how can relapses be detected and prevented in primary systemic small-vessel vasculitides?

Best Practice & Research Clinical RheumatologyVol. 19, No. 2, pp. 307–320, 2005

8

How can relapses be detected and prevented

in primary systemic small-vessel vasculitides?

Carol A. Langford* MD, MHS

Director, Center for Vasculitis Care and Research

Department of Rheumatic and Immunologic Diseases, The Cleveland Clinic Foundation,

9500 Euclid Avenue, A50, Cleveland, OH 44195, USA

Relapse is an important outcome measure in patients with Wegener’s granulomatosis,microscopic polyangiitis and Churg–Strauss syndrome. Although relapses are common in thesediseases, it remains unclear why these occur and whether they are influenced by exogenous orendogenous factors. A key to minimizing the consequences of relapse is early recognition throughmonitoring. This is particularly essential to detect glomerulonephritis that is often asymptomaticand can be rapidly progressive. While the presence of relapse is currently based on objectiveevidence of active disease, investigations seek to identify factors that may distinguish patients atrisk of relapse or markers that reliably predict the occurrence of relapse prior to organ injury.With the ability to successfully induce remission and the toxicities of available therapies, therelapse rate has become a critical issue in assessing the efficacy of new treatments. Recent clinicaltrials have sought to investigate safer therapeutic options that decrease disease relapse.

Key words: relapse; vasculitis; Wegener’s; polyangiitis.

One of the greatest challenges in caring for patients with vasculitic diseases has come inthe recognition and treatment of disease recurrence, which is also referred to asrelapse. With the opportunity for extended follow-up, there has been an appreciationof the predilection for most primary vasculitic diseases to relapse, as well as of theimpact of relapse in overall patient outcome. Relapses bring about not only thepotential for organ injury, but also the risk of morbidity or mortality from additionaltreatment.

Relapse is therefore a very important outcome measure within the vasculiticdiseases and raises many questions, including: what constitutes a relapse, howfrequently do relapses happen, what factors influence their occurrence, are there waysto monitor for relapse, and how does treatment influence relapse? This review will

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* Tel.: C1 216 445 6056; Fax: C1 216 445 7569.

E-mail address: [email protected]

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308 C. A. Langford

focus on these issues in three forms of primary systemic small-vessel vasculitis:Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strausssyndrome (CSS).

WHAT IS A RELAPSE?

The definition of active disease is fundamental to the concept of relapse. Active disease inthe primary systemic vasculitides is characterized by tissue injury resulting from bloodvessel or extravascular tissue inflammation. Disease activity may be most clearlydemonstrated at initial presentation when the diagnosis of a vasculitic disease isestablished by histologic or angiographic abnormalities in a clinically compatible setting.Treatment following diagnosis is aimed at protecting patient survival, inducing diseaseremission and preventing relapse. Remission would therefore be defined by the absenceof active disease, with relapse being the return of disease activity following remission.

Assessing disease activity, and thereby determining remission and relapse, ischallenging for all types of vasculitis. Repeat biopsies are not routinely performed toestablish relapse, although they may be necessary in select instances to differentiateactive disease from a life-threatening infection or other serious complication. Thepresence of relapse is usually based upon objective evidence from physical examination,laboratory studies and diagnostic imaging. Although these parameters remain the bestmeans of detecting relapse, new objective features can also result from other processesthat have a similar clinical appearance.

Because active disease cannot as yet be determined with absolute precision, theinterpretation of remission and relapse may be different between physicians. Thedevelopment and validation of instruments to better standardize the assessment ofdisease activity has been vigorously pursued.1 The recognition of the importanceof defining outcome measures in trial methodology and reporting has been an area ofsignificant progress in therapeutic investigations for WG, MPA and CSS.

HOW FREQUENTLY DO RELAPSES OCCUR?

Reported relapse rates for WG, MPA and CSS are listed in Table 1. The wide range ofrelapse values for each disease reflects differences in the definition of relapse used byindividual investigators, diverse treatment regimens, the duration of patient follow-upand the imperfection of our current means of assessing disease activity.

