CURRENT THERAPEUTICS

Management Strategies For SystemicLupus Erythematosus

CC Mok, MBBS, MRCP(UK)CS Lau*, MRCP(UK), MD, FHKAM(Medicine)

Department of MedicineThe University of Hong Kong

Introduction

The management of systemic lupus erythematosus (SLE) is a challenging task. All interventions to-date are palliativerather than curative as the pathogenesis of the disease remains enigmatic. Treatment-related side effects can be asproblematic as the disease itself. The following is a review of the practical management of the disease based on ourexperience. (HK Pract 1996; 18: 475-480)

-m •

To treat conservatively oraggressively?

It is essential to decide thestrategy of therapy for each individualSLE patient as once committed,treatment has to be maintained for along period of time. In general, non-life-threatening manifestations aretreated conservatively while life-threatening major organ involvementrequires aggressive immuno-suppressive therapy. Clinical subsets(e.g. the antiphospholipid syndromein which immunosuppression is notbeneficial) have to be recognised.(Table 1).

Table 1: Indications for conservative/aggressive treatment of systemiclupus erythematosus (SLE)

Indications for conservative treatment of SLEMusculoskeletal symptomsCutaneous lupus • 'Systemic upset ; >Serositis :

Indications for aggressive treatment of SLELupus nephritisCerebral lupusTransverse myelitisPeripheral neuropathyPneumonitis, pulmonary haemorrhageSevere and refractory serositisSevere haemolysis or thrombocytopeniaMyocarditis

(Continued on page 477)

' Address for correspondence: Dr C 5 Lau, Rheumatology Unit, University Department of Medicine, The University of Hong Kong, Queen Mary Hospital,Pokfulam Road, Hong Kong.

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Conservative management

Musculoskeletal manifestations

Arthralgia, arthritis and myalgia arecommon presenting symptoms of SLE.They are usually mild but cansometimes be very disabling. Non-steroidal anti-inflammatory drugs(NSAID) usually provide rapid reliefof symptoms. However, the use ofNSAID in SLE requires specialcautions. Through their inhibitoryeffects on renal prostaglandins, allNSAIDs (including sulindac) reduceglomerular filtration rate and renalblood flow, especially in patientswho have clinical and subclinicalnephritis, or are taking diuretics. Saltand fluid retention may elevate bloodpressure and cause peripheraloedema. Gastrointestinal toxicity withbleeding can develop at any timeduring therapy. Headache, dizziness,and aseptic meningitis (particularlywith ibuprofen) may occur andconfuse with central nervous systemmanifestation of the disease. Finally,SLE patients are more prone toNSAID-induced hepatotoxicity, whichis usually manifested as elevation ofliver transaminases. Therefore, it ismandatory to monitor patientsclosely for renal, gastrointestinal andhepatic side-effects after commence-ment of therapy.

When musculoskeletal symptomsare not well controlled with NSAIDs,a trial of antimalarials is indicated.Hydroxychloroquine is preferredbecause of its lower incidence ofretinal toxicity and other side-effects.The start ing dose is 300 mg to400mg/day and should be taperedto a maintenance of 200mg/dayonce a response is achievedbecause retinal damage is related tothe cumulative dose. In unmonitoredpatients, the incidence ofantimalarial retinopathy is 3-4%.1

Properly monitored, Spalton et al*have shown that irreversibleretinopathy is unlikely to occurwhen hydroxychloroquine, at adaily recommended dose of lessthan 6.5 mg/kg, in the absence of

renal dysfunction, is used for less than10 years. Most rheumatologistsrecommend referring patients to theophthalmologist for baseline eyeexamination before the start of thedrug and regular follow up,particularly when treatment has beencontinued for more than 3 years. Inour Unit, a drug holiday, viz treatmentfor 5 days per week, is introducedwhen the patient has been stable onhydroxychloroquine for 2 years. Ingeneral, the drug is seldom usedcontinuously for longer than 5 years.Besides retinopathy, other uncommonside-effects of antimalarials includecorneal deposits, gastrointestinaldisturbance, rash, peripheralneuropathy, proximal myopathy,cardiomyopathy and skinpigmentation.

