management of systemic vasculitis

Management of systemic vasculitis

Carol A. Langford* MD, MHS

Senior InvestigatorNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892,USA

The systemic vasculitides are a wide-ranging group of diseases that are characterized by thepresence of blood vessel in¯ammation. Despite this common feature, each type of vasculitishas a unique variety of clinical manifestations that in¯uences its degree of disease severity andultimately its management. Immunosuppressive therapy forms the foundation of treatment foralmost all forms of systemic vasculitis. Because of this, treatment can be associated with itsown risk of morbidity, or even mortality, related to speci®c medication side-e�ects orinfections which occur as a result of impaired host defences. This chapter seeks to review theapproach to management in selected forms of systemic vasculitis. Questions examined includethe following. When should one treat systemic vasculitis? How does the nature of the diseaseand its severity a�ect treatment decisions? What are the data regarding the e�ectiveness ofindividual therapeutic regimens?

Key words: vasculitis; arteritis; Wegener; treatment; toxicity; glucocorticoid; cytotoxic;cyclophosphamide; methotrexate.

The systemic vasculitides represent a broad range of diseases characterized by thepresence of blood vessel in¯ammation. When such in¯ammation occurs this can lead tovessel occlusion and organ ischaemia or weakening of the vessel wall with the potentialfor haemorrhage or the formation of an aneurysm.Although the pathophysiologyof thesystemic vasculitides remains poorly understood, multiple points of reasoning supportthe notion that these diseases are immunologically mediated. One of the most com-pelling pieces of evidence has been the e�cacy of immunosuppressive agents in treatingthese diseases. While such therapy is often bene®cial, these medications can havesigni®cant side-e�ects. In recognition of this, investigators have continued to seek outregimens which are e�ective yet minimize the potential for treatment-related toxicity.

The largest amount of data on the treatment of systemic vasculitis have come fromstudies in Wegener's granulomatosis (WG). However, the systemic vasculitides canvary greatly and they are not all treated in the same manner. This chapter outlinesimportant concepts in the general approach to treatment in systemic vasculitis anddiscusses the data on speci®c regimens in WG. The use of these regimens are thenreviewed as they apply to the treatment of polyarteritis nodosa (PAN), microscopicpolyangiitis (MPA), Takayasu's arteritis (TA), and giant-cell arteritis (GCA).

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Best Practice & Research Clinical RheumatologyVol. 15, No. 2, pp. 281±297, 2001doi:10.1053/berh.2001.0144, available online at http://www.idealibrary.com on

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*Current address: C. A. Langford, Laboratory of Immunoregulation, National Institute of Allergy andInfectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

GENERAL PRINCIPLES OF MANAGEMENT

Disease de®nitions

Disease de®nitions play an important role in the treatment of the systemic vasculitides,both in interpreting the results of therapeutic studies and in determining individualpatient care. The most important de®nitions involve three interrelated terms: activedisease, remission, and relapse. Active disease refers to that state where there isobjective evidence of ongoing organ injury that is directly attributable to the vasculiticdisease. For certain forms of systemic vasculitis, in particular WG and MPA, diseaseactivity is often thought of in terms of whether this is a�ecting a major organ. A majororgan site would be considered to be a location in which active disease could result inpatient mortality or signi®cant morbidity (i.e. lung, kidney, nervous system, or visuallythreatening ocular disease). As will be discussed, the determination of disease activityis not straightforward for many of the systemic vasculitides. While this shouldoptimally be based on the presence of objective parameters, this is not always possibleor reliable.

The term remission is typically used to indicate that point in time when there is noevidence of disease activity. In approaching the management of certain systemicvasculitides, treatment has increasingly been thought of as having two stages: induction,where active disease is put into remission, and maintenance, where remission iscontinued once it has been achieved.1,2 Relapse is then de®ned as a return of majororgan disease activity following remission. The return of non-major organ featureswould be considered to be a relapse if their severity required increasing or re-startingimmunosuppressive therapy.

Maximizing bene®t and minimizing risk

The opportunity for extended follow-up has given us a greater appreciation of thelong-term issues in patient management. These include features related to chronicsequelae of disease, the potential for certain vasculitides to have a relapsing course, andthe possibility of treatment-related toxicity that may not occur until many years later.Based upon this information, decisions regarding the treatment plan can often beassisted by considering several key questions, as are outlined in Table 1. Once aregimen is decided upon, in the absence of compelling individual factors (e.g. drugallergy, intolerance, or contraindication), medication dosages and schedules shouldideally be based on regimens on which there has been a published experience from astandardized trial.

A critical part of any treatment plan is recognition of the toxicities of the therapiesthat are being used and the aggressive application of strategies to minimize treatment-related adverse events. Table 2 outlines the side-e�ects of the main cytotoxic agentsdiscussed in this chapter and strategies for minimizing or preventing their occurrence.3

SPECIFIC TREATMENT REGIMENS IN WEGENER'SGRANULOMATOSIS

WG is a necrotizing granulomatous vasculitis which a�ects the small to medium-sizedvessels.4 Although it has a clinical predilection to a�ect the upper airways, lungs andkidneys, WG is a multisystem disease that can be life-threatening. Prior to thedevelopment of e�ective therapy, patients with WG had a median survival time of 5

282 C. A. Langford

months, with death most often occurring from pulmonary or renal failure. Thisoutcome changed dramatically with the introduction of combined treatment withglucocorticoids and daily cyclophosphamide. Despite the e�cacy of this regimen, itsuse remains complicated by the potential for drug toxicity and disease relapse. For thisreason, other therapeutic modalities have been explored that have allowed us toexpand the range of treatment options.

