American College of Rheumatology is an independent professional, mocicah ard sciemtic society whyeh docs not guarantee ‘Serato cndowse aay commercial product or sevice, Adress reprin requests to American Cellege of Rhewmstol gy, 1800 Century Pace, Suite 250, Alanta, GA 30345 Subrmitise for publication Januity 29, 1989; aevepled ie revised fort May 18, 1989, In addition to the persistent risk of disease flares, ‘more than one-half of SLE patients develop permanent organ system damage (11). This damage progresses over time ond is usually more severe in African American patients than in white patients (12). Although the prog- nosis of SLE has improved dramatically in the last 4 decades, mortality remains a major concern, The mor tality rate among patients with SLE is at least 3 times, that of the general population (13), Survival rates are ~80% at 10 yeurs after diagnosis and ~65% at 20 years (1-8,13-16). Deaths early in the course of SLE are usually attributed to active disease and infections, but deaths that ocevr later in the disease course are often due to atherosclerotic vascular disease (14). Therapy, espocially long-term high-dose glucocorticoid treatment, can contribute io myopathy, osteoporosis, hypertension, diabetes, atherosclerotic vascular disease, infections, and death. Timely and aggressive therapy, however, can delay or prevent morbidity and organ faifure and is cost effective (17), SLE is a systemic illness with multiple end-organ involvement. As such, it challenges both the patients and their families. Patients with newly diagnosed SLE often have anxieties about a possibly fatul chronic iliness with unpredictable flares and potential disability; these anxi- eties should be addressed, Patients must lean how to cope with and monitor thefr own disease and to assist the physician in distinguishing coincident unrelated symp- toms from signs and symptonis of a flare. Psychological support by either the physician andior an appropriate health professional is essential. SLB patients may need the expertise of professionals in the fields of social work, ‘vocational counseling, psychology, pitysica and occupa tional therapy, ophthalmology, dermatology, nephrot- 17851786 ini atures of systemic lupus exytheratosus ‘Stem Features ‘Constiaional Fave Fever (im the absenes of infection} ‘Weight toss Musculoskeletal Artis ethan Myesis stin Bute ash Photoerstity haces entre lesion poss Ranaut phenomenon rope Uniara Visca Renal Hemarutio Prous ca Nop Sado Gasset Navse,vmiting Abdomin pain' Palmooay eur Frmofary prenehyena Palmar hspetenson eadac Yerkes Enders Mises Retculbeadothsia Lyrphadenepaty Spceemegey Hesecmssay Anemia ‘Taremborytopenis pena Paycbosis Seteores Orgpote brain syndrome “Tramverse mye Cranial neurspathies Peripheral netropsthies Hematologic Newropsyehiatie ogy, cardiology, orthopedic surgery, and other disci- plines. Not all of these are needed at any one time, and their coordination is best done by a specialist, usually « rheumatologist, who has experience in following up patients with SLE and knows what value is adkled from these consultants. ‘These guidelines for the management of SLE were prepared to improve the quality of care for SLE, patients by primary care physicians. They are based on available evidence-based information for the diagnosis and management of the disease, Where such evidence is ACR COMMITTEE ON SLE GUIDELINES Table 2. Frequency of serologic aboosmalties in systemic opus cetheraosus™ ‘Avonset, AAtany time, Abnorralty % & ‘Aatnuclearaniloodie 76 3 Aasibodies wo ‘Doublesranded DNA, u a Sa 3 2 RNP. 2 35 Ress 3 @ Lasse n *” ‘Low complement a n Tom get 5 unavailable, the guidelines are trased on the recommen dations of SLE specialists. While the members of the American College of Rheumatology Ad Hoc Commitice "peice |p SUSPECT Aer! SLE Figure 1. Tasks of the primary eare physician in the management of steric lupus erjthematass (SEE).SLE REFERRAL AND MANAGEMENT GUIDELINES 1787 ‘Table 3. 1997 update of the 1982 American Callege of Rheumatology casifiation oriteria for gstemic pus eryhematosus* hem Definition Malar rash FFised erythema lat or rised, over the malar eminence, sparing the nasolabial folds Discoid rash ‘Erythematous coised patches with adherent keratosi sealing and flliolar plugging: atropbieserting may ‘osu in oles lesions Photosensitnty ‘Skin sash 98 cost of unusual reation to sunlight, by patient history or physiian observation On wees Ca or maopharngcl sean uml pias ya pian Noncose at Invi 2 or mot peri in sors by tndemese, vein, efion Puss or perc 4: Porsoominig ivory of pic pin or et ya phn reine of pa aon Pesionis—doementad by estos mb evince of pti lesion Renal discs 4: Penitent procinarin 05 gm ot yor > qantttion not pevormes cei casmay ered sf, Hemogobin, sala, abuso med Neurologic disorder 1. Seinures—in the absence of olfending drugs or town metabolic derangement, e uremia, Ketoocidess, or cetolyte imbalance ‘On b. Pajchosis—in the absenos of offending drugs or known metabolic derangement, «uremia, Jetoncicors or elective imbalance Hematologic disorder 1. Hemolytic anemia with roteuloeyesis ‘OR », Leukopenia—<,00mam* on =2 occasions On Lymphopenia—<1, Sih? on =2 occasions OR 4. Thrombocwtapenia—<100,000%men” ia the absence of offing drugs [nmanciogic disorder 13 AnlicDNA: antibody co native DNA fn abnormal titer ‘On , Amin: presence of anubody 10 Sm mucleae aatigen ‘OR «Positive (inding of antiphospholipid antibodies based on: 1) an abnorial serum level of Tg6 ot TEM nticeeditipin antibodies, 2) positive test eeslt for Iapus anticoagulant using a standard metiod, o¢ 3) i falac-posifve test eeslt for a Teast fame and confirmed by Trepencre pallor immobilization oF uorescen sreponemal antibody absorptica test, ‘Postve antinuclear antibody [An abnormal ter of antiaclear entity by immunoforescence oF an equivalent assay at ang poi in From ref 1 on SLE Guidelines were rheumatologists who are ex: perts in the care of patients with SLB, the guidelines ‘were reviewed by primary cate physicians who concurred with their content. ‘The 4 major tasks ofthe primary cate physician in the diagnosis and management of SLE (Figure 1) are 1) to be alett to the possibility of SLE in