update on the treatment of granulomatosis with polyangiitis (wegener’s)

Current Treatment Options in Cardiovascular Medicine (2012) 14:164–176DOI 10.1007/s11936-012-0165-x

Vascular Disease (H Gornik and E Kim, Section Editors)

Update on the Treatmentof Granulomatosiswith Polyangiitis (Wegener’s)Carol A. Langford, MD, MHS

AddressCenter for Vasculitis Care and Research, Department of Rheumatologic andImmunologic Disease, Cleveland Clinic, 9500 Euclid Avenue, A50, Cleveland,OH 44195, USAEmail: [email protected]

Published online: 24 January 2012* Springer Science+Business Media, LLC 2012

Keywords Wegener's I Vasculitis I Treatment I ANCA

Opinion statement

Granulomatosis with polyangiitis (Wegener’s) (GPA), formerly known as Wegener’sgranulomatosis, is a systemic vasculitis characterized by involvement of the upperairways, lungs, and kidneys. GPA shares many features with microscopic polyangiitis(MPA), so much so that recent trials have included both vasculitides. This articlefocuses on GPA only, as complete management includes modalities that are uniqueto this disease. The current treatment of GPA is stratified based on severity. Forthose patients who have active but non-severe GPA and do not have contraindica-tions, methotrexate and glucocorticoids can induce and maintain remission. Forpatients with severe disease, options include glucocorticoids combined with eithercyclophosphamide or rituximab. When cyclophosphamide is used, it is given for 3 to6 months, after which time it is stopped and switched to methotrexate or azathi-oprine for remission maintenance. In randomized trials, rituximab was found to beas effective as cyclophosphamide to induce remission of severe active GPA. Giventhe recency of experience with rituximab, there remain a number of questions re-garding relapse rate, use of repeat courses, long-term toxicity, and combinationwith maintenance agents. Until these questions are answered, the choice of wheth-er to use cyclophosphamide or rituximab must be decided between the patient andphysician. For patients with relapsing disease who have had prior cyclophosphamideexposure, rituximab is an excellent option. In newly diagnosed patients, the exten-sive experience with cyclophosphamide and its side effect profile must be weighedagainst these factors with rituximab. There has been limited experience with ritux-imab in patients with alveolar hemorrhage requiring mechanical ventilation or rap-idly progressive glomerulonephritis requiring dialysis, as these patients wereexcluded from the largest randomized trial. Until such data become available, cyclo-phosphamide remains the agent with which there has been the greatest experiencefor efficacy in these settings.

IntroductionOver the past 40 years, the treatment of granulomato-sis with polyangiitis (Wegener’s) (GPA), formerlyknown as Wegener’s granulomatosis, has steadilyevolved. GPA is a potentially life-threatening diseasecharacterized by a clinical predilection to affect the up-per airways, lungs, and kidneys, with histologic evi-dence of granulomatous inflammation, vasculitis ofthe small- to medium-sized vessels, and crescentic glo-merulonephritis that has few to no immune com-plexes. In the 1950s, GPA was a uniformly fataldisease for which there were no known treatmentoptions [1]. The introduction of glucocorticoids pro-longed survival to 12 months, but mortality continuedto occur from active disease or infection [2].

The outlook for patients with GPA changed dra-matically with the introduction of prednisone com-bined with daily cyclophosphamide, which inducedremission and allowed long-term survival [3–5]. How-ever, this treatment did not prevent relapse, and withextended experience there became a greater recogni-tion of the short-term and long-term toxicities of cy-clophosphamide.