In WG, the assessment of disease activity should be based on the presence ofobjective features, examples of which might include an abnormal chest radiograph oran active urine sediment. While subjective symptoms such as fatigue and arthralgiasshould prompt a careful evaluation, they can also be due to other causes, includingglucocorticoid withdrawal. Acute-phase reactants, such as the erythrocyte sedimen-tation rate (ESR), are non-speci®c and can be elevated with other processes such asinfections. Antineutrophil cytoplasmic antibodies (ANCA) occur in greater than 85% ofpatients, and antibody titres will often vary during the disease course. Whenexamining large populations, higher ANCA titres overall have been observed inpatients who have active disease. However, at the level of the individual patient,changes in ANCA titre have not been found to be a reliable indicator of diseaseactivity or relapse. Given the toxicity of therapy, a decision to increase immuno-suppressive therapy should not be based on a rising ANCA titre alone.

Glucocorticoid monotherapy

Glucocorticoids were the ®rst agents used to treat WG.While glucocorticoids delayedmortality in some instances, the median survival time remained only 12.5 months,with most patients dying from infection or uncontrolled disease.5 In a National

Table 1. Points to consider when deciding on a treatment regimen for a patient with an active systemicvasculitis.

Is the disease active? Di�erentiate active disease from:chronic sequelae of diseasemedication toxicityother diseases (in particular infection)

How severe is the active disease? Fulminant life-threatening disease requires moreaggressive management

What organ sites are being a�ected? Certain sites of organ involvement may not requireor may not respond to systemic immunosuppressivetherapy

What is the nature of the underlying diseaseprocess?

Is the disease potentially life-threatening?What is known about long-term survival?Do relapses frequently occur in the disease?

What is the data on di�erent therapeuticregimens?

Has the regimen improved survival?What is the likelihood of inducing remission?What is the relapse rate?What are the known toxicities?

Consideration of individual patient factors History of medication toxicityContraindications to certain medicationsPresence of previous organ damageAgeGender

Management of systemic vasculitis 283

Table 2. Cytotoxic agents frequently used in the treatment of systemic vasculitis: side-e�ect pro®le andstrategies for monitoring and preventing toxicity.

MedicationToxicity(frequency if known) Strategy for monitoring or prevention

Cyclophosphamide Bone marrowsuppression (50±100%)

. Complete blood counts every 1±2 weeks

. Anticipate cytopenias during steroid tapering andprolonged treatment

Bladder injury (50%) . Administer all at once in the morning with a largeamount of ¯uid

Transitional cellcarcinoma of thebladder (6%)

. Urinalysis every 3±6 months

. Cytology every 6 months

. Cystscopy in patients with non-glomerularhaematuria or abnormal cytology

. If bladder injury present, cystoscopy every 1±2 yearsMyeloproliferativediseases (2%)

. Consider when cytopenia does not resolve afterdrug discontinuation

Infertility (up to 100%) . Roles of testosterone and agents to modulateovulation remain unclear

Nausea (10%) . Administer with food. Use of mild anti-emetic. Do not give split dose or bedtime

Pneumonitis (1%)Teratogenicity . Contraception

Methotrexate Bone marrowsuppression (5±30%)

. Complete blood counts while adjusting dose andevery 4 weeks thereafter

. Calcium leucovorin 5±10 mg weekly or folic acid1 mg daily may be helpful

Increased transaminases(10±70%)Hepatic ®brosis (1±25%)

. Monitor liver function tests (aspartateaminotransferase (AST), alkaline phosphatase,bilirubin)/albumin every 4 weeks

. Liver biopsy based on guidelines established by theAmerican College of Rheumatology

. Alcohol consumption prohibitedPneumonitis (5±7%) . Perform baseline pulmonary function test and chest

radiographNausea (2±50%) . Split into two or three portions over a 24-hour

period. Administer by subcutaneous or intramuscular

injection. Use of mild anti-emetic. Calcium leucovorin 5±10 mg weekly or folic acid

1 mg daily may be helpful16

Mucositis (5±30%) . Calcium leucovorin 5±10 mg weekly or folic acid1 mg daily may be helpful16

Teratogenicity . Contraception

Azathioprine Bone marrowsuppression (5±30%)

. Complete blood counts weekly for the ®rst 2weeks and every 4 weeks thereafter

Increased transaminases(1±30%)

. Monitor liver function tests every 2 weeks for the®rst month, every 1±3 months thereafter

Nausea (5±20%) . Can be taken at bedtimeSevere hypersensitivity(1±2%)

. Consider re-introduction after possiblehypersensitivity with caution as reaction may bemore severe

Lymphoma . Risk outside of transplant recipients unclearTeratogenicity . Contraception

284 C. A. Langford

Institutes of Health (NIH) cohort, 96% of patients who had been treated withglucocorticoids alone prior to referral had progressive disease.6 Of the 45 patients withrenal involvement, none experienced sustained improvement with glucocorticoidmonotherapy. These data suggest that glucocorticoids alone are insu�cient therapy foractive WG a�ecting a major organ, and for glomerulonephritis in particular.

