EDUCATION & DEBATE

Fortnightly Review

Diagnosis and treatment ofsystemic lupus erythematosus

PatrickJW Venables

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Kennedy Institute ofRheumatology, LondonW6 7DWPatrickJW Venables, seniorkaurer

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The definitive diagnosis of a disease depends onknowledge either of its aetiology or on recognition of aunique pattern of clinical features. Neither appliesto systemic lupus erythematosus. Its aetiology isunknown and many of its clinical features such asarthritis, vasculitis, and serositis are shared by otherautoimmune rheumatic diseases. Although the wellknown wolverine rash (fig 1) from which lupus derivesits name is relatively specific, it occurs in only about50% of patients. The variability of clinical featureshas prompted a search for a specific laboratoryinvestigation. The lupus erythematosus cell pheno-menon described in 1948 and the DNA antibody testdescribed in 1968 were each thought in their time toprovide the answer. Subsequent experience has shownthat, like the clinical features, the autoantibodies areheterogeneous.' Nevertheless their definition hasdone much to improve diagnostic accuracy, provideinformation about subsets of the disease, and delineaterelated syndromes overlapping with systemic lupuserythematosus.

Diagnostic clinical featuresThe evaluation of diagnostic criteria,2 intended

primarily for classification of patients for research, hasalso done much to formalise the recognition ofpatternsthat constitute a clinical diagnosis. In systemic lupuserythematosus, as in most autoimmune rheumaticdisease, arthritis is common. The joint disease ischaracteristically non-erosive and can affect both largeand small joints. Peripheral joint disease is oftenassociated with prominent periarticular and tendoninvolvement, which can lead to Jaccoud-like defor-mities superficially similar to rheumatoid arthritis,though these deformities differ in that they are

correctable (fig 2). Raynaud's phenomenon occurs in

FIG 2-Jaccoud-he arrh*is systemic euhmatosus.

Although supesicialy resembing arthntis the deformiiesare corable and associated with relativey litte joint damage. This

type of arthnti also occurs in other connective tissue dseases,partculary Sjdgren's syndrome andsome overlap syndromes

about half of patients but is more common in systemicsclerosis and many of its related overlap syndromessuch as mixed connective tissue disease. Serositis,commonly manifest as pleurisy or pericarditis, occursin about 60% ofpatients. Cutaneous manifestations arecommon and include cutaneous vasculitis, livedoreticularis, oral ulcers, and the malar rash. The highlydistinctive skin lesions of discoid lupus (fig 3) andsubacute cutaneous lupus erythematosus (fig 4) canoccur on their own, indicating a benign form ofcutaneous lupus, but can also be associated with, orlater complicated by, systemic disease.

Renal disease and central nervous system involve-ment, reviewed by Ginzler and Antoniadis,' are themost important factors determining prognosis. Renaldisease probably complicates less than half of cases,and recent estimates of the frequency of centralnervous system involvement have suggested a preva-lence of 10-18%.3 Lung disease (interstitial pneumonia,obliterative bronchiolitis or fibrosing alveolitis) andmuscle disease (myositis or a non-specific proximalmyopathy) may also occur in lupus, though they tend tobe relatively mild. More severe muscle and lung diseaseoften points to one of the many myositis associatedoverlap syndromes.4'

Serological diagnosisAutoantibodies in systemic lupus erythematosus

react mainly with ubiquitous cellular antigens, and the

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Summary points

* There is no single test for systemic lupuserythematosus; its diagnosis depends on acombination of clinical and serological features* Antibodies to double stranded DNA and Smare relatively disease specific but do not occur inall patients* Antibodies to Ro, La, Ul ribonucleoprotein,and phospholipids are helpful in defining diseasesubsets and overlap syndromes* Steroids alone or in combination withazathioprine or antimalarial drugs remain thecornerstone ofdrug treatment* Cyclophosphamide is of proved benefit inrenal lupus, though its use is curtailed by almostinvariable side effects; side effects may beminimised by using pulse treatment and mesna* Results with other cytotoxic drugs, pulsesteroids, and plasma exchange have been disap-pointing in clinical trials