For occasional patients whosesymptoms are resistant toantimalarials, low dose prednisone(less than 15mg/day) and evenimmunosuppressives may beconsidered if quality of life isseriously impaired. These, however,should be discontinued as soon asthe symptoms are controlled. It isalso noteworthy that local causessuch as avascular necrosis may giverise to persistent pain in one or twojoints and should be seriouslyexcluded before more aggressivetreatment is considered.

Cutaneous lupus

Around 70% of all SLE patientsare photosensitive with f lares oflupus activity. Patients should avoidexposure to sunlight by wearingprotective clothings and applyingsunscreens. Acute lupus dermatitisusually responds to topical steroids.Fluorinated high.-potency prepara-tions such as betamethasone andfluocinonide are very effective butare more likely to cause atrophy,striae, acne and folliculitis. Theyshould not be used for more than 2weeks (especially on face lesions),after which less potent preparationssuch as hydrocortisone should besubstituted.

Antimalarials are also useful in thetreatment of cutaneous lupus (acute,subacute, chronic/discoid) becauseof their sun-blocking, ant i -inflammatory and immunosuppressiveeffect. Sixty to 90% of patients haveexcellent response to antimalarials.3

For hydroxychloroquine, improve-ment often requires 3 to 6 months.The dosage should be tapered oncewhen there is a response.

For patients who are resistant toantimalarial therapy, more aggressivetreatment including systemicglucocorticoids, dapsone, etretinate,or cytotoxic drugs such asazathioprine may be required. Theuse of dapsone in cutaneous lupusshould be very cautious because ofits significant haematologicaltoxicities. We recently reported 2cases of severe dapsone syndromeafter low dose treatment (50 mg/day).4 One died as a result offulminant toxic hepatitis andhypoalbuminaemia. The mechanismof this syndrome is unclear and isbelieved to be an extremeidiosyncratic reaction to the drug.

Systemic complaints

Systemic upset such as fever,fatigue and weight loss is commonand may be difficult to treat. NSAIDs,salicylates, antimalarials and low doseglucocorticoids are the main stay ofmanagement although occasionally ahigher dose of steroid is required.

Serositis

Lupus serositis causes episodes ofchest and abdominal pain. They usuallyrespond to NSAIDs (especiallyindomethacin), antimalarial or lowdose steroid (less than 15mg/day).Significant effusion in the pericardialor pleural cavities occurs infrequentlyand requires drainage because itcompromises the function of theheart and lung. More aggressiveimmunosuppressive therapy may beneeded in refractory cases.

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Aggressive treatment of SLE

Patients with life-threateningcomplications of SLE or involvement ofmajor orsan(s) should be assressivelytreated. This usually besins with highdose steroid, followed by cytotoxicagents. Manifestations of SLE thatrequire high dose glucocorticoids arelisted in (Table 2). Some lupusmanifestations are not steroidsensitive (e.g. pure membranousglomerulonephritis, thrombosis) andintense immunosuppression is notjustified. Infection may mimic diseaseflare and should be vigorouslyeliminated before the institution ofimmunosuppression. When in doubt,antibiotic coverage should be givenat the same time. Serologicalevidence of increased diseaseactivity includes raised titre of anti-DNA antibody and depressed serumcomplement levels. In general, serumC-reactive protein (CRP) level remainsnormal or low except when there issignificant synovitis, serositis, activevasculitis or coexisting infection.Raised serum CRP should alert thephysician of infective complications.

Corticosteroids

Daily oral short-actingglucocorticoids (prednisone,prednisolone, methylprednisolone) isthe standard regimen for steroidtherapy in SLE. The starting dose forprednisolone is usually between 0.5to 1.5 mg/kg/day. In general, a higherinit ial dose may be required forcontrol of central nervous systemdisease and severe renal andhaematological involvement. Therapidity of response to steroid variesamong individuals and diseasemanifestations. Organic brainsyndrome may improve within dayswhile cytopenia usually takes 5 - 1 5days to recover. Serology markersmay only respond 1-3 weeks aftertreatment. A complete response isusually expected after 4 to 10 weeks.If the desired effect is not obtainedwithin the appropriate time framedespite a good compliance, a reviewof the diagnosis, change of steroiddose, additional cytotoxic therapy orother modalities should beconsidered.