Cyclophosphamide and glucocorticoids

In the 1970s, Fauci and Wol� at the NIH revolutionized the treatment of WG bydeveloping a treatment strategy that combined low-dose daily cyclophosphamide(CYC) with glucocorticoids.7 This regimen remains the most e�ective treatment forpatients with active WG, and all patients with immediately life-threatening diseaseshould initially be treated with daily CYC and glucocorticoids unless a very strongcontraindication exists. In the standard NIH regimen, daily CYC 2 mg/kg/day is giventogether with prednisone initiated at a dose of 1 mg/kg/day.8 This prednisone dose iscontinued for 1 month after which time, if there is improvement, it is tapered on analternate day schedule, which is usually reached by 3±4 months, and then todiscontinuation, which usually occurs by 6±12 months. Patients receive CYC for 1 yearpast remission, after which time it is tapered and discontinued. Two critical parts ofthis regimen are the use of alternate-day glucocorticoid tapering and the deliberateavoidance of leukopenia. In studies where glucocorticoids have been tapered on a dailyschedule and leukopenia was a goal of treatment, the rate of infection and mortalityhas been markedly higher without an apparent improvement in e�cacy.9

Of 133 patients who received the NIH regimen, 91% exhibited a marked improve-ment in their disease, 75% achieved a complete remission, and an 80% survival rate wasobserved.4 Despite the e�cacy of this treatment, disease relapse occurred in 50% ofpatients and morbidity from drug-related toxicity was observed in 42%. Of particularconcern has been the development of transitional-cell carcinoma of the bladder in 6%of CYC-treated patients in this cohort.10 By Kaplan Meier estimates, the incidence ofbladder cancer may rise as high as 16% at 15 years following the ®rst dose of CYC.

The use of intermittent intravenous CYC has been investigated in three prospectivetrials with the hopes of identifying a less toxic method of administration. In an NIHstudy, 93% of 14 patients had initial improvement with intermittent CYC, but only21% of these patients were able to achieve a sustained remission.11 Reinhold±Keller etal12 treated 43 patients and found that only 42% experienced improvement orremission.12 Guillevin et al9 performed a randomized trial and observed that remissionwas achieved in 88.9% who received daily CYC and 78.3% who received intermittentCYC. Even though these rates were similar, the cohort sizes of 23 and 27 respectively,would be too small to demonstrate equivalence. Of greater concern was that 52% ofthose treated with intermittent CYC experienced a relapse compared to 17.6% ofthose who received daily CYC. Although the use of intermittent CYC remainscontroversial, the prospective standardized trials that have been performed to datesuggest that intermittent dosing is associated with a higher relapse rate. For thisreason, it is recommended that CYC be administered daily when it is being used totreat WG.

For critically ill patients who have fulminant disease, increased doses of gluco-corticoids and CYC may be considered. CYC can be increased to 3±4 mg/kg/day for 3days then reduced to a dose of 2 mg/kg/day.8 In addition, high doses of glucocorticoids(greater than 1 mg/kg/day of prednisone) given either as a single intravenous bolus orin split doses may be bene®cial. The use of such a regimen is associated with an


increased risk of side-e�ects and should not be undertaken unless justi®ed by theseverity of the illness.

Methotrexate and glucocorticoids

Outside of CYC, methotrexate (MTX) is the only other cytotoxic agent that has beenproven to be capable of inducing a remission of active WG. The use of MTX was ®rstexamined at the NIH in patients who had active but not immediately life-threateningdisease.2,13,14 In this regimen, patients receive prednisone at a dosage and scheduleidentical to that described above, together with oral MTX 20±25 mg once a week.MTX is given for 1±2 years past remission and then tapered and discontinued. In 42patients treated with this regimen, 33 patients (79%) achieved remission. MTX wasine�ective at controlling disease in only three patients and three fatalities occurred,none being due to active vasculitis. Nineteen patients (58%) relapsed at a median of 29months, with 79% of relapses occurring either after MTX had been stopped or afterthe dose had been reduced to 15 mg per week or less. Although patients with acreatinine of greater than 2.5 mg/dl were excluded from this trial, 50% had active renaldisease at study entry. The use of MTX and prednisone as initial therapy for patientswho had glomerulonephritis and a normal or near normal serum creatinine was notassociated with a long-term decline in renal function.15 The most frequent severetoxicity was Pneumocystis carinii pneumonia that developed in four patients (9.5%). Forthis reason, it is recommended that prophylaxis for Pneumocystis be provided to allpatients receiving daily glucocorticoids in addition to a cytotoxic agent. The remainingtoxicities included transaminase elevation (24%), leukopenia (7%) and stomatitis (2%),and two patients (7%) developed pneumonitis. Use of folic acid 1 mg daily or folinicacid 5±10 mg once a week given 24 hours after MTX may be useful to decrease sometoxicities, in particular gastrointestinal symptoms, bone marrow suppression andmucositis.16

The use of MTX for inducing disease remission has also been reported in two otherstudies. In a series by deGroot et al17 19 patients were treated with weekly MTX0.3 mg/kg/week combined with low-dose prednisone given at a median starting doseof 10 mg/day (range 5±50 mg/day). With this regimen, 10 patients (59%) achieved acomplete or partial remission. In a retrospective series of 19 patients treated by Stoneet al18, the combination of MTX and daily glucocorticoids was found e�ectively tocontrol disease, with remission being achieved in 14 (74%) patients.