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FIG 3-Discoid lupus affecting the ear as discrete hyperpigmentedlesions, and the hair ispatchy alopecia

disease is regarded as a prime example of non-organspecific autoimmunity. The cellular targets of theantibody response range from DNA in the nucleus tophospholipids on the cell surface, and at first sight theantibodies would seem as heterogeneous as the clinicalfeatures with which they are associated. A closeranalysis has shown that the antibodies fall into threedistinct groups: nucleic acids, nucleic acid bindingproteins, and cell membrane antigens (table I). Thenucleic acids are DNA, the nucleic acid bindingproteins are histones and ribonucleoproteins, and thecell membrane antigens are phospholipids and theproteins that bind to them. The nomenclature of someof the ribonucleoprotein antigens has been confusing.Ro, La, and Sm antibodies were originally named afterthe first two letters of the names of the patients inwhom they were first found. Ul ribonucleoprotein(formerly known simply as ribonucleoprotein or RNP)is so called because the antigen lies on polypeptidesbound to a specific uridine rich RNA. The Sjogren'ssyndrome A and B antigens (SS-A and SS-B) are nowknown to be identical to Ro and La respectivelyand this has become the preferred nomenclature.Extractable nuclear antigen originally referred to apartially purified saline nuclear extract which wasenriched for U1 ribonucleoprotein and Sm antigen.Now that its components have been identified, theterm extractable nuclear antigen should no longer be

FIG4-Subacute cutaneous hpus used. The delineation of anticellullar antibodies haswith the characteuistc resulted in two aspects of clinical application: the'"polycydic" lesions in a dphotosesitivedstribion This diagnosis and the identification of disease subsets andrash is strongly associated with overlap syndromes.anti-Ro antibodies Most antibodies in systemic lupus erythematosus

TABLE I-Autoantibodies in diagnosis and disease subsets of-systemic lupus erythmatosus (SLE)

Antibody Sensitivity Specificity Disease subset

DNA:DsDNA 50-700/% High (marker) Nephritis

Ribonucleoproteins:UIRNP 300/o Low Overlap (- mixed connective tissue disease), Raynaud's,

myositis, fibrosing alveolitisSm 7-30% High (marker) Membranous nephritisRo (SS-A) 400!% Medium Sj6gren's/SLE overlap, subacute cutaneous LE,

congenital heart block, membranous nephritisLa (SS-B) 100/0 Low Sjogren's/SLE overlap, subacute cutaneous LE,

congenital heart blockrRNP 5-15% Medium Cerebral lupus (?)

DNA binding proteins:Histones 500/o Low Drug induced SLEKu >5% Medium SclerodactylyPCNA > 5% High Severe disease

Cell membrane:Cardiolipin 20-30%/o Low Thrombosis, abortion

may be detected as antinuclear antibodies by indirectimmunofluorescence, and hence this remains the mostsensitive screening test (> 95%). Two importantantibodies, anti-Ro (SS-A) and anti-phospholipid, maybe associated with a negative result on this test. It islikely-though this has not been formally tested-thattesting for a combination of antinuclear, anti-Ro, andantiphospholipid antibodies would pick up more than99% ofpatients. All ofthe antibodies to specific cellularantigens are potentially useful in diagnosis, thoughwith varying disease sensitivity and specificity (table I).Antibodies to double stranded DNA and Sm arevirtually restricted to systemic lupus erythematosus, tothe extent that they have come to be called markers,but as the prevalence of antibody to DNA is 50-70%and that of antibody to Sm is as low as 7% in somestudies, the term marker may be misleading. Never-theless the specificity of these antibodies is highenough to warrant their inclusion in the reviseddiagnostic criteria. All of the other autoantibodies intable I occur in other autoimmune rheumatic diseases,but a combination is often highly suggestive of systemiclupus erythematosus. The relatively rare autoanti-bodies Ku and PCNA are useful when other standardautoantibody tests are negative results.The association ofantibodies with patterns ofdisease

expression in systemic lupus erythematosus may bemore of interest to the theoretician seeking evidencefor pathogenic mechanisms than to the clinicianseeking practical guidance in disease management.Nevertheless, specific antibodies may help to elicitwarnings of clinical value. The association of DNAantibodies with glomerulonephritis implies that a risein these antibodies may herald the worsening of renalfunction or the appearance of renal disease in somepatients. The presence of phospholipid antibodies maypredict thrombotic events or recurrent abortions.7 Inpregnancy maternal Ro antibodies should prompt anearly examination of the fetal heart rate because ofthe association with congenital heart block. Ulribonucleoprotein antibodies in high titre are no longerregarded as markers of mild disease and may promptthe search for occult but potentially fatal featuresresembling those of mixed connective tissue disease,such as fibrosing alveolitis or polymyositis.6