Table 2 Manifestations of systemic lupus erythematosus (SLE) which areresponsive/resistant to steroid treatment

are usually : responsive to ;high'.close'..

Vasculitis •PolyserositisMyocarditis

Haemolysis, thrombocytopenia

Transverse;myelitis , , . ., \ /:,;.::, ; ;: . ;.Peripheral neuropathy :: :

Manifestations of SLE which are often steroid-resistant

Thrombosis, antiphospholipid syhdrome... •. 'Pure membranous glomerulonephritis, scarred end-stage disease'Mild behavioural/cognitive disturbances

Daily high-dose intravenousmethylprednisolone (15mg/kg) for 3to 5 doses, followed by daily oralprednisolone (40 - 60 mg) mainte-nance, which is rapidly tapered, isincreasingly popular in the treatmentof SLE. Uncontrolled trials suggestthat more than 75% of patients withsevere nephritis, central nervoussystem disease, pneumonitis,polyserositis, vasculitis and throm-bocytopenia improve within a fewdays.5 The overall side effects areprobably not increased whencompared with the oral high-doseregimen but acute psychosis, seizure,rapid increase in blood pressure,gastrointestinal bleeding, arrhythmiaand sudden death have beenreported.6

Cytotoxic agents

Azathioprine (a purineantagonist) and cyclophosphamide(an alkylating agent) are the twocommonest cytotoxic agents used inthe treatment of SLE. Both drugsinhibit B-cells. Cyclophosphamidehas an additional suppressive effecton the T-cells and is more effective,but also more toxic. Previous studieshave shown that either of the drugstogether with corticosteroid is moresuperior than corticosteroid alone inthe control of the disease in the longrun.7

Azathioprine

Azathioprine (1 -3 mgAg/day) isused in lupus nephritis and as asteroid sparing agent in many of theless serious manifestations of thedisease. Although uncommon, anidiosyncratic reaction causing marrowaplasia or agranulocytosis may occurduring the first few weeks of therapy.Adverse ef fects of chronicazathioprine therapy includeincreased rate of opportunisticinfection (especially herpes zoster),marrow suppression (dose-related),hepatic damage and malignancy.8

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Cydophosphamide

Cyclophosphamide is more toxicthan azathioprine and is reserved fortreatment of more severe and life-threatening complications of SLE suchas proliferative/crescentic glomerulo-nephritis, lupus cerebritis, severethrombocytopenia, pneumonitis andpulmonary haemorrhage. Tworegimens are currently available.Intravenous monthly pulsecyclophosphamide (0.5 - 1 gm/m9

surface area) has the disadvantagesof the need for in-patient treatment,venous access and a higher incidenceof nausea and vomiting. Daily oralcyclophosphamide ( 1 - 2 mgAg/day)is convenient and probably moreeffect ive. However, the risk ofbladder toxicity such as haemorrhagiccystitis is higher. We generally adoptthe oral regimen for our lupuspatients and it appears that Chineselupus patients tolerate this well andthere are extremely few cases ofcystitis noted.

Long term toxicities ofcyclophosphamide are significantand it is generally agreed that thedrug should not be used for morethan 2 years. Opportunisticinfections may be life-threatening;bone marrow suppression, increasedmalignancies and infertility are ofmajor concern. Premature ovarianfailure contributes to osteoporosisand accelerates atherosclerot icdisease in women takingcorticosteroids. In our Unit,cyclophosphamide treatment isusually maintained for 6 months aftera remission is achieved. Thetreatment is then switched tomaintenance azathioprine. Thissequential therapy regimen has beenshown to be useful for patients withlupus nephritis.9

Monitoring of adverse effects duringimmunosuppressive therapy

Osteoporosis, acceleratedatherosclerosis, avascular necrosis,secondary diabetes, hypertension,psychiatric disturbances, andincreased opportunistic infection are

well known long term side effects ofcorticosteroids.10 It is thereforeimportant to reduce the steroid doseonce the disease is controlled. Thereare many ways of doing this and thealternate-day tapering regimen is mostpopular as this is associated withsignificantly less suppression of thehypothalamic-pituitary axis, as well asless nitrogen and potassium wasting,hypertension, Cushingnoid changesand infection.11