Although WG, MPA and CSS possess certain similarities, differences in their relapseprofile attest to their unique characteristics. Relapse has been found to occur morefrequently in patients with WG than in those with MPA in therapeutic studies that have

Table 1. Rate of relapse in three forms of primary systemic small-vessel vasculitis from reported series.

Vasculitic disease Rate of relapse (%) References

Wegener’s granulomatosis 18–64 2,3,17,32,40,49,52,53,64

Microscopic polyangiitis 8–35 2,3,17,56,65,66

Churg–Strauss syndrome 20–34 3,6,42

Relapses in small-vessel vasculitides 309

concurrently enrolled both diseases.2–5 Although the cause for this remains unclear, it ispossible that differences in the specificity of circulating antineutrophil cytoplasmicantibodies (ANCA), the presence of upper airways disease in WG or other factors playa role in modulating relapse rate. Asthma and eosinophilia are prominent clinicalfeatures in CSS, but they are not typically included in the definition of relapse.6 Asthmarecurrences may, however, potentially impact relapse by limiting the ability todiscontinue prednisone therapy.6

WHAT FACTORS INFLUENCE THE OCCURRENCE OF RELAPSES?

At the current time, there remain no factors that are clearly known to influencerelapse. Clinical and laboratory investigations, however, continue to explore severalareas.

Infection

The role of infection in the vasculitic diseases, particularly in WG, has been a topic ofinterest for many years.7,8 Although the response of WG to immunosuppressivetherapy argues against this being an active primary infectious disease, it cannot beexcluded that infection plays a role in triggering an aberrant immune response leadingto blood vessel inflammation and tissue injury. Firm evidence for such a link remainsabsent, but a number of observations continue to raise the question of whetherinfection could participate in the pathogenesis of WG. A role for respiratory infectionshas been suggested by some series that have demonstrated a seasonal variation fordisease onset9,10, but this pattern has not been reproducibly found.11,12 Studies inBrown Norway rats and MRL-lpr mice have also supported the fact that infectiouscofactors may be necessary for the development of vasculitis.13,14

The potential for infection to influence disease relapse is conceptually intriguingas the immune system is central to both vascular injury and clearance of infection.A wide variety of host defenses, including the cytokine-mediated priming ofmonocytes and neutrophils, become engaged in the process of responding to aninfection. These cells not only picture prominently in the histology of WG, but alsoplay a seminal role in the sequence of events that are hypothesized to occur inANCA-induced vascular injury.15 In one series that examined 20 relapses, Pinchingand associates reported that nine patients had experienced a bacterial or viralinfection prior to relapse.16 This association has, however, not been demonstratedin other series.17

The possible role of Staphylococcus aureus in the pathophysiology of WG and diseaserelapse has been actively investigated.18–21 Staphylococcus aureus is the organism mostfrequently cultured from the upper airways of patients with WG and can be found in theabsence of clinical infection. From in vitro and in vivo studies, S. aureus can stimulate animmune response characterized by the proliferation of T and B lymphocytes, thesecretion of immunoglobulin and increased cytokine production.20 Stegeman andcolleagues examined the rate of nasal carriage of S. aureus in patients with WG.18

Thirty-six of the 57 patients studied (63%) were found to be chronic nasal carriers ofS. aureus, of whom 21 (58%) experienced one or more disease relapses. Proportional-hazards regression analysis identified the chronic nasal carriage of S. aureus as anindependent risk factor for relapse. Interestingly, however, relapses of WG were not

310 C. A. Langford

found to be related to diagnosed infections. Subsequent studies have continued toprobe the role of S. aureus in WG, but it is currently unclear whether this organismplays a role in triggering or mediating disease pathophysiology.

Regardless of whether infection is associated with disease pathophysiology, it is animportant cause of morbidity and mortality that can have a similar appearance to activevasculitic disease. For all of these reasons, the prompt identification and treatment ofinfections is essential in patients with WG, MPA or CSS.