their patients, and to make a diagnosis as early as possible; 2) to manage and monitor patients with SLE who have mild and stable Gisease (ie,, those without miajor organ involverneat and/or comorbidity}; 3) to tecognize when referral to a rheumatologist is indicated; and 4) fo collaborate with the specialist in monitoring disease activity and therapy in patients with moderate to severe SLE. Initial evaluation: making the diagnosis Because of its multisystem involvement and its protean manifestations, the diagnosis of SLE may be ‘ifficuk. SLE should be suspected in say patient who has features affecting 2 or more organ aysiems as listed in Table 1. The American College of Rheumatology has1788 ‘Table 4. Condiions that may be confused with sfsemic lupus eythematesus| ACR COMMITTEE ON SLE GUIDELINES ‘Table $. Characerstis of patients with mild systemic lupus cezsthematorus (SLE) Unciferentiated connective seve disease Sitgree's syndrome Aniiphospholipid antibody syndrome Fibrompaigia with posive antinuclear suttody Idiopathic Uurombceytopenin purpura Drugeinduced ipo Esty rheomatoid artis Vacoulits published criteria for the classification of patients as having SLE (9,10), shown in Table 3. Although the criteria were designed to cusure that SLE patients reported in the literature do in fact have the disease, they are also useful in evaluating individual patients. Ifa paticat has, at any time in his or her medical history, 4 of the 11 criteria documented, the diagnosis of SLE éan be made with ~95% specificity and 85% sensitivity (18,19). If the patient meets fewer than 4 criteria, the diagnosis of SLE is possible (for example, a young woman with nephritis, antinuclear antibodies [ANA], and anti-DNA meets only 3 criteria but almost surely has SLE), and the diegnosis depends upon clinical judgment. If ANA are negativo, the patient has a very low probability of having SLE, Patients with positive ANA alone, without organ system involvement or typical laboratory findings, are unlikely to have SLE (20). ‘Other serologic tests may have @ higher predic~ tive value than ANA, and thus may aid in the diagnosis of SLE or related connective tissue disease. High-titer IgG antibodies to double-stranded DNA (dsDNA) and antibodies to the Smith antigen (anti-Sm) are usually specific for SLE. Antibodies to RNA proteins ¢anti- RNP, anti-Ro, anti-La) and to phospholipids (anticar- diotipin) occur in SLE and other connective tissue diseases, as does hypocomplementemia (18,21). The frequencies at which these serologic abnormalities occur in SLE are listed in Table 2. ‘A number of other diseases may be confused with early SLE because they present with either clinical or laboratory features that may be similar to those seen in SLE. These include undifferentiated connective tissue disease, primary Sjogren’s syadrome, primary antiphos- pholipid syndrome, fheomyalgia with positive ANA, idiopathic thrombocytopenic purpura, drug-induced Iu- pus, and early rheumatoid arthritis (22) (Table 4), SLE can be mild, moderate, or severe, Almost all patients with anything more than stable mild symptoms should be cared for by an experienced physician, who, in most ceases, will be a rheumatologist. Many SLE patients may 1. Diagnosis of SLE is confirmed or highly wuspocted 2. Disease is clinically stable 3. Disoass isnot life tresrening, 41 Body esters that can be 2 target of SLE have normal and stable function including 2 Kidacys Skin Joints 4. Hematologic sytem fe Langs t Heart ¢g Gastrointestinal system fh, Central nervous system 5. Taare ate Ro sgnlicant roxcties ofthe therapies for SLE, also prefer to have their specialist act as principal care provider to manage and coordinate their general healt cate, At any one time, one or more organ systems may be affected by SLE, Patients with mild SLE are those who 1) clearly have the diagnosis, 2) are clinically stable, 3) do not have life-threatening disease, and 4) have Stable normal function of body systems that can be damaged by SLE, such as kidneys, skin, joints, hemato logic system, lung, heart, gastrointestinal (GI tract, and central nervous system (CNS). In addition, the patient should have no significant toxicities from therapies for SLE. This definition of mild SLE is reviewed in Table 5. Referral We recommend referral 1o a rheumatologist andlor other appropriate specialist for the following purposes (Figure 1 and Table 6). Establishment ofthe diagnosis. Patients in whom SLE is suspected based on history, physical exzmination results, or laboratory date should be referred to a rheumatologist to establish or confirm the diagnosis, particularly if there are symptoms, signs, or laboratory evidence of disease that suggest moze than mild SLE. (Table 5). As noted above, diagnosis can be difficult because of multisystem involvement and variability of ble 6 Reasons for sefettal to 4 sheumatolosist, 1 To eonfiem a dggnonis 2To asese disease acti and severity 43. To provide general dicase management 4. To manage uncontrolled disease 5. To manage organ involvement or Hfechecatoaing disease 6 To manage/prevent treatment toxics 1m other specie ercimestances, nciadingantiphoopho i syndrome, pregnancy, gerySLE REFERRAL AND MANAGEMENT GUIDELINES presentation of the disease. ‘Thus, in most cases, a theumatologist may be needed to interpret laboratory findings and confirm the diagnosis. ‘Assessment of disease activity and severity. As- sessment of disease activity and severity is important for the establishment of an appropriate treatment program for an individual patient. Since patients with very active and severe disease are likely to require ongoing care by fa theumatologist, it is necessary to assess both the activity and the severity of the disease early on. Vali- dated indices have been developed for the assessment of both disease activity und disease severity (15,23). Establishment of a plan for disease management. A patient with established SLE. may be referred 10 an appropriate specialist to establish a treatment plan that say then be followed by the primary care physician if the disease remains stable and mild. SLE patients: may be referred to a rheumatologist to monitor eiicacy and tox City of treatment (2.., antimalarial