These data support the notion that MTX and glucocorticoids may be an acceptablealternative regimen to induce remission in selected patients who do not have imme-diately life-threatening disease or who have had signi®cant CYC-related side-e�ects.

Cyclophosphamide for induction and methotrexate for remissionmaintenance

The most recent approach to the treatment of WG has been the use of a stagedregimen whereby patients with active disease are treated with CYC and gluco-corticoids until disease remission, at which time the CYC is stopped and weekly MTXis substituted. By using such an approach patients would initially receive CYC, yet bylimiting the duration of exposure to this agent, the potential for toxicity wouldhopefully be decreased. Another advantage of this regimen is that it can be used inpatients who have severe disease at onset provided they are able to receive MTX atthe time of remission.

286 C. A. Langford

In a standardized prospective trial at the NIH, patients received a prednisoneregimen identical to that described above, together with CYC 2 mg/kg/day.1 Atremission, CYC was stopped and patients were treated with MTX 20±25 mg perweek. MTX was continued for 2 years after which time the dose was tapered anddiscontinued. Thirty-one patients were enrolled in this trial, of whom 16 (52%) hadsevere disease as de®ned by speci®c renal, pulmonary and neurological criteria. Nodeaths occurred, and all 31 (100%) achieved remission. The median time to remissionand duration of CYC treatment was 3 months (range 1±12 months). Five patients (16%)experienced disease relapse, all of whom had been o� prednisone for 6 months and onMTX for a minimum of 10 months. Neither the presence of glomerulonephritis northe severity of disease was associated with relapse. Two patients (6%) developedcystitis, which represents a signi®cantly lower incidence than the 50% rate previouslyobserved with the standard CYC protocol. Other toxicities included leukopeniarequiring dosage reduction (CYC (10%) and MTX (6%)), MTX pneumonitis (6%),bacterial pneumonia (6%), cutaneous herpes zoster (13%), avascular necrosis (2%),cataracts (2%) and diabetes mellitus (2%).

Similar results were reported in a non-standardized trial by deGroot et al.19 In thisstudy, patients received either intermittent pulse or daily CYC as induction therapyand were switched at partial or complete remission to MTX 0.3 mg/kg/week with orwithout concomitant prednisone. These authors found that a partial or completeremission was maintained in 86% of the 22 patients who received MTX alone and 91%of the 11 patients who received MTX and prednisone.

Data from these studies support the notion that patients with WG can be safely ande�ectively treated with a regimen using glucocorticoids and daily CYC to inducedisease remission, followed by MTX for remission maintenance. Such treatmentprovides a less toxic alternative to the standard CYC regimen in patients who havesevere disease at onset.

Other cytotoxic and immunosuppressive agents

The available data regarding other immunosuppressive and cytotoxic agents comeslargely from case reports and small series. Given this limited experience, other agentsshould be considered only as initial therapy in the setting where a contraindication toCYC or MTX exists. Unless immediately life-threatening disease is present, CYCshould not be used in patients with a prior history of CYC-induced bladder injury,lymphoproliferative disease or bladder cancer. Because of its speci®c side-e�ect pro®le,MTX is contraindicated in patients with pre-existing liver disease or severe chronicpulmonary impairment. In addition, MTX is eliminated by the kidneys and should notbe given to patients with severe renal insu�ciency (serum creatinine of42.5 mg/dl orcreatinine clearance 535 ml/min) as increased drug levels can occur and result insevere bone marrow suppression.

Azathioprine has not been found to induce remission successfully.8 However, insmall series, it has been reported e�ectively to sustain a remission induced with CYC.8

Azathioprine may have a particularly useful role for those people who cannot takeMTX, and its e�cacy in maintaining remission is being investigated by the EuropeanVasculitis Study Group. Mycophenolate mofetil has been reported to maintainremission in eight of nine WG patients following CYC induction.20 Although theseresults remain too preliminary for generalized application, the use of this agentwarrants closer investigation. Chlorambucil and cyclosporin have had variable e�cacyin reports involving a small number of patients. As these agents have signi®cant


potential for malignancy and nephrotoxicity respectively their use should be con®nedto very selected patients who cannot be treated with other approaches. There islimited experience with the use of intravenous immunoglobulin. Although bene®cialresults have been reported by some authors21, in other series no impact on major-organ disease was observed and no patients experienced a complete remission.22

Trimethoprim/sulphamethoxazole

Trimethoprim/sulphamethoxazole (T/S) has been reported by several authors to havea bene®cial role in WG.23 Unfortunately, interpretation of these series has beencomplicated by methodological concerns. In a series of nine patients treated with T/Swhere infection was ruled out and other therapy had not been added or changedduring the prior 3 months, no patient experienced sustained improvement orremission.4 While T/S monotherapy may be considered in patients with diseaseisolated to the upper respiratory tract, it is not recommended for treating lowerrespiratory tract disease and should never be used alone to treat glomerulonephritis.