Antineutrophil cytoplasmic antibodies

ANCA are commonly found in patients with active WG, MPA and, to a lesser degree,CSS. In large cohort studies, patients with active WG were found to be ANCA positivemore often than those with inactive disease.22–24 Although the direct pathogenicity ofANCA in producing human vasculitis remains a point of uncertainty, an increasing bodyof evidence from in vitro and in vivo studies has supported a means by which ANCAmay produce vascular injury.15,25,26

If one works from the hypothesis that ANCA are pathogenic, it should follow thattheir consistent presence should predispose to relapse. In support of this view, severalseries have found that those patients who remain persistently ANCA positive have ahigher risk of relapse.4,5,27,28 In these and in other studies29, however, there remainpatients with a persistently elevated ANCA who did not go on to a relapse. Relapsesalso occurred at variable points in time, with one study finding seven relapses in whichsustained high levels of ANCA were present for 14–67 months before the diseasebecame clinically active.27 Elucidation of the mechanisms through which theseobservations could occur will be important to understanding whether ANCA aredirectly pathogenic in humans.

Although it seems likely that patients who remain persistently ANCA positive mayhave a higher rate of relapse overall, current evidence does not support the fact thatthis should be factored into patient management decisions. Relapses may occur at anytime or not at all in persistently ANCA-positive patients, and treatment has not yetbeen proven to prevent or delay relapse in such individuals.

Organ manifestations

Several investigations have sought to identify whether certain manifestations orpatterns of disease may be associated with a higher rate of relapse. Some reports havenot found specific organ sites to be associated with a higher rate of relapse30,31,whereas other analyses have found higher rates of relapse to be associated with specifictypes of organ involvement, including heart32 and lung disease.4

In a recent publication, Stone and colleagues examined differences in baseline dataobtained from 180 patients enrolled onto the Wegener’s Granulomatosis EtanerceptTrial.33 For the purposes of assignment to conventional therapies and for stratificationof the randomization in this trial, patients were classified as having either limited orsevere disease. As part of an extensive analysis to examine whether there wereimportant similarities and differences between these groups, patients with limiteddisease were found to be more likely to have had disease relapses following periods ofremission. The significance and potential causes of this finding remain unclear butremains a point for future investigations.


Other pathophysiologic mechanisms

A wide range of data from novel immunologic, genetic and molecular techniques arebeginning to emerge that may allow us to better understand the pathophysiologicmechanisms of the vasculitic diseases.15,26,34–38 Among the most interesting questionsbeing asked by these investigations is whether it is possible to stratify relapse risk andapply this information to the treatment approach in individual patients. It is also possiblethat these studies may lead to the recognition of parameters that can reliably detect animpending relapse prior to organ damage occurring.

HOW SHOULD PATIENTS BE MONITORED FOR RELAPSES?

Monitoring provides the most reliable means of detecting a disease relapse andpreventing organ damage. This is particularly important as certain disease features maybe asymptomatic and recognized only by ongoing vigilance. Effective monitoringincludes the evaluation of both subjective and objective parameters.

Monitoring of subjective symptoms

The education of patients regarding their disease and the symptoms or signs for whichthey should seek immediate medical attention is very important. Although patients mayexperience similar symptoms and disease features with relapse as they did at the time oftheir initial presentation, relapses may manifest very differently and affect diverse organsites. Patient symptoms should be carefully explored, with the recognition that theymay originate from a diverse range of causes, including active disease, chronic diseasesequelae, medication toxicity or other processes, especially infection.

Patients who develop new symptoms suggestive of a specific site of organinvolvement should receive a thorough evaluation with history, physical examination,laboratory tests and other diagnostic studies as indicated. Constitutional features suchas anorexia, weight loss, malaise, arthralgias and myalgias can also accompany activedisease in most forms of vasculitis. Unfortunately, these symptoms may also be seen in avariety of other settings, with arthralgias in particular commonly occurring withglucocorticoid dosage reduction. New or worsened constitutional symptoms shouldnevertheless be evaluated in a thorough manner as they may provide clues to emergingdisease activity.