drugs, ghieocortinids, and immunosuppressiveleytotoxic drugs) or to provide patient education. In adition, the rheumatologist may be asked to coordinate care with allied health professionals and other medical specialists, Patients for whom compli- cated management decisions are necessary should be re- ferred to a theumatologist or other appropriate specialist depending on the major organ system involved. Examples cf such complicated management decisions are the ré= quirement for long-term glucocorticoid therapy to eonttol the disease; prevention of the development of complica tions froma glucocorticoid therapy or planning treatment of those complications; the need to consider therapy with sex hormones, antimalarial agents, or immuzosuppressive/ eytoioxic drugs; and consideration of investigational treat- ment modalities such as apheresis, intravenous gamma lobulin, dapsone, debjdroepiandrosterone (DHEA), and new experimental therapies, Management of uncontrolled disease. In patients ‘whose SLE manifestations persist despite therapy, consul tation with a rheumatologist or other appropriate special- ist, depending on the organs involved, is required. Exam- ples of uncontrolled disease include pleurisy, pericarditis, ‘andor arthritis not controlled by nonsteroidal antinflam- matory drugs (NSAIDs); rash not controlled by topical therapy; active vasculitis; digital ulcers; muscle weakness andor elevated creatine phosphokinase (CPR) despite steroid therapy; any CNS manifestation; and contiming, evidence of active renal disease, cardiopulmonary disease, oor hematologic manifestations despite therapy. The spe cific management for such patients is best provided by specialists, and is reviewed briefly below in the section on the treatment of severe SLE, Persistent laboratory abnor 1789 malities such as hypocomplementemia or highetiter anti DNA may also suggest underiving uncontrolled disease and constifute a reason for referral, When patients dem- onstrate a persistent need for dosages of medication so high that side effects are likely 10 occur, they should be referred to an experienced consultant Management of disease with major organ dam- age. Patients demonstrating end-organ compromise should be referred to a rheumatologist or other appro- priate specialist depending on the oxgan(s) involved. Examples inchide GI involvement witht motility dlisor- ders oF ischemia, lung involvement causing shoriness of breath, pulmonary hypertension, malignant hyperten- sion, renal insuficiency, nephrotic syndrome, severe peripheral or CNS disease (2g., psychosis, confusion, disorientation, paresthesias, seizure, cognitive dysfune- tion, severe unremitting headache, cerebrovascular acci- ent, transient ischemic attack, retinal vasculitis), muscle atrophy or weakness, deforming arthritis, osteoporosis (with fracture), avascular necrosis of bone, and severe skin involvement (scarring, alopecia, ulcers) (11) Management/prevention of complications of therapies. In some patients, the treatment is effective ‘out drug toxicity or intolerance occurs. These patients may present with serious infections, steroid myopathy, avascular necrosis of bone, hypertension, osteoporosis, diabetes, cushingoid appearance, GI intolerance, and persistent eytopenias (see Table 7). ‘Management of special clinical situations. There are special conditions that pose additional problems for the SLE patient and necessitate close observation and freqnest alteration of drug regimens. Appropriate con- sultation is recommended, Some of these conditions, and teasons for close observation and consultation, arc as follows: antiphospholipid antibody syndrome (manage~ iment of recurrent fetal loss; venous and/or arterial thrombosis); pregnancy (assessment of disease activity, which may be confounded by the normal physiologic and immunologic effects of the pregnancy; management of the gestational and postpartum treatment regimen; risk of neonatal SLE ia infants of mothers with antibodies to ROISSA and La/SSB); surgery (preoperative disease as- sessment and clearance for surgery; management of the intra- and postoperative treatment regimen [eg., glu cocorticoids, anticoagulants, immunosuppressive) eytotoxic agents) Monitoring SLE, Once a diagnosis is established and referral made for any of the above reasons, the following guidelines should be followed by the aranaging physician(s).1790, ACR COMMITTEE ON SLE GUIDELINES ‘Table 7. Recommended monitoring stratepy for drugs commonly used in systemic hyp erythematosus” ‘Monitoring “Toxics requiring Dwg monitoring Baseline evaluation ‘System review Laboratory Salcgaes, Gastrointestinal beeaing, CBC, ewatinne, urinaly-——Darkiblack stool, CBO yeany, ereatnine ‘nonsteroidal Tepatic toxic, senal fox sis, AST, ALT ‘pepsi, yealy antinflammstory iy, hypertension fauenhomiting, rugs atsomiaal pain, fhortnessof| Gtucocoricnds Hypertension, BP, bone densitometry, Urinary dipstick for glvose Iyperghcemia, slucse, potassium, rary 3-6 months, ota, Iypertipidemin, ‘holesterel, ema, shortness cholesterol yeary, bone Inypokalema,esteo trigycerides (HDL, of breith, BP at densitometry yearly 2 porosi, avascular 1B) each visit, sual assess osteoporanis Decrosi, cataract, weight changes, bone aia, tafections, fait aia retention Hyéreehloroguine —— Macolar damage ‘None unless patient ional changes Fanduscopie and vious) over 40 yeas of age or fields every 6-12 months fu previ ve Aatthioprine | Myclosuppresion, (CBG, paielet count, Symptoms of| (CBC and platelet count " ‘icy, mphopreiferaive creatinine, AST or myelosuppression every 1-2 weeks ith tHsordere Aur changes in dose (every TS tonthe therefter), AST yet, Pap test at regular intervals ‘Qyplophosphamide —— Myeloxuppresion, (CRC and differential and Symptoms of (CBC and sialic Tayelopreierste platelet count urinal myelosuppression, monty, urine eytalogy Aisorders, malignancy, sis hemausr and Pap test yearly tor Ismunesuppresicr, snteriity ite hemorehope rss, secondary ater Methotrexate Msclosippression, hepatic CBC, chest radiographs Shmptoms of CBC and platelet count Tosi rth, wha past yea, ‘myelosuppression, every 4=8-woeks, AST or pulmonary inftraces, hhepatids B, Cserology shortness of ALT every 