Other laboratory testsThe search for, and failure to discover, the holy grail

of a single autoantibody test to diagnose systemic lupuserythematosus has tended to eclipse the potentialvalue of other, simpler investigations in diagnosis.Leucopenia, particularly lymphopenia, may be foundin two thirds of patients with active disease. Thrombo-cytopenia may be an indicator of poor prognosis, andserum creatinine concentration has been reported asthe best marker of an unfavourable outcome in renaldisease.78 Patients with systemic lupus erythematosus,in common with those with other autoimmunerheumatic diseases, have raised polyclonal immuno-globulin concentrations but a normal acute phaseresponse providing there is no additional infection.The erythrocyte sedimentation rate, which is affectedby serum proteins and acute phase reactants, has cometo be regarded as unreliable in diagnosis, though achange may correlate well with disease activity.Reduced serum complement concentrations are

useful in diagnosis and in assessing disease activity.One mechanism for this is thought to be consumptionby immune complexes. However direct measurementof circulating complexes, intensively investigatedduring the 1980s, has proved to be unrewarding.Assays for complement breakdown products have notbeen shown to be superior to simple measurements ofplasma C3 and C4 concentrations.

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TABLE iI-Treatment strategies and drug doses in systemic lupus erythematosus

Indications Drugs (dose) Major side effects

Symptoms:Arthritis, pleurisy NSAIDs, analgesics Peptic ulcers orbleeding, constipation,

addictionRashes Barrier creams

Topical steroids Skin atrophy, telangiectasiaModification of disease or disease

maintenance treatment:Failure of symptomatic treatment or Prednisolone (5-15 mg/day) Osteoporosis, weight gain, diabetes,

after induction treatment infectionsRash or arthritis Hydroxychloroquine Retinal damage, acne, rashes, nausea

(200-400 mg/day)After induction; steroid sparing Azathioprine (1-2 mg/kg/day) Infections, marrow suppression,

infertility, nausea, lymphoma(<5%)

Induction ofremission:Life-threatening illness, nephritis, Oral prednisolone Osteoporosis, diabetes, infections,

cerebritis, fibrosing alveolitis, (0 75-1 mg/kg/day) avascular necrosis, psychosismajor haematological Methylprednisolone intravenous Steroid side effects, sudden death,manifestations 0 5-1 g x 3 pulses on altemate withdrawal syndromes

daysNephritis (diffuse proliferative), Cyclophosphamide: oral Infections, marrow suppression,

cerebritis (?), major haematological 1-3 mg/kg/day, orintravenous infertility, menopause, nausea,manifestations 8-20 mg/kg every 4 weeks with cystitis, bladder carcinoma

mesna

TreatmentThere is no specific treatment for systemic lupus

erythematosus, but several drugs can modify thedisease sufficiently for the patient's symptoms to betolerable or vital organs to be protected from permanentdamage. Side effects are common with these drugs andit is therefore essential to plan treatment strategies foreach individual patient (table II). The potential benefitof each treatment regimen will be balanced by the sideeffects which, with cyclophosphamide, are almostinevitable. Certain precautions are mandatory. Theseinclude regular full blood counts for detecting possiblemarrow depression and giving mesna as a protectionagainst cystitis or bladder carcinoma. Counsellingand, if appropriate, sperm or ovum banking may berequired as a precaution against infertility, whichmay be as high as 50% in patients treated withcyclophosphamide. It should also be remembered thatone ofthe commonest causes of death in systemic lupuserythematosus is now infection, even though the fiveyear survival has improved from a reported 50% in the1950s to greater than 90% in the 1990s.' This impliesthat, although both diagnosis and treatment haveimproved, a substantial proportion of the deaths arelikely to be due to immunosuppressive treatment.