Monitoring of objective parameters

As the determination of active disease is optimally based upon the presence of objectiveabnormalities, laboratory studies and diagnostic imaging form a critical part ofmonitoring. The type and frequency of monitoring will depend upon the patient’sunderlying treatment and disease status as the recency of active disease and the needfor monitoring medication toxicity will be influenced by these factors. Suggestedmonitoring schedules for individual settings are outlined in Table 2. Four areas ofmonitoring warrant additional discussion.

Table 2. Suggested monitoring during different treatment periods in patients with Wegener’s

granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome.

Agent or clinical setting Monitoring Rationale

Cyclophosphamide Every 1–2 weeks

CBC

Every 1–4 weeks

Chemistries

ESR

Urinalysis

Prevention of cytopenia

Monitor for bladder toxicity

Frequent disease activity moni-

toring during the induction

period

Methotrexate Every week during dose escalation,

then every 4 weeks thereafter

CBC

Chemistries

LFTs

ESR

Urinalysis


Hepatic monitoring

Disease activity monitoring

Azathioprine or myco-

phenolate mofetil

Every week for the first 4 weeks,

every 2 weeks for the next 2 months,

and every 4 weeks thereafter



CBC

Chemistries

LFTs

ESR

Urinalysis

On no immunosuppres-

sive medications

Every 1–3 months

CBC

Chemistries

ESR

Urinalysis

Every 6 months for first 2 years then

every 6–12 months

Chest radiograph

Monitoring for long-term

treatment sequelae


New or worsened

symptoms or signs sug-

gestive of active disease

CBC Detection of disease activity

Chemistries

ESR

Urinalysis

Chest radiograph

Other diagnostic studies as indicated

by site of features

CBC, complete blood counts; ESR, erythrocyte sedimentation rate; LFTs, liver function tests.

312 C. A. Langford

Urinalysis

Urinalysis provides invaluable information in detecting glomerulonephritis, whichtypically lacks symptoms and can be rapidly progressive leading to renal failure. Thepresence of new-onset hematuria detected by the laboratory should promptmicroscopic inspection of the urine sediment by a physician skilled in the recognitionof red blood cell casts, and a full evaluation including history, examination, serum


laboratory tests and chest radiograph. While raising concern for possibility of activerenal disease, the presence of hematuria alone is not conclusive evidence ofglomerulonephritis. This is especially true in patients who have received previouscyclophosphamide (CYC) therapy, who may develop bladder injury or transitional cellcarcinoma many years after having discontinued CYC.

One technique that has increasingly been employed has been patient self-monitoringvia urine dipsticks, with instructions to seek immediate medical attention should theirurine demonstrate the presence of blood where none was present previously. Althoughsuch monitoring may be useful, it cannot be utilized reliably in patients with ongoinghematuria from urologic or gynecologic sources.

Acute-phase parameters

Monitoring of acute-phase parameters such as the erythrocyte sedimentation rate(ESR) or C-reactive protein level can provide useful but non-specific information.Although it is uncommon to have a normal ESR in the setting of active small-vesselvasculitis, this can occur. At the other end of the spectrum, the presence of an elevatedESR can be seen in many settings other than active disease. In patients with WG, asuperimposed sinus infection is a common cause of an abnormal ESR. An increasing ESRin an asymptomatic patient should prompt evaluation with a history, physicalexamination, laboratory tests and chest radiograph. If no other objective evidence ofdisease activity is found, a sole increase in ESR should not prompt a change in therapybut warrants close observation with frequent physician visits and laboratorymonitoring.

Antineutrophil cytoplasmic antibodies

The utility of serial ANCA monitoring to identify patients at imminent risk of relapseremains controversial. Early in the investigation of ANCA, it was noted that, prior todisease relapse, levels of ANCA frequently increased.22–24 This raised the questionof whether changes in ANCA could be used to predict relapse in individual patientsand to guide treatment decisions. Although such an approach would be desirable,with the hope of preventing organ damage, in order to outweigh the considerablerisks of treatment toxicity, a rise in ANCA titer would need to be uniformlyassociated with a relapse and occur immediately prior to clinical evidence of activedisease. Unfortunately, neither of these essential points has been supported by theavailable data.