4-8 necks, Fovesis {in high-vsk patents, breath nausea! ftbumin every 4-8 weeks, AST, slunin, somitig, oral Serb creatinine, urinal bib, creatinine ker Hs = CBC — complete Blood cell count, AST Hipoprotei LDL = low-density fipoproein. Lifelong monitoring is required for most pa- tients. The comerstone of managing SLE is tifelong patient monitoring to detect flares of disease eariy and to institute prompt, appropriate therapy. In patients who have moderate to severe disease at any time, this lifelong monitoring may best be supervised by a physician with experience in treatment of SLE. This is accomplished by seeing patients on a regular basis. A history-taking that emphasizes features of SLE, appropriate physical exam- ination, and laboratory tests are required (for review, see refs. 1-8, 23, and 24) (Table 8). The frequency of these evaluations will depend on the sctivity, severity, and exlent of the SLE, the response to treatment, and the type of treatment, including the need for toxicity monitoring. SLE disease activity can be diagnosed by specific clinical features (e.g. arthritis, serositis, ee.) or ‘spurte transaminase: ALT nine transaminase; BP = blood pressare: HDL = high-density laboratory features (€.g,, antidsDNA antibodies or complement levels), or by using a global activity index. At routine followup visits, the following should be obtained: complete biood cell count, platelet count, creatinine measurement, and urinalysis, even if the patient has had normal values in the past. Patients with known renal disease should have a urinalysis, 24-hour urine collection for protein, creatinine measurement, complete blood cell count, and determination of choles terol, calcium, phosphorus, alkaline phosphatase, so- dium, and potassium levels approximately once a month at the onset of nephritis and more often if the condition is unstable. Measurement of 24-hour urine protein, creatinine clearance rate, or the more accurate measure- rent of glomerular filtration rate is useful to indicate espouse to thetapy. In many patients, particularly thoseSLE REFERRAL AND MANAGEMENT GUIDELINES 1791 Table &, Monitoring of patients with nstemic lupus erythematosus History Fever ‘Weight change Fatigue New rash Increased bai oss Pleurtic chest pain Joint pot and well Physical examination “int sling Rash, discoid lesions Alopecia ‘Mucous membrane mleers ‘Vasculiie hsions Funciscapic earmination Baers Other features” Tavestigations Hematology Chemisty Urinals Serology tony Ss suggested by the bison. with nephritis, iis also useful to monitor serum levels of complement component C3 and anti-dsDNA antibodies at regular intervals (20,21,25-27), Patients with longstanding SLE can develop new organ system involvement aver time (15). This is espe- cially trne for renal disease in African Americans. Pa- tients with severe hemolytic anemia require a hematocrit measurement and a reticulocyte count initially weekly Patients with severe thrombocytopenia {<50,000jmm?) require platelet count monitoring initially weekly. ‘The frequency of subsequent laboratory tess in such patients will depend on the response to therapy. in many SLE patients, changes in the results of certain laboratory tests, such as a decrease in serum complement fevels, an increase in auti-dsDNA level, a rive in erythrocyte sedimentation rate, @ decrease in hemoglobin level or leukocyte oF platelet counts, a rise in CPK level, of the appearance of microscopic hema- turia or proteinuria, may precede a clinical disease flare. Modification of treatment at the time a change in laboratory resuits is noted can significantly reduce the chance of flare (27). The clinician should establish the uility of various tests in an individual patient, then perform those selected tests regularly to detect early flare. In some SLE patients, abnormalities in the results of such tests (particularly antibodies to dsDNA and serum complement levels) do not predict disease activa- tion (28), Monitoring of laboratory findings in patients With SLE may be facilitated by the use of flow charts, particularly for tracking serologic abnormalities. In ad- dition, global activity indices ate useful for the assessment of SLE disease activity in the otficeclinc setting (15,23). Finally, it iS important to establish a team cela- tionship among all of the health care providers, includ ing primary caré physician, specialists, nurses, hospital staff, pharmacists, and the patient and fariy. This team approach will allow manifestations of disease flares oF ‘medication toxicity to be detected at an early stage. The team approach wonld also facilitate the identification of additional features of the disease such as fibromyalgia (6), which may be confused with disease manifestations but require a different management approach than the treatment of active disease or complications of therapy. When should a kidney biopsy be performed? Kisiney biopsy is indicated for diagnostic purposes in SLE patients in whom nephritis is suspected. ‘Thus, patients with persistent urinary sediment abnormalities, such as hematuria and pyuria withoat adequate expla- nation (infection, menstrual period, stone), patients who have urinary casts, or patients who have increased serum, creatinine fevels should have a renal biopsy. The prog- nostic value of kidney biopsy, although controversial, has been demonstrated, particularly for patients with normal serum creatinine levels (15,24,29). Patients with prolif- erative glomerular fesions and chronic changes found on kkicney biopsy are at a higher risk for end-stage renal disease and death than patients who do not demonstrate these changes. Patients with deteriorating renal func- tion, or patients not responding to conventional therapy, may need a kidney biopsy to outline a course of treat- ‘meat (29). Frequency of followup visits. The frequency of followup visits is determined by the activity and severity of the disease and its complications. Patients with very mild stable disease may require followup Visits at 3-6-month intervals by a primary care physi- cian, internist, pediatrician, or theumatologist. Pa- tients with more severe disease or with complications. of therapy, as well as patients with active