The use of T/S has also been investigated for its ability to prevent disease relapse. Ina study by Stegeman et al24, patients were randomized to receive either T/S or placebowhen their disease was in remission. At 24 months, 82% of patients in the T/S groupremained in remission as compared to 60% of patients who had received placebo.However, when broken down by type of relapse, only the recurrence of upper airwaydisease was signi®cantly reduced in the T/S group with no di�erence being observed inmajor organ system relapses.

T/S does play an important role in the prophylaxis of Pneumocystis carinii for patientsreceiving a cytotoxic agent in combination with glucocorticoids. It should be notedthat while prophylactic doses have been well tolerated2, full doses of T/S(trimethoprim 160 mg/sulphamethoxazole 800 mg twice a day) should not be usedin combination with MTX as severe bone marrow suppression can occur.

Other treatments

Not all features of WG require or respond to cytotoxic therapy. Nasal and sinussymptoms are common in patients with WG and can be related to acute or chronicdisease or superimposed infection. In the setting of isolated sinus symptoms, a stepwiseapproach should be considered, beginning with a programme of irrigation and nasalglucocorticoids, combined with a course of antibiotics to treat superimposedinfections. Patients who are treated in this manner must be monitored closely forthe development of disease activity a�ecting other organs. If these measures areine�ective, and there is no evidence of disease activity elsewhere, use of low-doseglucocorticoids followed by MTX could be considered. The use of CYC is rarely, ifever, justi®ed for the treatment of isolated sinus or nasal disease.

Subglottic stenosis occurs in about 20% of patients with WG and is typicallyunresponsive to systemic immunosuppressive treatment. One approach that has beene�ective is a surgical technique which combines mechanical dilation of the trachea withthe intratracheal injection of a long-acting glucocorticoid.25 Given the unresponsive-ness of this lesion to medical therapy, patients who require immunosuppressive treat-ment for other manifestations of WG should undergo this procedure concurrently.However, in the absence of major organ disease activity, WG-related subglotticstenosis is best managed using this technique alone.

288 C. A. Langford

TREATMENT REGIMENS IN OTHER VASCULITIDES

Polyarteritis nodosa

PAN was described in 1866 and was the ®rst recognized form of systemic vasculitis.Since that time, PAN has gone through many changes in nomenclature, the mostrecent of which occurred at the 1994 Chapel Hill Consensus Conference where PANbecame designated strictly as a medium-sized vessel vasculitis. Patients withglomerulonephritis or small-vessel vasculitis in the absence of granulomatousin¯ammation were considered to have MPA. Although investigations on theseindividual entities have begun, prior therapeutic studies did not distinguish PAN fromMPA.

PAN often presents acutely with involvement of the medium sized arteries of thenervous system, gastrointestinal tract, kidneys or heart. The assessment of diseaseactivity is based on the presence of objective disease parameters from sites ofinvolvement. Although there remain limited data on the natural history of PAN, as ithas most recently been de®ned, some authors have considered this to be characterizedby a severe initial illness with relapses being uncommon.26 Untreated PAN has beenassociated with a poor outcome, with one observed 5-year survival rate being 13%.27,28

Earlier studies in which patients were treated with glucocorticoids alone found the 5-year survival rate to be 48±57%.27 Subsequent investigations involving small numbersof patients suggested that combined treatment with glucocorticoids and eitherazathioprine or CYC28,29 may improve outcome.

Since these early studies, one of the largest questions in the treatment of PAN hasremained whether combined therapy with glucocorticoids and CYC is required in allinstances. A multicentre co-operative group in France has performed the most recenttrials in PAN. While these have provided us with the largest body of information,many of these studies included patients with Churg±Strauss syndrome as well aspatients with glomerulonephritis whowould be classi®ed as having MPA. A 1991 studyfound that the addition of CYC to glucocorticoids and plasma exchange was bene®cialin preventing relapse but did not signi®cantly alter the 10-year survival rate, which was73% overall.30 In 1996, these authors examined survival curves from ®ve separate trialsand demonstrated that no di�erences in survival were observed regardless of whetherCYC was part of the initial treatment regimen.26

Practice points

. patients with immediately life-threatening WG should initially be treated withdaily CYC and glucocorticoids unless a very strong contraindication exists.Once remission is achieved, consideration should be given to stopping CYC andbeginning MTX or azathioprine to maintain remission

. the use of MTX and glucocorticoids may be considered for induction ofremission in patients with active but not immediately life-threatening WG

. CYC and MTX are the only cytotoxic agents that have been demonstrated toinduce remission. Other medications should be used only as initial therapy inpatients who are unable to take either of these agents

. glucocorticoids alone are insu�cient therapy for patients with active WGa�ecting a major organ system


In the hope of identifying which patients may have a poorer outcome and thusrequire more aggressive treatment, Guillevin et al examined prognostic factors in 342patients. Five factors were found to be associated with mortality: renal insu�ciency(creatinine 41.58 mg/dl), proteinuria 41 g/dl, gastrointestinal involvement, cardio-myopathy, and central nervous system (CNS) involvement.26 When more than two ofthese factors were present, patients had a 5-year survival rate of 54% as compared withan 88% survival in patients who had none. Studies are currently underway todetermine whether treatment can be strati®ed based on the presence or absence offactors associated with a poor prognosis.