Recent therapeutic strategies have investigatedmeans to minimize or eliminate the need for cyclo-phosphamide, such that the current treatment ap-proach to GPA is stratified based upon diseaseseverity. For patients who have active but non-severeGPA, methotrexate has been found to be as effectiveas cyclophosphamide to induce remission [6]. Forpatients who have severe disease, the use of staged reg-imens has provided patients with the efficacy of cyclo-phosphamide while decreasing its risk of side effects

through a reduced duration of exposure. In this ap-proach, cyclophosphamide is given for 3 to 6 monthsto induce remission after which time it is stopped andswitched to a less toxic agent for remission mainte-nance. The maintenance agents for which the greatestdata exist include methotrexate [7] and azathioprine[8]. As studies have found these to have similar ratesof adverse events and relapse, the choice of which ofthese agents to use is based on individual patient fac-tors such as contraindications and relapse history.Mycophenolate mofetil is another maintenance agentand although it was found to have a higher relapse ratethan azathioprine, it is a useful option in selectedpatients [9•]. The maintenance agent is typically givenfor at least 2 years in the absence of side effects, al-though continuation for longer durations should bestrongly considered in patients who have had signifi-cant organ damage or who have already experienceda relapse.

The most recent innovation in the treatment ofsevere GPA has been the introduction of rituximab(anti-CD20) and glucocorticoids. Rituximab wascompared against cyclophosphamide for remissioninduction of severe active GPA and microscopicpolyangiitis (MPA) in two randomized trials thatprovided evidence that rituximab is as effective ascyclophosphamide to induce remission [10••,11••]. However, due to the short duration of fol-low-up that is currently available, there remain anumber of questions regarding the longer-term effi-cacy and toxicity and how frequently rituximabshould be administered in GPA.

TreatmentDiet and lifestyle

& There are no specific dietary recommendations on the basis of thedisease itself. There may, however, be restrictions based on specificfeatures or treatment complications. Examples would includepotassium- and protein-restricted diets for patients who have renalfailure and glucose restrictions in patients with glucocorticoid-in-duced diabetes mellitus.

& Immunosuppressed patients, in particular those receiving high-doseglucocorticoids plus another immunosuppressive agent, shouldtake measures to avoid settings where there is a high risk of exposureto infection.

Update on the Treatment of Granulomatosis with Polyangiitis Langford 165

& Occupational or recreational lifestyle changes occurring as a resultof GPA or its treatment will depend upon individual patient factorsand the activity.

Pharmacologic treatment

Glucocorticoids

Glucocorticoids are a necessary part of the treatment regimen for all GPApatients who have active disease, but used alone they are insufficienttreatment and must be combined with another immunosuppressiveagent.

Standard dosage Patients with active severe disease are treated with prednisone 1 mg/kg/day,usually consisting of 60 mg/d for 1 month after which time the dosage isreduced. There are differing approaches to glucocorticoid reduction, with oneschedule being to reduce the dose by 5 mg every 1 to 2 weeks to 20 mgthen by 2.5 mg every 1 to 2 weeks until 5 mg daily or to complete discon-tinuation. For patients with severe disease immediately threatening to life,methylprednisolone 1000 mg/d intravenously may be given for 3 days fol-lowed by prednisone or methylprednisolone 1 mg/kg/day thereafter.

Contraindications For patients who have a severe infection, the risks of glucocorticoids must beweighed against their necessity to treat the GPA.

Main drug interactions None.

Main side effects Infection, hyperglycemia, hypertension, osteoporosis, avascular necrosis,myopathy, peptic ulcer, cataracts, glaucoma, poor wound healing, insomnia,mood changes including psychosis, weight gain, striae, acne, skin fragility,growth retardation in children.

Special points Glucocorticoids are usually administered all at once in the morning toapproximate adrenal function. Splitting the total dose to twice a day for thefirst 1 to 2 weeks may be beneficial, although consolidation to once dailyshould be pursued thereafter.

Cost/cost-effectiveness Prednisone costs about $0.20–$0.60 per day. Methylprednisolone costsabout $31.50–$72.00 per 1000-mg dose plus infusion costs.

Cyclophosphamide

Cyclophosphamide combined with glucocorticoids has been the standardtreatment for active severe GPA for 40 years. In the original regimen of Fauciand Wolff [3], patients were treated with 2 mg/kg/day combined with glu-cocorticoids. With this regimen, complete remission is achieved in 75% to95% of patients [4, 5]. Following remission induction with cyclophospha-mide, relapse of GPA occurs in 50% to 70% of patients [5, 12•].Cyclophosphamide has a significant side effect profile in which toxicityrisk increases with duration of exposure. From the initial studies in whichcyclophosphamide was given for 1 year past remission, 42% experiencedmorbidity solely as a result of treatment. Current treatment utilizes astaged approach as discussed below whereby cyclophosphamide is lim-ited to 3 to 6 months.Although the frequency of many side effects is comparable, somephysicians have favored intermittent cyclophosphamide administration.