disease, need more frequent followup, as will patietets during pregnancy and postpartum periods. Patients begin- ting immunosuppressive medication will also requite imore frequent followup. Monitoring for treatment tonicity (Tables 7 and 8). All of the medications used in SLE reguire vigilance to assure their safe use Patients taking NSAIDs should be observed for the possibility of Gi, liver, and renai toxicity. In addition, several of the NSAIDs infrequently cause aseptic men- ingitis in patients with SLE (30), Their most serious side1792 effects are gastritis, gastric ulceration, and GI bleeding. Patients at high risk for these complications should be ‘cated with gastroprotective agents, of which the most ‘effective may be proton pump inhibitors; H, blockers rand prostaglandin analogs are also acceptable (31). The role of the newer eyclooxygenase 2 (COX-2) inhibitors in the management of SLE is as yet unknown, ‘These drags have not been tested in patients with SLE, nd their effect on kidney function is unclear. Most authorities recommend regular ophthalmo- logic assessments (every 6-12 months) to detect early retinal toxicity of antimalarial agents. The incidence of this side effect with hydroxychloroquine is low (32). Tn patients receiving long-term ghicocorticoid therapy, electrolyte, glucose, and lipid levels should be monitored to identify metabolic complications. They should also undergo bone densitometry (dual x-ray absorptiometry scanning) to identify osteoporosis and to monitor its response to treatment (33). Patients with hip, knee, or shoulder pain suggestive of avascular necrosis of bone should undergo radiography of the appropriate site, If radiographs are not informative, magnetic reso- zance imaging should be considered to detect avascular necrosis at an early stage, to allow for early intervention. such as core decompression (34). Patients taking ste- roids are compromised hosts in whom signs of infection may be masked. Therefore, one should always be vigilant for infectious complications and infection with atypical onganisms (13). Patients receiving immunosuppressiveteytotoxic medications (methotrexate, azathioprine, cycio- phosphamide) should be monitored carefully for evi- dence of hematologic toxicity, liver and renal toxicity, and the possibility of infection (Table 7). At times itis, fficult to distinguish between manifestations of active SLE and side effects of medications. While eytopenias may represent drug toxicity, they may also result from active inflammation for which drug doses should be eased. TE the eytopenias occur in association with serologic abnormaitics, it is more likely that the SLE is active than that this isa result of drug toxicity. Likewise, fever may represent active lupus or infection, If there are other clinical or laboratory manifestations of active disease, the diagnosis is facilitated. However, since in- fection is more likely to develop in the context of active SLE, the differentiation may become difficult (35). Paticnts with SLE are often treated for infection and active disease simultaneously uot the results of cultures are obtained. ACR COMMITTEE ON SLE GUIDELINES ‘Table 9. Treatment of mild ystemic upus erythematous 1. Patent edveatoa ‘a Realistic expectations 1, Avoid extensive ultraviolet ight exposure © Avoid exhtstion 1. demttysenptoms and sgos of Mare «©, Comply with recommended teatent Keep aediel appointments 2, Analgasic treatment as needed 5. Nonsteroidal auiiaammatory drog westment as needed (Crions regarding ide effect: gate eosionulzers bleeding, Aeerease in real function, increase I) ler eneym levels, axeptc roeningii) 4. Topical glueccnticoid treatment for rath (Caution: aveid using high-potency preparations onthe fave for more than sera days) 5. Fopical sunscreens (onnimum sim protection facta of 1S secommended) 6, Rest when patent senses Mae beginning 1, Antimalarial drug treatment (hydzoxychloronine x most requently wed, a 200-00 apy ‘(Canton patient will need ophthalmelogc examination at Feast stoncaly therapy is continved longer than 6 oats)" 5, Lim-dose pIuccenticed therapy (net to exceed 10 mg of prednisone or equivalent dail)" = Refertal w sperai rege. {s recommended i these interventions Management General considerations. All SLE patients need education, counseling, and support due to the complex- ity and unpredictability of the disease process. Patient education programs for SLE patients and their families are designed to provide information, knowledge, and social support with an emphasis on enhancing. seli- ‘management skills (36). Such support may also come from local organizations such as the Lupus Foundation of America, Lupus Canada, and the Arthritis Founda- tion, Patients need advice regarding physical measures, including minimizing sun exposure, using sunscreens, and exervising regularly. Diet management for preven- tion of obesity, osteoporosis, and hyperlipidemia is of particular importance. Routine health maintenance, in- cluding reguiar gynecologic assessments, dental care, and ophthalmologic examinations (especially for pa- tients taking glucocorticoids or antimalarial drugs), is ‘very important in this chronic systemic disease. Preven- tive measures such as immunizations (c.g, hepatitis B, Haemophilus influenzae, Pneumevas, and influenza) or the use of hormone replacement therapy should beSLE REFERRAL AND MANAGEMENT GUIDELINES 1793 coordinated with the SLE care expert. Since cardiovas- cular disease is a major cause of long-term morbidity and mortality among patients with SLE (13,14), strate- gies to identify and treat risk factors are essential Treatment of mild SLE (Table 9). Topica? sun- screens. Patients with SLE may experience cutaneous or systemic disease flares when exposed to ultraviolet light (3D; these patients should be encouraged to protect themselves from such exposure. Wearing protective clothing, applying sunscreens with a sun protection factor of at least 15 whesever outdoors, and avoidance of sunbathing should be emphasized. Topical glucocorticoid preparations, Creams, oint- ments, and other vehicles are used to apply glucocorti- coids to affected areas. Intermediate- rather than high- strength topical steroids