Another issue has been how CYC should optimally be administered if it is used. In a1997 study, Gayraud et al randomized 25 patients with good-prognosis PAN or Churg±Strauss syndrome to receive oral glucocorticoids combined with either daily or inter-mittent CYC.31 No superiority of e�cacy was observed between the two regimens,although the number of patients in each group was too small to conclude equivalence.Although a higher number of side-e�ects were observed in the daily CYC group, manyof these were attributable to glucocorticoids, and of note was that infections wereobserved equally between groups. Not all authors, however, have found intermittentCYC to be e�cacious. In one small series, daily CYC was successfully initiated afterintermittent administration failed to control active PAN.32 While it has been arguedthat PAN may represent a pathophysiological process di�erent from that of WG, andthus possibly more responsive to intermittent CYC, its use remains controversial.

At the present time, the optimal therapeutic approach to PAN is unclear. Currentinformation would support the initial use of combined CYC and glucocorticoids inpatients with immediately life-threatening disease manifestations such as vasculitisa�ecting the gastrointestinal system, heart or CNS. In those patients in whom thedisease manifestations do not pose an immediate threat to life or major organ function,glucocorticoids alone can be considered as initial therapy, with a cytotoxic agent beingadded in patients who continue to have evidence of active disease or who are unableto taper prednisone.33

A PAN-like form of vasculitis may also occur in association with hepatitis B or otherviral infections. In this setting, an antiviral agent should be part of the treatmentregimen ± the goal being to contain viral replication and favour seroconversion. Inorder initially to gain control of the active vasculitis, patients may require gluco-corticoids alone or in combination with CYC, depending on disease severity. However,once clinical improvement is observed, this therapy should be rapidly withdrawn whileantiviral treatment is continued as the virus will persist and replicate in the setting of

Practice points

. patients with immediately life-threatening PAN or factors associated with apoor prognosis should be treated initially with CYC and prednisone

. in selected patients with active but non-severe disease, consideration may begiven to treating with prednisone alone, with CYC being added forunresponsive or worsening disease

. treatment of hepatitis B-associated vasculitis that has an appearance similar tothat of PAN should include antiviral therapy. The use of immunosuppressivetherapy should be limited to what is necessary to initially control vasculiticdisease, after which time it should be rapidly withdrawn

290 C. A. Langford

immunosuppression. In the approach used by Guillevin et al, in addition to antiviralagents and initial glucocorticoids, patients also received plasma exchange which theseauthors believe aids recovery by removal of immune complexes.34

Microscopic polyangiitis

MPA is a small- to medium-sized vessel vasculitis that can be associated with severepulmonary vasculitis and rapidly progressive glomerulonephritis.35 Although it is saidto be di�erentiated fromWG by the absence of granulomatous in¯ammation, MPA hasmany comparable clinical and histological features which provide us with guidanceregarding its treatment. Similar to WG, MPA can be a life-threatening disease a�ectingthe lungs and kidneys and also appears to have a propensity for relapse. In a series of 85patients examined by Guillevin et al, 34% were observed to have one or more diseaserelapses.35

To date, there have not been any prospective studies that have speci®cally examinedthe treatment of MPA alone. In earlier unstandardized retrospective studies ofmicroscopic periarteritis, treatment with glucocorticoids and either azathioprine orCYC appeared to improve outcome.36±38 Until further information becomes availableregarding the speci®c treatment of MPA, data from WG and PAN would support theinitial use of daily CYC and glucocorticoids in any patient with MPA who hasglomerulonephritis, pulmonary haemorrhage, or other major-organ-threateningdisease manifestations.

Takayasu's arteritis

TA is a granulomatous vasculitis that predominantly occurs in young women anda�ects the aorta, its main branches and the pulmonary arteries. The clinical featuresinclude manifestations of vascular ischaemia as well as systemic symptoms such asfatigue, weight loss, night sweats, fever and arthralgias. Although North Americanreports have found survival to be 94% or greater39, the 5-year mortality rate fromother series has ranged from 0 to 35%. Disease-related mortality is usually due tocongestive heart failure, cerebrovascular events, myocardial infarction, aneurysmrupture or renal failure. Even in the absence of life-threatening disease, TA can beassociated with substantial morbidity.39 TA has been found to be a chronic andrelapsing disease. In one study, regardless of treatment, 45% of patients were found toexperience at least one disease relapse, and 23% of patients never achieved aremission.39

A critical limitation in the treatment of TA is that no single parameter has beenfound to be uniformly reliable in assessing active disease. Although clinical featureshave typically been used to de®ne disease activity, active arteritis has been observed in44% of surgical bypass specimens taken from patients judged to be quiescent by

Practice points

. to date there have been no prospective trials on the treatment of MPA. Patientswith pulmonary haemorrhage, glomerulonephritis or other life-threateningdisease manifestations should be treated as for WG, with daily CYC andglucocorticoids


current methods.39 Disease activity has most frequently been assessed using informa-tion combined from multiple parameters including ESR, systemic symptoms, new orprogressive features of vascular ischaemia, and new or progressive arteriographicchanges.