Prevention and treatment ofsymptomsAlthough the cause of systemic lupus erythematosus

is unknown, certain factors such as ultraviolet light,hormones, and intercurrent infections lead to exacer-bations of the disease. Simple measures such as usingbarrier creams; avoiding preparations containingoestrogen, such as the contraceptive pill; and promptor prophylactic treatment of infections may preventdisease flares. Many of the common features arewithout long term sequelae and therefore can betreated symptomatically. The arthritis is rarelydeforming, rashes usually heal without scarring, andpleurisy does not indicate parenchymal lung disease;such complications can be treated with simple measuressuch as anti-inflammatory drugs and analgesics.

DISEASE MODIFYING DRUGS

When these simple measures fail to maintain atolerable quality of life in patients with limited diseaseit may be necessary to resort to drugs that modify thedisease. Steroids have a potent anti-inflammatoryeffect, and even in low dose (5-10 mg of prednisolone)may control symptoms satisfactorily where simplemeasures have failed. There is a long tradition of theuse of antimalarial agents in treating patients with a

predominance of cutaneous and joint disease; theyhave symptomatic benefit as well as showing someeffect on underlying disease activity. Azathioprine mayalso be used in this context, usually in doses and withprecautions similar to those used in maintenancetreatment (see below).

INDUCTION AND MAINTENANCE TREATMENT

Induction treatment is indicated in all potentially lifethreatening complications such as glomerulonephritisor neuropsychiatric disease. In systemic lupuserythematosus, true remission is rarely obtained,though the principles of treatment are analogous tothose for leukaemia. The initial aim is for substantialsuppression of the disease, which is then controlled bymaintenance therapy.

SteroidsAlthough much of the recent literature has con-

sidered cytotoxic or immunosuppressive regimens,steroids remain the core treatment for the more seriousmanifestations of systemic lupus erythematosus.The starting dose is usually 0 75-1-0 mg/kg; this ismaintained for 6-10 weeks and then reduced to amaintenance dose. The preparation most commonlyused in the United States is prednisone; prednisolone,which is equipotent but with less mineralocorticoideffect,9 is more popular in Britain. Deflazocort,"' whichwas claimed to spare both bone and carbohydrate, isbeing increasingly prescribed in specialist units insome European countries, but it does not have a licencein Britain or the United States.

In the 1970s and 1980s there was much interest inthe use of high dose (1 g) intravenous pulsed methylprednisolone as a way of avoiding cumulative sideeffects from steroids and exploiting what seemed to bea "different" spectrum of pharmacological properties9of steroids given in this way. An early controlled studysuggested that initial pulse therapy followed by oralsteroids accelerated the response of proliferativenephritis in comparison with oral treatment alone,though the final outcome in terms of renal function didnot differ between the two groups." A more recentstudy found no difference between intravenous pulsetherapy and oral treatment with 100 mg ofprednisolonedaily. It was concluded that there was no justificationfor the expense or potential dangers of pulse treatment-but there are many reports of individuals whoresponded to pulse treatment after being refractory toconventional oral therapy (reviewed in reference 9).There is now a consensus that pulse therapy isprobably not indicated as routine treatment in systemiclupus erythematosus, though it may be held in reservefor special circumstances such as failure to respond tohigh dose oral steroids or rapid treatment of flares ofdisease when patients are already compromised bycumulative side effects. Alternate day steroids probablyhave no place in the management of acute diseaseflares,'3 though they may be associated with fewerCushingoid side effects when they are used in main-tenance treatment.

Cytotoxic drugsCyclophosphamide and azathioprine have now

become standard adjunctive treatment (with steroids)for the more severe manifestations of systemic lupuserythematosus. In renal lupus, several studies haveshown that the incidence of renal failure is significantlylower in patients treated with cyclophosphamide plussteroids than with steroids alone (reviewed in referenes9 and 13)."' Benefit has been shown for continuous oraltreatment (1-3 mg/kg/day) and for intermittent pulsetherapy, 8-20 mg/kg once a month intravenously withmesna. There is no doubt that intravenous pulsetherapy is associated with fewer side effects. To date