The absence of relapse following ANCA rise has been found to range from 18

to 44% in a diverse number of series.39 In a prospective study of 100 patients, Boomsmaand colleagues found that of the 38 patients who had a rise in proteinase 3-ANCA level,29% did not go on to relapse.30 This was even more pronounced when measured byindirect immunofluorescence, in which a relapse did not occur in 43% of patients whohad a rise in titer of cytoplasmic-staining ANCA (cANCA). Using a Kaplan–Meieranalysis, this study additionally demonstrated that 50% of those who had a rise incANCA remained disease free at 12 months following the rise.

These findings support the fact that were ANCA used as a basis for guidingtreatment, a substantial number of patients would have been exposed to the toxicitiesof therapy they would not have needed. As ANCA measurements should therefore notbe factored into making therapeutic decisions, the role of serial monitoring is uncertain.Although some physicians choose to monitor ANCA serially, with the view that it may

314 C. A. Langford

help to guide the frequency of follow-up and monitoring, it remains unclear whetherthis provides additional benefit beyond a regularly performed schedule of monitoring asoutlined in Table 2.

Chest radiographs

The need to perform chest radiographs in the absence of respiratory symptoms has beensupported by the observation that up to 34% of WG patients with radiographicabnormalities may lack pulmonary symptoms.40 However, the optimal frequency withwhich asymptomatic patients should be monitored by chest radiography remains unclear.In clinical trials performed at the National Institutes of Health, chest radiographs areperformed at 6 month intervals in patients in remission who are on immunosuppressivetherapy, and during the first 2 years after stopping such treatments. Beyond that timeperiod, chest radiography should be considered at 6–12 month intervals.

New radiographic abnormalities that develop in a patient with WG, MPA or CSS mayresult from many causes and should not be assumed to be due to active disease. Drug-induced pneumonitis from methotrexate (MTX) or less commonly CYC may have asimilar clinical and radiographic appearance to active small-vessel vasculitis. Newpulmonary infiltrates occurring in an immunosuppressed patient must always raise aconcern of bacterial or opportunistic infection. A consideration of the clinical contextin which new or worsening pulmonary disease is occurring is essential to determiningthe differential diagnosis and planning the appropriate course of evaluation andmanagement.41

HOW DOES TREATMENT INFLUENCE RELAPSE?

Relapse is an important outcome measure that must be critically assessed wheninterpreting the results from any published therapeutic trial in WG, MPA or CSS. Themajority of therapeutic data have come from studies in WG, although recent multi-center studies have inclusively enrolled WG, MPA and CSS as forms of ANCA-associated vasculitis. Because of its rarity, treatment literature in CSS has primarilycome from series where CSS was grouped together with polyarteritis nodosa andMPA6,42, and more recently from series of ANCA-associated vasculitis.

Prior to the time of available treatment, active generalized WG was uniformly fatal,with mortality occurring from pulmonary or renal failure. The introduction ofcombined treatment with prednisone and daily CYC dramatically changed patientoutcome.43 In a long-term series of 133 patients who received this regimen, 91%showed marked improvement, 75% achieved complete remission, and an 80% survivalrate was seen.40 Despite this success, 50% of patients experienced a disease relapse,and 42% experienced serious morbidity as a result of treatment. For this reason, recentinvestigations have sought to identify safer treatment approaches that effectively induceremission and are associated with a lower relapse rate.

As has been discussed extensively in Chapter 7 in this volume, one of the firstconsiderations was the use of intermittent CYC as this may be associated with lesstoxicity, particularly involving the bladder. Although the question of the comparativeefficacy with daily CYC to induce remains unanswered, the available data have supportedthe fact that intermittent CYC is associated with a higher rate of relapse.44–48

The most recent CYC induction regimens have employed a staged therapeuticapproach whereby the duration of CYC is limited to the period required to induce


remission, after which time CYC is stopped and a less toxic agent is used to maintainremission. The largest remission maintenance experience has been with the use ofMTX or azathioprine (AZA).