166 Vascular Disease (H Gornik and E Kim, Section Editors)

Results from a randomized trial in 149 patients with GPA/MPA foundthat intermittent cyclophosphamide 15 mg/kg every 2 weeks for 3 dosesthen 15 mg/kg every 3 weeks was as effective as cyclophosphamide2 mg/kg/d to induce remission, although this may be associated with ahigher rate of relapse [13••]. Daily cyclophosphamide resulted in ahigher cumulative dose, although doses were comparable when durationwas limited to 3 months. Daily cyclophosphamide also resulted in ahigher frequency of leukopenia but many of these events occurred whenblood count monitoring was performed less frequently. These datasupport that either daily or intermittent cyclophosphamide may be usedbut that the duration of treatment should be limited to 3 to 6 monthswith frequent blood count monitoring.There has been insufficient data to demonstrate efficacy of cyclophos-phamide 500 to 1000 mg/m2/month in GPA. If intermittent cyclo-phosphamide is to be used, it should be administered according to theregimen utilized in the randomized trial as previously outlined.

Standard dosage Daily administration consists of oral cyclophosphamide 2 mg/kg/day. Inhospitalized patients who are unable to take medications by mouth, thesame daily dose can be given by vein. Intermittent administration consists ofcyclophosphamide 15 mg/kg given intravenously every 2 weeks for threedoses then 15 mg/kg every 3 weeks thereafter. As cyclophosphamide isrenally eliminated, the dose should be reduced in patients with renal func-tion impairment.

Contraindications Bladder cancer, hemorrhagic cystitis from prior cyclophosphamide, leuko-penia, thrombocytopenia, myelodysplasia, pregnancy. For patients who havea severe infection, the risks of cyclophosphamide must be weighed againstthe necessity to treat the GPA.


Main side effects Infection, bone marrow suppression, cystitis, transitional cell carcinoma ofthe bladder [14–16], myelodysplasia, leukemia/lymphoma, skin cancer, al-opecia, mucositis, infertility, teratogenicity, pulmonary fibrosis.

Special points Daily cyclophosphamide should be given all at once in the morning witha large amount of fluid to minimize urothelial toxicity [16]. Considerationcan be given for giving 2-mercaptoethane sulfonate sodium (MESNA) inpatients receiving intermittent cyclophosphamide. Blood counts can be an-ticipated to decline over time as a result of glucocorticoid tapering and bonemarrow fatigue. To prevent leukopenia, all patients receiving cyclophos-phamide should have complete blood counts every 1 to 2 weeks for aslong as they are taking cyclophosphamide. Cyclophosphamide-treatedpatients who develop non-glomerular hematuria should undergo cystoscopy[14].

Cost/cost-effectiveness Costs $11.5–$21.80 per day. Intravenous cyclophosphamide costs $54.62–$105.76 per dose plus infusion costs.

Methotrexate

In patients with non-severe GPA, methotrexate has been found to ef-fectively induce and maintain remission. Following successful open-labelstudies in the 1990s [17–21], a trial was conducted in 100 patients withnon-severe GPA/MPA who were randomized to methotrexate 20 to


25 mg/week or cyclophosphamide 2 mg/kg/day [6]. At the primaryendpoint of remission at 6 months, methotrexate was not inferior tocyclophosphamide.Methotrexate has also been used as a maintenance agent following re-mission induction with cyclophosphamide. Open-label studies foundthat the use of methotrexate for remission maintenance did not increasethe rate of relapse and reduced the rate of toxicity as compared tocyclophosphamide [7, 22].Given that both methotrexate and azathioprine had been found to success-fully maintain remission, a randomized trial was conducted to determinewhether there were advantages towards one agent [23]. In a randomized trialof 159 patients, methotrexate 0.3 mg/kg/week progressively increased to25mgperweekwas found tohave a comparable frequency of side effects andrelapse as azathioprine 2mg/kg/d. These results support that in patients whowould be eligible to receive eithermethotrexate or azathioprine, the decisioncould be made individually between the patient and physician as there wasno specific safety or efficacy advantage of either agent.Methotrexate is renally eliminated and thus contraindicated in renal in-sufficiency, which may prevent its use in a number of patients with GPA.