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there have been no published clinical trials comparingoral and pulse therapy, though Hahn is of the opinionthat the oral regimens, though more toxic, are alsomore effective.10 Maintenance therapy can consist of alower dose of oral cyclophosphamide (0-5-2-0 mg/kg!day) or more widely spaced intravenous pulses (every6-12 weeks). Cyclophosphamide is also used in treatingcerebral lupus, but it is important to remember thatthere are no controlled studies showing benefit, andmany units use steroids alone for central nervoussystem manifestations.'5

Azathioprine is probably less effective than cyclo-phosphamide and is used mainly for its proved steroidsparing effects in maintenance treatment. It is used in adose of 1-0-2-5 mg/kg/day and either started withsteroids or added at a later date if the requiredmaintenance dose of steroids is too high. One of themost feared side effects of azathioprine is lymphoma.These fears have been somewhat allayed by a studywhich found that in patients with rheumatoid arthritistreated rather eccentrically with very high doses ofazathioprine (median 300 mg/day) only 4% developedlymphoma compared with 2% of patients treated withother drugs. Because of its relatively low toxicityazathioprine may be preferred to cyclophosphamidefor maintenance treatment even after induction withcyclophosphamide.'6 A protocol used by our unit andother units'7 is to give 3-6 pulses of 750-1000 mgintravenous cyclophosphamide monthly with reducingdoses of oral steroids and then switch to oral azathio-prine 100-150 mg/day plus a maintenance dose ofsteroids.

Cyclosporin is effective treatment for lupus,8 thoughits renal toxicity makes it difficult to monitor inpatients with lupus nephritis. It is probably bestreserved for patients unresponsive to conventionalimmunosuppression or for those in whom marrowtoxicity is a particular problem. Methotrexate has along history of rather intermittent use in systemiclupus erythematosus (reviewed in reference 18),though interest in the drug may have been reawakenedby its well established use in rheumatoid arthritis. Inone recent uncontrolled study of 17 patients, low doseweekly treatment resulted in improvement in 57%,though with a rather high frequency (71%) oftoxic sideeffects.'9 A potent steroid sparing effect was noted,however, and it was concluded that a controlled studywas indicated.

PlasmapheresisPlasmapheresis has long been used as adjunctive

treatment for severe lupus, but a much neededcontrolled study was published only recently (reviewedin reference 20). Of 86 patients, all of whom werereceiving conventional doses of steroids and cytotoxicdrugs, 46 were additionally treated with plasma-pheresis. There was no significant difference in theresultant serum creatinine concentration, though therewas a trend towards a more rapid lowering of urinaryprotein excretion in the plasmapheresis group.The outcomes were similar and the study seriouslyquestioned whether plasmapheresis was of any value inthe treatment of renal lupus.

Other treatmentsOther treatments that have been tried for specific

manifestations of systemic lupus erythematosus havebeen reviewed by Miller.20 These include the use ofsynthetic androgens, with negative results; benefitfrom intravenous immunoglobulins for autoimmunethrombocytopenia; and a possible therapeutic effect ofdapsone for bullous or discoid skin lesions. Forpatients with lupus anticoagulant or phospholipid

antibodies, or both, and a history of thrombosis orrecurrent abortions, low dose aspirin is now routinetreatment. The place of steroids or anticoagulants isstill controversial, though most units now recommendlong term anticoagulation with warfarin for patientswith a history of a major thrombotic event. Thetreatment of pregnant patients with recurrent fetal lossis more problematic. The now classic paper of Lubbeet al, which claimed protection from miscarriage bytreatment with prednisolone,2' has been challenged bymore recent studies (reviewed in references 6 and 17),and low dose aspirin with careful monitoring maysuffice. 17

ConclusionSuprisingly little has changed in either the diagnosis

or treatment of systemic lupus erythematosus in thepast 10 years, though there has been refinement ofprevious practice. The autoantibody tests havebeen standardised and most of the commonly usedtreatments have been examined in controlled trials.Encouragement by the improvement in survival hasprobably been tempered by the realisation that sideeffects of drugs have been an increasing problem bothin mortality and morbidity. The trend is towardsmodification of established regimens to reduce sideeffects. At present, it has to be conceded that there isno evidence that any novel diagnostic test or treatmenthas fundamentally changed the management ofsystemic lupus erythematosus in recent years.