Two open-label trials have examined the use of MTX for remission maintenance.Langford and colleagues conducted a prospective, standardized, open-label trial inwhich 42 patients with active WG received daily CYC 2 mg/kg per day and prednisone1 mg/kg per day to induce disease remission, followed by MTX 20–25 mg per week formaintenance of remission.29,31 In this trial, there was an 98% survival rate and 100% ofpatients achieved remission. Relapse occurred in 22 patients (52%), with glomerulone-phritis occurring in 16 patients. Of these, four patients showed a rise in serumcreatinine of R0.2 mg/dl (maximum elevation of 0.4 mg/dl), but this returned tobaseline with treatment. There was no significant difference in the rate of relapse seenin this trial compared with that seen in a historical cohort from the same institutionwho were treated with daily CYC for 1 year past remission.

In another MTX maintenance study, Reinhold-Keller and associates treated 71patients with intravenous MTX 0.3 mg/kg per week after complete or partial remissionwas induced with daily CYC.49 Twenty-six patients (37%) experienced a disease relapse.Of these, 16 patients had relapsing glomerulonephritis, 14 exhibiting a rise in serumcreatinine to 1.5–2.0 mg/dl. One patient relapsed with rapidly progressive glomer-ulonephritis and pulmonary hemorrhage that was fatal. Both of these studies thereforefound MTX to be a well-tolerated therapy for the maintenance of remission in WG, butthey varied in the severity of renal relapse. The reason for such divergent findings isunclear, although differences in study design were present. Given the potential forglomerulonephritis to be asymptomatic, close renal monitoring is important, regardlessof the treatment regimen.

AZA has emerged to be an important agent for maintenance of remission. Initialreports from open-label series suggested that AZA might be able to maintain remissionfollowing induction with daily CYC.50 The European Vasculitis Study Group conducteda randomized trial in patients with active generalized ANCA-associated vasculitiscomparing AZA with CYC for maintenance of remission following induction with dailyCYC and glucocorticoids.2 Of 155 patients, 144 (93%) achieved remission. At 18months, 15.5% who had received AZA for remission maintenance had relapsed,compared with 13.7% of those who remained on CYC (PZ0.65). These data supportthe conclusion that limiting the duration of CYC exposure to the period required toinduce remission and then switching to AZA for maintenance of remission was notassociated with a higher rate of relapse at 18 months.

In published standardized trials of staged regimens to maintain induction2,29, thetransition from CYC to MTX or AZA was made at the time of remission, which wasbetween 3 and 6 months for most patients. In a recent retrospective study, Slot andcolleagues observed a higher rate of relapse in patients who were still ANCA positive atthe time of treatment switch from CYC to AZA.51 Although these findings might raisethe question of whether ANCA should guide the duration of CYC treatment, theseauthors calculated that for every three continuously positive patients treated with CYC,two would be treated unnecessarily. Given the toxicity profile of CYC, the transition tomaintenance medication should therefore continue to be based on objective clinicalevidence of disease remission and should not be determined by ANCA.

There have currently been no randomized trials comparing different non-CYCmaintenance agents to establish whether advantages exist in relapse prevention.The low rate of relapse seen in the AZA maintenance trial is likely reflective of its 18month duration. During this time interval, Kaplan–Meier plots from the MTX and AZA

316 C. A. Langford

maintenance trials2,29 suggest a similar rate of relapse, although an evaluation of dataacross different studies must be regarded with caution. Until such a time that acomparative experience exists, the choice of maintenance therapy should be based onmedication toxicity profiles, the patient’s disease history and the physician’s experiencewith each medication.

The use of prednisone combined with MTX to induce and maintain remission hasbeen studied in patients with active but not immediately life-threatening disease who donot have underlying hepatic disease or renal insufficiency. In a prospective,standardized, open-label trial, Sneller and colleagues treated 42 patients withprednisone 1 mg/kg per day and MTX 20–25 mg weekly.52 Thirty-three patients(79%) achieved remission with 19 patients (58%) experiencing a relapse, 79% of whichoccurred either after MTX was discontinued or at a dose of %15 mg per week.53 Twoother open-label studies also observed favorable results with the use of MTX to induceremission.54,55 As there have been no direct comparisons, it cannot be concludedwhether the use of MTX to induce remission is associated with a higher rate of relapsethan induction with CYC and whether this may be balanced out by a lower risk of sideeffects. Therefore, in patients with active WG that is not immediately life threatening,the decision of whether to use CYC or MTX for induction of remission must be basedon individual factors.