Standard dosage Methotrexate is typically started at 15 mg/week for 2 weeks then increased to20mg/week after 2weeks if laboratory results are acceptable. Somepatientsmayfurther increase to 25mg/week. Methotrexate can be given orally or parenterally(most often as a subcutaneous injection). Studies suggest that bioavailabilitydifferences betweenoral andparenteralmethotrexatemay exist in somepatients[24, 25]. Although most patients prefer oral administration, a switch to paren-teral dosing (most often by subcutaneous route) should be considered in thosewho have a return of mild symptoms or signs in whom remaining on metho-trexate is an option.

Contraindications Renal insufficiency, alcoholic liver disease or other chronic liver diseases,severe chronic pulmonary impairment, leukopenia, thrombocytopenia,myelodysplasia, inability to abstain from alcohol, pregnancy. For patientswho have a severe infection, the risks of methotrexate must be weighedagainst the necessity to treat the GPA.

Main drug interactions Trimethoprim 160 mg / sulfamethoxazole 800 mg twice a day or higher.Lower dosages such as those given for Pneumocystis prophylaxis can be safelycombined with methotrexate.

Main side effects Infection, bone marrow suppression, hepatic toxicity including cirrhosis,pneumonitis, possible lymphoma, alopecia, mucositis, teratogenicity.

Special points Folic acid 1 mg given daily or calcium leucovorin 5 to 10 mg given once aweek 24 h after methotrexate should be given concurrently to reduce sideeffects. Laboratory monitoring for methotrexate should include completeblood counts, creatinine and transaminases every 1 to 2 weeks for the firstmonth then every 4 weeks. Alcohol consumption must be avoided whiletaking methotrexate.

Cost/cost-effectiveness Costs $40.50–$52.60 per week.

Azathioprine

Azathioprine was the first agent proven in a randomized trial to maintainremission after cyclophosphamide [8]. In one study, 158 patients


with GPA/MPA were initially treated with glucocorticoids and dailycyclophosphamide to induce remission and then randomized to eitherto azathioprine 2 mg/kg/day or remain on cyclophosphamide. At theprimary endpoint of remission at 18 months, the rate of relapse was nodifferent between azathioprine and cyclophosphamide. These data sup-ported that a staged induction-maintenance regimen could reduce theduration of exposure to cyclophosphamide while not increasing the rateof relapse.Azathioprine has not been found to be effective for remission induction[4] and should only be used as a maintenance agent.Azathioprine is metabolized by the enzyme thiopurine methyltransferase(TPMT). Patients who make insufficient TPMT are at risk of drug under-metabolism and enhanced toxicity. In settings where testing is available,it is recommended that TPMT genetics be performed prior to adminis-tration of azathioprine. Azathioprine should be avoided in patients whoare TPMT homozygous and used with caution at a reduced dose inpatients who are TPMT heterozygous.

Standard dosage The target dose for azathioprine is 2 mg/kg/d orally. A lower starting doseshould be given to patients with intermediate-level TPMT.

Contraindications Leukopenia, thrombocytopenia, myelodysplasia, hypersensitivity. Homo-zygosity for TPMT deficiency. For patients who have a severe infection,the risks of azathioprine must be weighed against the necessity to treatthe GPA.

Main drug interactions Allopurinol and febuxostat interfere with the metabolism of azathioprine,resulting in higher levels and toxicity. It is not recommended that azathio-prine be given to patients taking febuxostat and it should generally beavoided in patients receiving allopurinol. If azathioprine must be givenconcurrently with allopurinol, the azathioprine dose should be reduced to25% of the normal dose with weekly blood count monitoring initially toassure safety.