At the time of diagnosis, approximately 20% of patients with TA will be clinicallyasymptomatic. Although these patients require regular follow-up and educationregarding their illness, for the most part they do not require medical treatment. Theremaining 80% of patients have features of active disease necessitating treatment.

Glucocorticoids are considered the mainstay of treatment in TA. However, the dataregarding their e�cacy in improving outcome has been di�cult to obtain. A promptimprovement in systemic symptoms has been observed in 25±100% of patients, andselected reports have demonstrated that glucocorticoids bring about improvement inarteriographic blood ¯ow and return of previously absent pulses. The optimal doseand length of glucocorticoid treatment has not been speci®cally de®ned as there havebeen no comparative dose and duration trials. Retrospective series have utilized abroad spectrum of initial prednisone doses ranging from 20 to 100 mg daily.40 In thelargest prospective standardized experience, ®rst-time therapy with glucocorticoidsresulted in remission in 52%, and 60% achieved remission at least once.39 In this study,patients initially received prednisone 1 mg/kg/day (60 mg daily) for the ®rst 1±3months with careful observation for adverse e�ects and response. Over the next 2±3months, when disease activity decreased, the prednisone was tapered to an alternate-day schedule. Although these time estimates should be optimally pursued, it is oftennecessary to halt or slow the prednisone taper temporarily because signs of activedisease develop.

The use of cytotoxic therapy in TA has primarily been considered in patients whohave persistent disease activity despite daily glucocorticoid treatment, or whenremission cannot be maintained on alternate-day glucocorticoids. Using these criteria,Kerr et al39 observed that 52% of patients required the addition of a cytotoxic agentduring the course of their disease, with 40% of these patients achieving remission atleast once.

The largest prospective experience with a cytotoxic agent in TA has involved theuse of MTX in a glucocorticoid-resistant population.41 In this study, methotrexate wasstarted at 0.3 mg/kg/week (not to exceed 15 mg) and increased up to a maximum doseof 25 mg once a week. This was given together with prednisone 1 mg/kg/day whichwas tapered after 1 month to an alternate-day regimen within 3±6 months. If therewas no evidence of active disease and the prednisone dose was able to be reduced,then the methotrexate was continued for about 12 months after which time it wastapered and discontinued. Out of 16 patients, this regimen lead to remission in 81%,with 25% experiencing a sustained remission for 1 year in the absence ofimmunosuppressive medications. However, remission was followed by relapse in54%, and 19% of patients had progressive disease. The therapeutic toxicities in thispopulation included reversible elevated hepatic transaminase levels (28%), nausea (22%)and stomatitis (6%), and there was one episode of Pneumocystis carinii pneumoniawhich was successfully treated.

Although daily CYC was the ®rst studied cytotoxic agent in TA, the data regardingits use are limited. In seven patients treated with CYC in a regimen similar to thatused for the treatment of WG, all seven were able to decrease their glucocorticoiddose.42 Cessation of the progression of vascular lesions occurred in four patients, all ofwhom had experienced progression on prednisone alone. When a cytotoxic agent isindicated in TA, MTX is often considered to be the preferential choice, particularly as

292 C. A. Langford

this is typically a chronic disease that a�ects young women. CYC should be reservedfor patients who have clear evidence of active in¯ammation in which glucocorticoidsare e�ective but cannot be tapered and where the patient is unresponsive, intolerantor unable to take MTX.

Data regarding the e�cacy of other cytotoxic agents in TA are con®ned solely tocase reports. Bene®cial results with mycophenolate mofetil were recently reported inthree patients, although a larger experience will be needed to determine the e�cacyof this agent.43

Non-immunosuppressive therapies also play an important role in the treatment ofTA. Medical or non-medical management of hypertension is important as this occurs in32±93% of TA patients and contributes to organ injury. Surgical modalities play animportant role in managing ®xed vascular lesions that are producing signi®cantischaemia.44 Percutaneous transluminal angioplasty can be e�ective for controllinghypertension related to renal artery stenosis and may also be bene®cial in treatingshort stenotic segments of other aortic branches.45

Giant-cell arteritis

GCA is a granulomatous vasculitis of the medium and large vessels which has apredilection for the branches of the external carotid artery. It is the most commonform of systemic vasculitis and occurs predominantly in women over 50 years of age.Frequent clinical manifestations include headache, jaw or tongue claudication, scalptenderness, and associated polymyalgia rheumatica. However, the most dreadedcomplication of GCA is visual loss due to involvement of the ophthalmic or posteriorciliary arteries. GCA is rarely directly responsible for patient mortality although therehave been reports of deaths due to acute coronary and cerebral vasculitis and latemortality associated with thoracic aortic aneurysms.

As with TA, there are no uniformly reliable indicators of active vasculitis in GCA.Disease activity has often been assessed by considering symptoms, clinical examinationand laboratory tests. Although an elevation in ESR is often used, this can occur inother settings and does not always predict or concur with clinical relapse.