should be used on steroid: sensitive areas that ate prone to atrophy, such as the face. Cyclical application of more potent glucocorticoids may be required (38). NSAIDs, NSAIDs are sometimes helpful for con- trol of fever, arthritis, and mild serositis. However, salieylate-incuced hepatitis has been noted ariong pa- tients with SLE, and aseptic meningitis has developed in ah cause similar reactions. NSAIDs may cause or aggravate hypertension, peripheral edema, and renal impairment in SLE patients. Whether the COX-? inhibitors will have a beiter safety profile among patients with SLE remains unknown. Antimalarial agents (eg, hydroxyehloroguine). An- timalarial agents are useful for skin and joint manifes- {ations of SLE, for preventing flares, and for other constitutional symptoms of the disease (32,3840). They may also reduce fatigue and decrease levels of low- density lipoproteins. Oral glucocorticoids. Patients with mild SLE usu ally do not need systemic ghicocorticoid treatment. However, some patients do not have an acceptable quality of life unless treated with low-dose daily or alternate-day glucocorticoids (=10 mg of prednisone! day or equivalent). Given the significant toxicity of glucocorticoids, initiation of therapy with these agents, along with strategies to minimize steroid side effects (e.g, coasideration of steroid-sparing agents, and pre- vention of osteopordsis and infections), is an indication for referral ‘Treatment of serious, life-threatening, or organ- threatening SLE (Table 10), Organ involvement may lead to irreversible damage in the affected organ. For example, patients with Iupus nephritis may develop rapidly progressive renal failure, Patients with cardiac ‘Table 10. Evamples of ongan- or Me-threatening disease ‘manifestations Carag Pulmonary Coronary vasculitis) Pulrtonary hypertension ‘aseulopathy Pulmonary hemorage Litman Sacks endocarditis Pneumoratis Myocarditis Enibolvinfarcts Peviatdial tamponade Sinking upg Malignant hypertersion Inersttio) fbosie Hematologic Gastrointestinal Hemolytic anemia Mesenteric vascuits Nevtropenis (wite blood eels Pancreatitis = 1000 “Trombocytopenia (50,0007 Renal ma} Persistent nephritis “Thrombotic thrombocytopenic pil progressive porpurs ‘lomerulonephis ‘Thrombosis (venous or [Nephrote syndrome ‘rnerial) sein Nestoogie ‘Vasculitis ‘Seiames Distose severe cash, ‘Acnte eontusonal state ‘nth lceraion oF Coma DBlstering Seroke Conattutionsl igh fever (prestration) In the absense of inteston ‘Transiere myelopathy Monoueurits, pbmeusiis Optic neuste Pajeosis ‘Demyeinatng sydrome Muscle Myositis involvement may develop heart failure, valvular insufi- ciency, or pericardial tamponade. Severe anemia or thrombocytopenia may be life threatening. These pa- tients require care by a specialist skilled in the manage- ment of SLE. High-dose glucocorticoids (1-8, 16,24,41~43). Glo- cocorticoids are used for refractory manifestations of SLB, as well as for severe organ-threatening disease. High-dose, daily glucocorticoid therapy (40-60 mylday of prednisone) improves survival among patients with severe forms of SLE nephritis (41), but is associated with virtually universal undesirable side effects. The dosage and mode of administration of glucocorticoids will de- pend on the nature and severity of the condition. Thus, refractory serositis may require relatively low doses, up) 10 20 mg per day of prednisone ot equivalent, However, depending on the individual's sensitivity to steroids, that osage may cause significant side effects, The treatment of active SLE nephtitis, cerebritis, or thrombocytopenia may require high doses of 40-60 mg of prednisone per dlay, or intravenous puises of up to 1 gm of methylpred- nisolone per day for 3 consecutive. days. Studies of monthly high-dose intravenous methyiprednisolone (in4794 addition to daily oral glucocorticoids) have shown a positive effect on severe SLE nephritis, although the therapy is not as effective as intermittent intravenous cyclophosphamide added t0 oral glucocorticoids (4). The exact dosage will depend on the sensitivity of the individual, und the exact nature of his or her disease. Immunosuppressiveteytotoxic agents (1-9,16,24, 42-48). 8 umber of immunosuppressivefeytotoxic medi- cations have been used to treat SLE. These include aza- thioprine, cyclophosphamide, methotrexate, chlorambucil, «yclosporine, and nitrogen mustard. The choice of drug will depend on the nature and severity of the condition, as well as individual preference. For example, for patients with particularly severe arthritis, methotrexate may be preferred as the first cytotoxic medication, whereas for SLE nephritis, azathioprine ar eyclophosphamie may be chosen first. In fa series of long-term studies (>20 years of followup) in patients with SLE nephritis, treatment with glucocorticoids plus eyclophosphamide for 2 years appear tobe superior to elscacarticoids plus azathioprine, and both seem supe- sige to glucacorticaids alone in preventing renal failure in these patients (16:24,42,43). There is evidence that cyt- toxic agents plus low-dose steroids prevent scarring in the kidney better than do phncocorticoids alone (21), However. some patients with severe disease (renal or extrarenal) respond well over both the short term and the Hong term t0| alucocosticoids alone, or they require only afew mionths of treatment with cytotoxic agents plus glucocorticoids to achieve long term improvement. Noarenal manifestations of SLE that may respond to cytotoxic drugs if glacocorti- coid treatment is unsuccessful oF is not tolerated include cytopenia, CNS manifestations, pulmonary femorthage, and vasculitis (1-84546), There are several reports of SLE aithtitis or aephitis responding to methotrexate (47,48). Variations in responses to therapy, in addition 40. the considerable toxicity of all of the regimens, necessitate ‘expert management. Management of severe SLE without renal involve ‘ment, Additional treatment approaches have been used in certain circumstances among patients with SLE. In & vontrolled ‘tial, intravenous gamma globulin was not superior to daily high-dose glucocorticoid therapy among patients with idiopathic thrombocytopenic pur- pura (49), However, intravenous gamma globulin can produce Short-term improvement in patients with SLE- ‘elated immune thrombocytopenia or hemolytic anemia, as can splencetomy, cunazal, cyclosporine, and various chemotherapy regimens (30-32). Plasmapheresis has ot provided atkded henetit to glucocorticoids plus eyelo- phosphamide ia controlled trials of SLE nephtitis (53,58), However, apheresis has heen used for cytope- ACR COMMITTEE ON SLE GUIDELINES nias, eryoglobulinemia, and occasionally for CNS dis- cease. Plasmapheresis or plasma exchange is often fife- saving in SLE-assoviated thrombotic thrombocytopenic purpura (55). Cyclosporin A fas been used to treat severe disease (82); however, its low efficacy ratio requires that it be administered by a physi is expert in its use. Dapsone has been used primarily for refractory skin lesions, Retinoid derivatives have also been used for resistant skin lesions (38). Paticats who have had thrombotic events in the setting of SLB usually require anticoagulation rather than immunosuppres- sion (56) End-stage renal disease. Tn spite of optimal ther- apy, in some cases SLE advances to end-stage rental disease, necessitating dialysis and/or tenal transplanta- tion. The rate of recurrence of SLE in trensplanted Kidneys is ~6%, and rejection rates may be somewhat higher than those in the general population of patients who have undergone renal transplantation (57). Hi ‘eves, most patients do well, and choosing this modal rather than vigorous immunosuppressive treatment should be considered by both patient and physician, Investigational treatments, Several experimental interventions are being studied in SLE. Some, such as DHEA, may have a steroid-sparing effect in individuals with mild disease ($8). Others, such as new fymphocyte- specific immunosuppressive strategies, tolerogens, and biologic modifiers that prevent B cell activation and autoantibody production, may be useful in the treatment of severe SLE. All such interventions should be super vised by specialists with experience in their use, Summary SLE is a complex disorder with variable presen- tations, course, and prognosis. Since its prevalence is only 1/1,000, most primary care physicians and general internists will not have sufficient experience in the management of moderate-to-severe life-threatening dis- ‘ease. The major tasks of the primary care physician in the diagnosis and management of patients with SLE include early diagnosis, appropriate referral, monitoring patients with mild, stable disease, and collaboration with, a specialist in the management of severe disease. Guide- lines for the initial evaluation, ceasons for referral, and management of mild and severe SLE are provided. ACKNOWLEDGMENTS ‘The Ad Hoc Committee acknowledges the contribu tions of Dr. Suzanne Guitliam (Portland, OR), Dr. GordonSLE REFERRAL AND MANAGEMENT GUIDELINES 1795 Herdacre (Toronto, Ontario, Canada}, Dr. Laura, Robbins (New York, NY), and the members of the American College of Rheumatology Board of Directors for their helpful contrib tions 40 the manuscript. REFERENCES 1. Labia RG, evr. Systemic lupus erythematosus, 3rd ed, San Diego: Academie Pres: 1996 2, Wallace DI, Hain BH, editors, Dubois lupus erythematesus 5th ed, Balimore: Wilians & Wikins; L297 4, Schur P, editor. The chnical management of systemic lupus cejthemtcaus. 2nd ed, Philadelphia: Lapprneat: 956, 4. Kippel J, edior Primer on the rheumatic diseases, 14h ed. Atlanta: Arthritis Foundaton; 1997 5 Klippel JH. Dieppe PA, editors Rheumatology. Londoa: Mosby, 198, 6, Koopman W, editor, Attritis and allicd conditions, 15th. Baluzore: Willams & Wilkins, 1997 1. Kelley WN, Hares ED, Ruddy 5, Sledge CB, eitors Tetbook of sheumajology. sth ed. Piladeiphia: WR Saunders, £997. 8, Madson PY, Isenberg DA, Woo P, Glass DN, editors. Oxford fenibuck of theumatelogy- Oxford: Oxford University Press 1997, 9, Tan EM, Cohen AS, Fries JE, Masi AT, MeShane DJ, Rothfilé [NF vet. The 1982 rested citeia forthe easification of temic Ips erythematosus. Astiitis Rheum {98225:1771-7, 1. Hochberg MC. Updating the American College of Rizomatology revised etteris forthe casfcaion of systemic Iopus erythems- ts letter], Artheis Rheum 199730.1725 11. Gladman D, GinalerB, Goldsmib C. Fortin P, Liang M, Urowiv: Myctal The developroeat and init vatidatian ot the Systemic Enpus International Collaborating ClmieAmerican College of Rheumatology Domage Index for systemic apss eryihernaiets. ‘Antti Rew 199689:368-9. 12, Sill T, Seiler! B, leabeeg DA. SLICCIACR damage index i ‘ali, and renal and pulmonary organ scones are preaitors ‘severe outcome im patents with temic Tepus ervthemtosus BrT Rheumatol 1996:35:208-54, 18, Abu-Shakrs M, Ulesitz MB, Gladman DD, Gough J. Mortality Sodies in systemic lupus efythematorus: rests fom 2 single ‘Cente 1 Cvscs nf death 1 Rhourratel 1995,22:1250-54 14, Urowie MB, Bookman AAM, Koehler BE, Gordon i, Sinjthe HA, Ogryaa MA, The bimodal mortality patern of ystemic pus ccythematones, Aum 1 Med 197650221-5. 15, Glasinan DD, Prognosis and treatment of systemic lye rythens slots. Cure Opin Rheumatol 19968:330-1 1s Boumpes Br, Fee Bf. usin HA I, Balm Klippe! Lostehin MB. Systemic lupus erythematosus: emerging oom ‘cepts, Part 2. Dermatologic and joint disease, the antipho=pho- lipid antibody syndrome. pregnancy and ormotal therapy. rmosbidity and moctality, and pathogenssis. Ann Intera Med 1995;]23.42-52. 1, Exdsle JM, Joseph L, Mackensi T, Kishgarian M, Hayslet JP. “The benefit of avy featment wath inmaunosuporessive agents in fupes nephetis J Rheumatol 199424 2086-5 18 Weirstoin A, Bardwell B, Sione B, Tiers C, Rothtetd NF. ZAnibouies ty ative DNA and serauy complement (C3) keels Application ta Jngposs snd classification of systemic hops ery ‘hamatesus. Am # Med 1983;174:205-16 19, PoressGutthan 8, Betz M, Hochberg MC. Comparison of dior ent methods of closing pation with systemic lapus eres {ons J Rhcomatol VLU 7G=9, 20, Shiel WC Te, Jason M. The diagnostic associations of patents ith Antinuclear anbisadies referred to a commumy rhewmitolegit T'Rieunato! 