For patients taking long termsteroids, electrolytes, blood counts,sugar level, blood pressure, intraocularpressure and the lens should beregularly checked and monitored.Signs of infection and osteroporosisshould also be looked out for.Patients should be advised to haveadequate calcium intake (1000 -1500 mg/day) and Vitamin D can beconsidered if 24 hour calciumexcretion is less than 120mg. Regularcomplete blood counts and liverfunction tests are mandatory inpatients taking cytotoxics.Microscopic haematuria should bescreened for patients takingcyclophosphamide. Finally, patientsshould be warned of the possibilityof infert i l i ty and increasedmalignancies before the start ofcyclophosphamide.

Special situations

Pregnancy

Patients with SLE should not bedeprived of the opportunity toconceive. Exacerbation occurs inaround 50% of patients duringpregnancy and in the post-partumperiod. The risk is higher whendisease is active within 6 monthsbefore conception.12 Relapse of thedisease may lead to irreversible organdamage while aggressive treatmentmay lead to fetal death. It is thereforeimportant to give patients adequatepre-pregnancy counselling andcontraceptive advice. In general,pregnancy is only recommendedwhen the disease has been stable fora comfortable period of time (e.g. 1 -

2 years) and should be closelymonitored, with the collaboration ofan experienced obstetrician. Alldrugs used in SLE, with the exceptionof corticosteroids, are potentially Iteratogenic/embryotoxic and shouldbe avoided, especially in the f irsttrimester of pregnancy.

Antiphospholipid syndrome (APS)and recurrent abortion

APS is characterised by recurrentvascular thrombosis, pregnancywastage, and thrombocytopeniaassociated with a persistently positivelupus anticoagulant or anti-cardiolipinantibodies.13 It can exist alone as aprimary form or associated with SLE.Daily low-dose aspirin or long-termanticoagulation is the treatment ofchoice. Immunosuppression is notjustified as the anti-cardiolipinantibodies are notorious for itssteroid resistance. For those patientswho experience recurrent fetal loss,low-dose aspirin, aspirin plusprednisone, or subcutaneous heparintreatment throughout the pregnancyimproves fetal survival.

Cytopenias

Severe cytopenia definitelycontributes to mortality in SLE. Highdose glucocorticoids (prednisone 1 -1.5 mg/kg or intravenous pulsetherapy) is often needed. For severethrombocytopenia, intravenousgammaglobulin (0.4gm/kg/day for 5days or 1 gm/kg/day for 2 days) canlead to a rapid increase in plateletcount and is reserved for emergencytreatment for life-threatening bleedingor preparation for emergency surgery.Cytotoxic agents includingazathioprine, cyclophosphamide andvinca alkaloids may be tr ied insteroid-resistant cases. Danazol, ananabolic steroid, may be useful insome cases of lupusthrombocytopenia. However, it is lesseffective in the younger patients andthe side effects of hirsutism,menopausal symptoms, deepening ofvoice, hepatitis and weight gain may notbe acceptable.

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Table 3 : Experimental therapies for systemic lupus erythematosus

Experimental therapies for SLE . . . / . . ; ' . . . /• ." ^ .^Plasmapheresis, leukopheresis, cryophersis ^Cyclosporin A . ^ . / . , .^ , / .Intravenous immunbglobulins (IVIG) -Manipulation of sex hormone levels (androgens, luteinizing hormone blocking

' :agents) ' ' - ; ' , ̂ . ' : ; ; . ^ ' ' " ' : • • • " • . / • ; ' 'Newer immunosuppressives (FK506, rapamycin, mycophenolic acid)Interventions of T-B cell interactions (monoclonal antibody against CD4, CD3, or

112 receptor, total lymphoid irradiation)

Drug-induced lupus

Many drugs are capable ofinducins a lupus-like syndrome,characterised by fever, rash, arthritis,serositis, a positive ANA and anti-DNA-histone antibodies. Chlorpro-mazine, hydralazine, procainamide,isoniazid, a-methyl-dopa arenotorious for this. However, it shouldnot be confused with the many otherdrugs which may exacerbate anexistins lupus. Sulphonamides,anticonvulsants and oestrogen-containing contraceptive pills havebeen attributed to exacerbate lupusactivity from earlier studies andshould therefore be avoided in SLEpatients.