Main side effects Infection, bone marrow suppression, increased transaminases, hypersensi-tivity, possible leukemia/lymphoma.

Special points Laboratory monitoring for azathioprine should include complete bloodcounts and hepatic testing every 1 to 2 weeks for the first month then every4 weeks.

Cost/cost-effectiveness Costs $2.60–$5.75 per day.

Mycophenolate mofetil

In open-label trials, mycophenolate mofetil was found to maintainremission after cyclophosphamide induction [26, 27]. A randomized trialwas conducted in 156 patients to compare mycophenolate mofetil to aza-thioprine for remission maintenance following induction with either dailyor intermittent cyclophosphamide [9]. In this study, patients treated withmycophenolate mofetil had a higher rate of relapse than those treated withazathioprine (P=0.03). Although these results suggest that mycophenolatemofetil may be less effective than azathioprine as a maintenance agent, itremains an option in patients who have relapsed through, are intolerant of,or who cannot take azathioprine or methotrexate.


Mycophenolate mofetil has been examined in open-label studies forremission induction of non-severe disease and in glomerulonephritiswithout a rise in serum creatinine [28]. Although this approach has notbeen studied in a randomized trial, mycophenolate mofetil may be atreatment option in selected patients who have mild disease who cannottake methotrexate.

Standard dosage The target dose of mycophenolate mofetil is 1000 mg twice a day orally. Insome instances, consideration may be given to dose increase to 1500 mgtwice a day.

Contraindications Leukopenia, thrombocytopenia, myelodysplasia, pregnancy. For patientswho have a severe infection, the risks of mycophenolate mofetil must beweighed against the necessity to treat the GPA.


Main side effects Infection, bone marrow suppression, possible leukemia/lymphoma, gastro-intestinal toxicity, teratogenicity.

Special points Pregnancy testing should be performed in all women of child-bearing po-tential prior to the initiation of mycophenolate mofetil. Laboratory moni-toring should include complete blood counts and hepatic testing every 1 to2 weeks for the first month then every 4 weeks.

Cost/cost-effectiveness Costs $40.88–$69.48 per day.

Rituximab

Rituximab is a chimeric monoclonal antibody that binds to the CD20 an-tigen present on the surface of normal and malignant B cells. Although theinitial rationale for the study of rituximab was based upon potential inter-vention with antineutrophil cytoplasmic antibodies (ANCA) through the Bcell, it appears likely that its mechanism of action is more complex.The first use of rituximab in GPA involved a patient with relapsing dis-ease that was resistant or intolerant to standard therapies who improvedafter treatment [29]. Favorable results were similarly observed in com-passionate and open-label trials [30, 31].In the pivotal trial that lead to approval of rituximab for GPA and MPAby the US Food and Drug Administration (FDA), 197 patients withsevere active disease underwent a blinded randomization to either re-ceive rituximab 375 mg/m2/week for 4 weeks or cyclophosphamide2 mg/kg/day, both combined with glucocorticoids [10••]. Patients wererequired to be ANCA positive and could not have a creatinine level94.0 mg/dL or require mechanical ventilation. This was designed as anon-inferiority trial and at the primary endpoint, which was being inremission with a prednisone dose of 0 mg at 6 months, rituximab was aseffective as cyclophosphamide (PG0.001). For those enrolled at the timeof a relapse, rituximab appeared statistically superior. The overall rate ofadverse events was similar between arms.In another study, 44 patients were randomized unblinded at a 3:1 ratioto receive glucocorticoids combined with either cyclophosphamide15 mg/kg every 2 weeks for 3 doses then every 3 weeks thereafter orcyclophosphamide 15 mg/kg for 2 doses given 2 weeks apart combinedwith rituximab 375 mg/m2/week for 4 weeks [11••]. This was designed


as a superiority trial and although comparable rates of remission inductionwere seen in the rituximab and cyclophosphamide arms, rituximab did notmeet its endpoint of superiority. The overall rate of adverse events wassimilar between arms. Of note was that this study had a high mortalityrate of 18% that was likely influenced by the median age of 68 years andmedian glomerular filtration rate of 18 mL/min, both of which are poorprognostic factors in GPA [32]. This trial did provide additional support forthe efficacy of rituximab, although the use of concomitant cyclophospha-mide did confound full interpretation of its effectiveness.Although the data from these randomized trials provides evidence thatrituximab can effectively induce remission, there remain many importantquestions with regards to relapse rate, long-term toxicity, use of repeatinfusions, and whether the use of concomitant maintenance agents suchas azathioprine or methotrexate increases efficacy or toxicity.