The optimal duration of maintenance therapy remains unclear. In most publishedstandardized prospective trials, once remission has been achieved, the immunosup-pressive agent is continued for an additional 1–2 years. Although relapses can occur atany point in the treatment course40, most series have demonstrated that relapsescommonly develop through the first 2 years after coming off of all immunosuppressivemedications.17,48,51,56 This raises the question of whether prolonged immunosuppres-sive therapy would be beneficial. The continuation of immunosuppressive treatment isby no means a protection against relapse2,29,49,52, and extending the duration of therapyraises the risk of medication toxicity. At the current time, the decision regarding howlong to continue treatment must be made on an individual basis taking into accountpublished data and the presence of organ damage, and balancing the impact of relapseagainst the risks imposed by treatment for an individual patient.57

The utility of trimethoprim/sulfamethoxazole (T/S) to reduce relapses has beeninvestigated. Stegeman and colleagues conducted a randomized placebo controlled trialin which 81 patients who achieved remission with CYC and prednisone receivedtrimethoprim 160 mg/sulfamethoxazole 800 mg twice daily, or placebo.19 At 24 months,82% of patients in the T/S group were in remission compared with 60% of the placebogroup. However, only the recurrence of nasal or upper airway lesions was significantlyreduced, and no difference was observed in relapses involving other organ systems. T/Swas discontinued in 20% of patients because of side effects. Based upon these data, theuse of T/S for relapse prevention must be considered on an individual basis with cautionregarding concurrent medications. T/S given at Pneumocystis prophylaxis doses can safelybe given to MTX-treated patients, but twice daily dosing should not be combined withMTX as this may cause life-threatening bone marrow suppression.

Reduction of relapse remains one of the main objectives in future clinical therapeutictrials in WG, MPA and CSS. Monoclonal antibody and recombinant DNA technologyhave led to an expanding range of biologic therapies capable of directly targetingcomponents of the immune response. Although reports on the use of biologic agents inWG, MPA and CSS have begun to appear in the literature, none of these allows anyconclusions to be drawn regarding their efficacy.58–63 Prior to their use in clinicalpractice, it is essential that the safety and efficacy of biologic agents be thoroughly


investigated in prospective standardized clinical trials as they have the potential forunexpected toxicities and effects on disease.

SUMMARY

Disease relapse remains an important cause of morbidity and mortality in patients withWG, MPA and CSS. The frequency of relapse following apparent disease remission raisesmany intriguing questions. Does relapse represent new inflammation from underlyingmechanisms that our current treatment approaches cannot permanently modulate, or isit possible that there remain components of disease activity undetectable by our currentparameters that re-emerge at the time of relapse? Gaining a better understanding ofdisease pathophysiology and the mechanistic events that lead up to relapse will be criticalin developing strategies to detect relapse prior to organ damage, identifying risk factorsfor relapse and guiding novel therapeutic approaches.

Practice points

† relapse is an important cause of morbidity and mortality in WG, MPA and CSS† relapse should be based on objective evidence of active disease† similar clinical features can occur as a result of active disease, chronic disease

sequelae, medication toxicity or other processes, in particular infection† some manifestations of relapse, especially glomerulonephritis, may be

asymptomatic† regular monitoring provides an important means of detecting relapse early† the frequency of relapse and its definition are essential to the interpretation of

efficacy for any vasculitis therapeutic trial

Research agenda

† are there exogenous or endogenous factors that trigger disease relapse?† does relapse represent new inflammation following remission or the re-

emergence of subclinical disease that cannot be detected by current means?† are there markers that can reliably predict relapse prior to its occurrence?† can patients be stratified based on factors that place them at greater risk of

relapse?† could it be possible to individualize treatment based upon risk of relapse?† are there treatment approaches that reduce the rate of relapse?

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how can relapses be detected and prevented in primary systemic small-vessel vasculitides?

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