Glucocorticoids are the treatment of choice in GCA. In addition to bringing about arapid improvement in cranial and systemic symptoms, glucocorticoids moreimportantly prevent visual complications. Aiello et al found that the probability ofloss of vision after starting glucocorticoids was calculated to be only 1% using Kaplan±Meier estimates.46 In literature from the 1950±60s, initial prednisone doses of440 mgdaily were used47, and in retrospective series published in the 1970±80s, patientsreceived similar doses of 40±60 mg daily.48,49 It has been from these collective studies

Practice points

. assessment of disease activity remains a critical limitation in TA

. cytotoxic therapy should primarily be considered in patients who worsen onglucocorticoids or where prednisone cannot be tapered. MTX is oftenpreferred over CYC given the nature of TA and the patient population it a�ects

. non-medical treatment modalities play an important role in the treatment of®xed vascular lesions


that the majority of experience regarding glucocorticoids in GCA has been gained.Although some authors have supported the use of initial prednisone doses of less than30 mg daily, there has been no clear evidence to demonstrate that these doses preventvisual complications. At this time, the e�cacy of lower doses of glucocorticoids inGCA remains unclear and the majority of data support the initial use of prednisone40±60 mg daily.

The optimal duration of glucocorticoid treatment in GCA remains unestablished. Inretrospective series, none of which used a standardized tapering schedule, mostpatients required glucocorticoids for 42 years, with many receiving such treatmentfor 44 years. Relapses have been reported to occur within 2 years of diagnosis at afrequency that ranges from 26 to 90%. Ideally, the glucocorticoid dose should bedecreased and stopped as directed by the status of disease activity. In the absence ofuniformly reliable indicators, the rate of tapering is usually individualized to thepatient and based upon clinical parameters and the presence of glucocorticoid toxicity.In GCA, glucocorticoids have historically been tapered on a daily schedule. Twostudies did not ®nd an alternate-day regimen to be e�ective in GCA, although neitheremployed a schedule similar to that used successfully in WG.50,51

At the current time, cytotoxic therapy does not play a signi®cant role in thetreatment of GCA. In examining the risk of glucocorticoid toxicity in GCA, 36±65% ofpatients have been found to experience one or more side-e�ects related to treatment.Osteoporosis is of particular concern in the older population who are a�ected byGCA. In all patients, a plan for monitoring and minimizing glucocorticoid-inducedbone loss should be actively pursued. With the goal of diminishing glucocorticoidtoxicity, several small reports have used azathioprine, dapsone and MTX. However,there remains insu�cient evidence to date to support the use of these agents for thispurpose. Glucocorticoid-resistant GCA is another setting where cytotoxic agents havebeen utilized. This issue is further complicated by lack of a universally acceptedde®nition for glucocorticoid resistance. There have been brief reports using dapsone,MTX and CYC in the setting of glucocorticoid-resistant GCA, but none of thesestudies allow de®nitive conclusions to be reached.

SUMMARY

Treatment of the systemic vasculitides presents a number of challenges. One of thegreatest di�culties remains our inability to assess active disease accurately inmany typesof vasculitis. While disease activity should be based on objective parameters, these arenot uniformly reliable. Features similar to active vasculitis can also be observed in othersettings such as chronic damage fromprior disease,medication toxicity, orother diseaseprocesses, particularly infection.Vigilance for suchpossibilities remains important as the

Practice points

. glucocorticoids form the foundation of treatment in GCA. Although mostphysicians begin with a starting dose of prednisone 40±60 mg daily, to datethere remains little to no standardized data regarding optimal dose, taperingschedule or treatment duration

. at the current time, cytotoxic agents play no role in the treatment of GCA

294 C. A. Langford

use of immunosuppressive therapy has no role in such settings and may worsenoutcome. The identi®cation of better means of identifying active disease remains animportant area for future study.

Although we have treatments that are e�ective, these can be associated withsigni®cant toxicity. In addition,manyof the systemic vasculitides are by nature relapsingdiseases, such that patients may require repeated courses of treatment. For this reason,therapeutic management has increasingly become based on regimens that minimizetoxicity and yet remain e�ective at inducing remission of active disease. In addition tothe use of less toxic medications, part of this approach has also involved identi®cation oftreatment based on disease severity and site of organ involvement. The development ofsuch strategies has become possible as we have had the opportunity to observe long-term patient outcome and organ-speci®c patterns of damage. Continued investigationsinto the course of these diseases and their pathophysiology will remain critical todeveloping improved treatments in the future.

REFERENCES

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Research agenda

. further investigation is needed to determine a better means of assessing diseaseactivity in many of the vasculitides

. research into disease pathogenesis may suggest means for therapeuticinterventions that target immune mechanisms involved in disease while leavinghost defences intact

. continued standardized studies are necessary to further optimize the use ofthose agents for which there has been established e�cacy but risk of toxicity

Practice points

. careful consideration must always be given to di�erentiating active vasculitisfrom other processes that may have a similar appearance

. treatment should be based on using the most e�ective and least toxic optionwith which there has been published experience

. when considering the choice of medications, factors that should be consideredinclude the site of organ involvement, disease severity, nature of the underlyingdisease and individual patient factors


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