Standard dosage Rituximab 375 mg/m2/week intravenously for 4 weeks was the dosage usedin the cyclophosphamide comparison trials and represents the FDA-ap-proved dosage. Some smaller studies have also utilized 1000 mg times 2doses given 2 weeks apart intravenously, although these have not been di-rectly compared against cyclophosphamide [33–35].

Contraindications Hepatitis B. For patients who have a severe infection, the risks of rituximabmust be weighed against the necessity to treat the GPA.

Main drug interactions No drug interactions. As plasma exchange removes heavy proteins, patientsshould not undergo this procedure immediately after receiving rituximabbecause this will theoretically remove the drug.

Main side effects Infusion reactions, infection including reactivation of hepatitis B and pro-gressive multifocal leukoencephalopathy (PML), mucocutaneous reactions,arrhythmias.

Special points Testing for hepatitis B should be performed in all patients prior to rituximab,as reactivation has been reported. Rituximab-treated patients should receivePneumocystis prophylaxis in the same manner as given for all other inductionregimens in GPA. Monitoring during the infusion should be considered inpatients with known cardiac arrhythmia.

Cost/cost-effectiveness Costs $3985.92–$7971.84 per dose plus infusion costs.

Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole was first studied in the treatment ofsinonasal isolated GPA [36]. Although benefit was reported, the antimi-crobial actions of trimethoprim/sulfamethoxazole confound the ability toassess it therapeutic value. Trimethoprim/sulfamethoxazole should neverbe used alone for treatment of disease affecting a major organ site.The role of trimethoprim/sulfamethoxazole in reducing relapse wasstudied in a randomized trial in which 84 patients in remission wererandomized to receive either trimethoprim 160 mg / sulfamethoxazole800 mg twice a day or placebo [37]. At 24 months, although those whoreceived trimethoprim/sulfamethoxazole had a lower rate of relapseoverall, when broken down by location it provided no benefit in re-ducing the rise of major organ relapses.The most important role of trimethoprim/sulfamethoxazole has beenin the preventionofPneumocystis jiroveci, anopportunistic infection reported


in 10% of patients with GPA receiving induction therapy [38, 39].Standard dosage For Pneumocystis prophylaxis: trimethoprim 160 mg / sulfamethoxazole

800 mg three times a week or trimethoprim 80 mg /sulfamethoxazole400 mg daily. For patients with upper airway disease who are not onmethotrexate: trimethoprim 160 mg / sulfamethoxazole 800 mg twice a day.

Contraindications Known hypersensitivity to sulfa. A dosage of trimethoprim 160 mg/ sulfa-methoxazole 800 mg twice a day should not be given to patients on meth-otrexate, although the Pneumocystis dose can be safely combined.

Main drug interactions Methotrexate.

Main side effects Rash including Stevens-Johnson syndrome and toxic epidermal necrolysis,blood dyscrasias, interstitial nephritis, hepatic necrosis.

Special points Trimethoprim/sulfamethoxazole can increase creatinine and confound theclinical picture in patients with recent glomerulonephritis. Trimethoprim/sulfamethoxazole should be spaced away from laboratory monitoring tominimize potential confounding. For sulfa-allergic patients who cannot taketrimethoprim/sulfamethoxazole alternate methods of Pneumocystis prophy-laxis include inhaled pentamidine 300 mg/month, atovaquone 1500 mg/day, and dapsone 100 mg/day.

Cost/cost-effectiveness Costs $8.64–$28.80 per week.