Pure membranous glomerulo-nephritis

Lupus membranous glomerulo-nephritis (WHO class V) is well knownfor its resistance to steroid orcytotoxic therapy, usins daily proteinexcretion as a measure of response.Renal failure occurs less frequentlyand later than with proliferativeSlomerulonephritis. We usually treatour patients with moderate to hishdose steroid tosether withazathioprine. If no response isobtained after 6 - 1 2 weeks,

immunosuppression will begradually withdrawn, provided thatit is not due to other causes like renalvein thrombosis and change ofhistology into a more serious ormixed form.

Experimental therapies

Table 3 lists the currently availableexperimental therapies for SLE. It isout of our scope here to mention allof them in details. One drug that isnoteworthy, mentioned here, iscyclosporin A (3 - 5 mg/kg/day)which, when added to gluco-corticoid therapy, has been shown toimprove renal and extrarenalmanifestations of SLE.14 Undesirableeffects include tremor, hirsutism,hypertension, hyperlipidaemia andnephrotoxicity. However, it isexpensive and should only beconsidered in patients with steroid-resistant disease or marrowsuppression when cytotoxic agentscannot be use.

Conclusion

SLE is a complex disease withdiverse manifestations and wideindividual variability in the

presentation and severity. The goalof management is not just to induceremission in the short term, but alsoto minimise toxicities of long termtherapy. Expert care fromexperienced rheumatologists isneeded. The use of various drugs likeantimalarials, corticosteroids andcytotoxic agents should be fullyjustified and carefully monitored. •

References

1. Bernstein DHN. Ophthalmologic considerationsand testing in patients receiving long-termantimalarial therapy. Am J Med 1983; 75: 25.

2. Spalton DJ, Verdon Roe GM, Hughes GRV.Hydroxychloroquine, dosage parameters andretinopathy. Lupus 1993; 2: 155-158.

3. Callen JP. Treatment of cutaneous lesions inpatients with lupus erythematosus. DermatolO/n 1990; 8: 355-365.

4. MokCC, Lau CS. Severe dapsone syndromein cutaneous lupus. j Rheumatoid 1996;23(4): 766-768.

5. Isenberg DA, Morrow WJW, Sanith ML.Methylprednisolone pulse therapy in thetreatment of systemic lupus erythematosis.Ann Rheum Dis 1982; 41: 347.

6. Hahn BH. Management of systemic lupuserythematosus. In: Textbook of RheumatologyEds: Kellar WN, Harris ED, Ruddy S, SledgeCB (Eds). Saundars WB; 4th edition 1993;pp 1043-1055.

7. Balow JE, Austin HA, Tsokos GC et al. NIHConference. Lupus nephritis. Am Intern Med1987; 106: 79.

8. Mok CC, Kwong YL, Lau CS. Secondaryacute myeloid leukaemia with 7q-complicating azathioprine treatment forrheumatoid arthritis. Ann Rheum Dis 1995;54: 155-156.

9. Chan TM, Li FK, Wong RW, Wong KL, ChanKW, Cheng IK. Nephron. Sequential therapyfor diffuse proliferative and membranouslupus nephritis: cyclophosphamide andprednisolone followed by azathioprine andprednisolone. 1995; 71(3): 321-327.

10. Mok CC, Lau CS, Poon SP. Primary nocardialmeningitis in systemic lupus erythematosus.Br J Rheumatol 1995; 34(2): 178-181.

11. Fauci AS. Alternate-day corticosteroidtherapy. AmJMed 1978; 64: 729.

12. Kitridou RC, Mintz G. The mother in systemiclupus erythematosus. In: Dubois' LupusErythematosus. Eds: Wallace DJ, Hahn BH.Lea and Febiger, Philadelphia 1992; pp 487-507.

13. Lau CS. Antiphospholipid syndrome. VascMed Rev 1994; 5(1): 33-45.

14. Tokuda M, Kurata N, Mizoguchi A, eta/. Effectof low-dose cyclosporin A on systemic lupuserythematosus disease activity. ArthritisRheum 1994; 37(4): 551-558.

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