198016°782-5, 21, Hahn BH. Mechanisms of disease: antibodies to DNA, N Engl J Med 1958;598:1359-68 22. Calvo-Alén J, Bastian HM, Straton KV; Burgard SL, Mutha 18, Alaeén GS, Ieentication of patient subse among those pre= Surtptively diagnosed with, eefered, andar ‘ollowed up for 35+ ten lupus erythematosus ats Iegefetiary core center ARPES hewn 1985; 247598, 23, Kaluoiin. KC, Detinition, catsfication, activity and damage ndices. Ta: Wallace DJ, Hahn BH, editors. Dubois) pus erythematosus, Sthed. Baltimore: Willis and Wilkins 1997 p13, 24, Boumpas DT, Austin HA IIL, Fessler BF, Balow JE, Klippel 7H, Lockahin MB_ Systemic lupus erythematosus: emerging com opts. Pact I. Renal, neuropeycbiate, cardiovascular, Palme nary and hematologic disease. An Tatern Med 1995 122-940 50 25, Ter Borg EJ, Host G, Hummel EJ, Limbueg PC, Kallenberg CGM. Messsremient of increases in ti-double-sranded DNA antibody levels a «predictor of disease exeerbaiion in aysteric Tupus erythematosus: 4 Jong-team, prospective study. Arti hour, 1903563413 26, Petti M, Genavese M, Enyle E, Hochberg M. Definition, inci= ‘dence, an! enical estripton of fre in systemic pus ery tosis: prospective cohort stay. Avani Rheum 1991 3437 4. 277, Rootsnis H, Spronk P, Derksen R, dle Boor G, Wolters Dicks H, Heraans J etal Proxentin of elses in seme Lupus ery szosus. Lane! 19987145:1595-9. 28, Wate Leblone Gladman DD, Urowite MB, Goodman PI Setolygieally active clinically quieeeat SLE, J Rhewmarol 1995 2330-4, 29, Enduile JM, Cverent role of renal bsopsy in SLE, Baierss Clin Rkeomsal 1998 12135-8 10, Agus B, Nokon J, Kramoe N, Mahal $6, Rosenstein ED. Acute ‘eral ners systen smpoms caused by buproten i eonece Hive tise dtcase J Rheverstol 1958) 7094-8, A Hawkey Cl, Karrasch TA, Szezeponsét L, Walker DG, Barkun ‘A, Swanwelh AJ, etal. Omeprazole compared with misoprostol [er ulsers assaclated with nanseruidal antialaminatony ergs Dimepravole versie Misoprostal for NSAID-Induced Uleer Management (OMMIUM) Study Group, Nv Engl J Med 1998, ARTE 34 232, Wallace D1. Ansimalaria gents snd lupus, Rheum Dis Cia Nowth Am 1994 30.243-25, 43. America Collegeof Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of ghucoooecsideinducad osteopowss. Atcvisls Rhewra 1986338 TL 30. “1M, Moot MA, Glusck CJ, Pacheco M, Wang, Hungerford DS, Pets M. Risk actors lor oxconeesosisin system ops ervthem tess, J Rheumatol 1972465482. 38. Waanabe Dutfy KN, Dutér CM, Gladitan DD. Infection and Aseaxe activity im SLE: 2 zeviow of omitalized pation. ? Reo ‘atol 199118: 1180-4 26, Robbins L. Patient education. Tn: lippel J, Wevand , Westman AR editors, Primer om the rhoumsalse omeases. [1th ed. Atlanta Acts Foundation, S97. p- d16—8 37. Wyscnbcck Al, Block DA, Fries JF Prevelence and expression of photesensieasy io stems lupeseryhemsatosis, Ann Rheum Dis sss 4861 38, Drake PA, Dinohart $M, Farmer ER, Golte RW. Graham OF, Hovdinshy SK. ct al Guidelines of ze for cutsncous Iapus enihematoaus: 2 Am Acad Dermatol 1696385006 29, The Canadian Hydronyenlorogaine Study Group. A random. ined study of the effect of withdraving hydruxyshlorcauine fullace in systemic lupus erythematosus. N Eng! J Mod 1891, S2151796 0. 4 2 8 “a 48. 46, 4, 8. 4%, ele! M, Lakatta C, Mager L, Goldman D. Effect of prednisone and lydronehlorcquiae on coronary artery disease risk factors ia ‘Sstemic pus erythematorus = longitudinal dts analyse: Am 3 Med 193462549, Pollak VE, Pirani CL, Kark RM. Eifect of large doses of pred nisone on the renal Kesions and ie span of patients with lupus slomeruloneptits. J Lal Cin Med 1861:57.485-511 Haka BH, Kaotor OS, Osterland CK. Azatbioprive plus pred nisore verius prednisone alone in the trcatent of systemic hupor enthematesis a report of a prospective, controlled trial fo 28 patients Ann lteen Med 1975:5:397-608 Steinberg AD, Steinberg SC. Long tora preservation of renal {unction in pation with lupos nephviie vecowvinglreatment that inelodes yelophosphamide versus those treated ith prednisone only. Arches Rheum 1991:34845- 51, Gourley MF, Austin HA Itl, Scoit D, Yarboro CH, Vaughsa EM, Muir J, et al. Methyipredaisoione and cyclophesphar mie alone or in combination, im patients with [upus nephritis randomized, controlled trial Ana Intern Med 1996,125:589— 3 Bounpas DT, BatezS, Klippel JH, Balow IE. Intermittent cyco- ‘phosphamide for the teatment of thrombocytopenia ia systenve Topas erythematosus. Ana Tateen Med 1990.102:974-7. ‘Bourspas DR, Yamada H, Putconas NJ, Scot D, Hlippel JH, Balow JE. Pulse qlophospheaide for Severe neuropsyehiairic Jpos. QUM 1993,81975- 84. Walz-Leblanc 3,” Urowite MB, Gladmen DD. Methotrexate in SLE. 7 Rheumatel 1994,21:836-8 ‘Wilson Ke Abels M, A 2 year, open ended tial of methotrexate in ‘stem lupus erythematosus. 3 Rheumatol 1994211674. Jacobs P, Woods L. The comparison of sammaglobulin tos %. 3h 2 8 53 s. 56. s 8 ACR COMMITTEE ON SLE GUIDELINES fo testing adult meaune thrombocytopenia: an Fnterim anaiss hus 1985,59:90-5. ‘West SG, Johnson SC, Danszol forthe teateent of refractory futoimmoae thrombesyopenis in sjsemic hus erythematests, ‘a Tavern Med 1988;108:703-6, (Coon WW. Spleneciom for eeopeoias associated with systemic lupus erythematosus. Am J Surg 1988,185391-4. “Tokuda M, Kurata X, Mizoguchi , Inoh M, Sete K, Kinsshi M, ef a. Elect of iow dose cjelogporin A on sjstemic lupus eryther: tosis disease stivity. Arties Rheum 1994:4S51-8, Levis EJ, Humsicker LG, Lan SP, Rohde RD, Lachia JM. A onttlled tial of plasmapheresis terapy in severe lupus aepht- fuss Engl I Med 19,30601573-9 Ener EH, Schwab UM, Schroeder JO, Hesford J. The Lopus Pissmapacresis Sty Group: vationale and updated inteciy re port. Arif Orguns 1995:20:355 Rand D, Schaap T, Gils S.Tntensive plasmaphevest for severe Urrombove thrombocytopenic purpuca: lougterm clnisl ou ome. J Clin Apheresis 198721545. ‘Khamashia MA, Cuadrado MJ, Muse F, Taub NA, Hunt BY, Fioghes GRY. The memagement of thrombosis io the antiphos: holipi untidy syndrome. N Engl } Med 1995;332595-7, Stone JH, Milvard CL, Olson JC, Amend WIC, Caswell LA, Frequency of reeutrent igous nephits mong ninety seven rent transplant patients uring the elosperine cra. Arthritis Rheum 1996 4678-6, Van Vollenhoven RF, Engleman EG, McGuire JL. Debydivepi andiosterone in sitevi upus erythematosus: aus of 2 double- Blind, plcebo-centrolied, randomized clinical tal. Asthets Rheur 1995;38 1825-31,