1 Harley JB. Autoantibodies. In: Systemic lupus erythematosis. Rheum Dis ClinNorthAm 1988;14:43-56.

2 Tan EM, Cohen ES, Fries JF, Masi AT, McShane DJ, Rothfield NF,et aL The 1982 revised criteria for the classification of systemic lupuserythematosus. Arthritis Rheum 1982;25:1271-7.

3 Ginzler EM, Antoniadis I. Clinical manifestations of systemic lupuserythematosus, measures of disease activity and long-term complications.Curr Opin Rheum 1992;4:672-80.

4 Marguerie C, Bunn CC, Beynon HLC, Bemstein RM, Hughes JMB, So AK,et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyltRNA synthetases. QuartJMed 1990;77:1019-38.

5 Venables PJW. Overlap syndromes. In: Maini RN, Kalden JR, Smolen JS,eds. Rheumatology. London: Gower Medical Publishing (in press).

6 McNeil HP, Chesterman CN, Krills SA. Immunology and clinical importanceof anti-phospholipid antibodies. In: Dixon F, ed. Advances in immunology.Duluth: Academic Press, 1991:193-280.

7 Gladman DD. Prognosis of systemic lupus erythematosus and factors thataffect it. Curr Opin Rheum 1992;4:681-7.

8 Levey AS, Lan S-P, Corwin HL, Kasinath BS, Lachin J, Neilson EG, et al.Progression and remission of renal disease in the lupus nephritis coliabora-tive study. Ann Intern Med 1992;116:114-23.

9 Kimberly RP. Treatment: corticosteroids and anti-inflammatory drugs. In:Systemic lupus erythematosus. Rheum Dis Clin NorthAm 1988;14:203-21.

10 Deflazocort-a new glucocorticoid with bone sparing and carbohydrate-sparing properties: comparison with prednisolone. J Rheumatol 1981;8:783-90.

11 Barron KS, Person DA, Brewer EJ Jr, Beale MS, Robson AM. Pulse methylprednisolone therapy in diffuse proliferative lupus nephritis. J7 Pediatr1982;lOl:137-41.

12 Edwards JCW, Snaith ML, Isenberg DA. A double blind controlied trial ofmethyl prednisolone infusions in systemic lupus erythematosus. Ann RheumDis 1987;46:773-6.

13 Hahn BH. Management of systemic lupus erythematosus. In: Kelley WN,Harris ED Jr, Ruddy S, Sledge C, eds. Textbook of rheumatology. 1993:1043-56.

14 Steinberg AD, Steinberg SC. Long-term preservation of renal functionin patients with lupus nephritis receiving treatment that includes cyclo-phosamide versus those treated with prednisolone only. Arthritis Rheum199 1;34:945-50.

15 McCune WJ, Golbus J. Neuropsychiatric lupus. In: Systemic lupuserythematosus. Rheum Dis Clin NorthAm 1988;14:149-67.

16 Silman AJ, Petrie J, Hazelman B, Evans SJ. Lymphoproliferative cancerand other malignancy in patients with rheumatoid arthritis treated withazathioprine; a twenty year foliow-up study. Ann Rheum Dis 1988;47:988-92.

17 Vyse TJ, Walport MJ. Connective tissue diseases: advances in diagnosis andmanagement. BrJHosp Med 1993;50:121-32.

18 Lieberman JD, Schatten S. Treatment: disease-modifying therapies. In:Systemic lupus erythematosus. Rheum Dis Clin NorthAm 1988;14:223-43.

19 Wilke WS, Krall PL, Scheetz RJ, Babiak T, Danoa T, Mazanec DJ, et al.Methotrexate for systemic lupus erythematosus: a retrospective analysis of17 unselected cases. Clin Exp Rheumatol 1991;9:581-7.

20 Miller ML. Treatment of systemic lupus erythematosus. Curr Opin Rheum1992;4:693-9.

21 Lubbe WF, Palmer SJ, Butler WS, Liggins GC. Fetal survival afterprednisolone suppression of matemal lupus anticoagulant. Lancet 1983;i:1361-3.

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