Interventional procedures

Nasal care

Nasal care is an important part of treatment for patients with GPA whohave sinonasal involvement [40]. When damage occurs to the micro- andmacroscopic anatomy, moisturization and irrigation play an importantrole in maintaining sinonasal health and preventing infection. Somepatients also benefit from local nasal glucocorticoids.

Standard procedure There is no single standard procedure and a variety of techniques havebeen used. Moisturization can be achieved through the use of salinespray, emollients, and room humidification. Irrigation techniques alsovary including bulb and Toomey syringes, squeeze-bottle irrigation, in-stallation receptacles, and soft-tipped nozzles affixed to mechanical irri-gators.

Contraindications None.

Complications None.

Special points Preferred techniques may vary from patient to patient. Rotation of techni-ques can also be beneficial for individual patients.

Cost/cost-effectiveness Dependent on the techniques used.

Intratracheal dilation-injection therapy for subglotticstenosis

Subglottic stenosis in GPA begins as an inflammatory lesion but is rap-idly accompanied by fibroblastic scarring. As a significant degree ofscarring is often present at the time the lesion is first detected, systemicimmunosuppressive medications provide little to no benefit.For patients with subglottic stenosis who have severe airway narrowing


with respiratory compromise, tracheotomy can be life-saving.A procedure that has been beneficial for treatment of subglottic stenosisis a surgical procedure combining mechanical dilation with the injectionof a long-acting glucocorticoid [41–43].

Standard procedure The procedure is individualized by the surgeon but typically involvesmechanical dilation of the subglottis followed by intratracheal injection of along-acting glucocorticoid. Some physicians also utilize topical mitomycinC. Use of lasers should be avoided as this has been shown to increase thepotential for scarring and inflammation.

Contraindications None.

Complications Pneumothorax.

Special points Procedure requires both a skilled otolaryngologist familiar with GPA and ananesthesiologist comfortable with the use of jet ventilation.

Cost/cost-effectiveness Dependent on the institution, surgeon, and procedure.

Nasal reconstruction

Collapse of the cartilaginous portion of the nasal bridge can occur in GPA,leading to nasal deformity. Although this is understandably traumatic forpatients, care must be taken in how and when to approach reconstruction,as the potential exists for poor outcomes that can worsen appearance.Key factors include timing the procedure when there is local and systemicdisease quiescence and involving a surgeon who has experienceperforming this procedure in patients with GPA.

Standard procedure There is no single standard procedure.

Contraindications Active local or systemic GPA.

Complications Nasal deformity can worsen if a poor result is achieved.

Special points Timing and surgical expertise are paramount.

Cost/cost-effectiveness Dependent on the institution, surgeon, and procedure.

Plasma exchange

Plasma exchange is a procedure in which heavy proteins are removedfrom the blood. Plasma exchange is an adjunctive therapy prescribedonly in addition to standard induction therapy.The efficacy of plasma exchange remains unclear [44, 45]. In one study,137 GPA/MPA patients who had biopsy-proven glomerulonephritis witha creatinine of 9500 mmol/L (95.8 mg/dL) were treated with cyclo-phosphamide and prednisolone and randomized to receive either plas-ma exchange or methylprednisolone 1000 mg for 3 days [46]. At3 months, 69% of those who had received plasma exchange were offdialysis as compared to 49% of those who received methylprednisolone(P=0.02). However, there was no difference in 1-year survival, and lon-ger-term results from this study have raised questions as to its renalbenefit. There have been no adequately powered studies to examine therole of plasma exchange for other severe manifestations.

Standard procedure Differing methods of plasma exchange can be performed, with 5 to 7 exchangesessions usually being performed in GPA. Albumin, with or without crystalloid,is typically used as a replacement solution. Plasma exchangemay be performed


by centrifugation or filter separation technique with anticoagulation providedby citrate or by heparin with monitoring of coagulation parameters.

Contraindications Hypotension.

Complications The intravenous catheter can serve as a nidus for infection and thrombosis.Hypotension can occur during plasma exchange. Coagulation abnormalitiescan occur.

Special points Intravenous immunoglobulin should not be given after plasma exchange.Plasma exchange will remove rituximab.

Cost/cost-effectiveness Dependent on facility, number of treatments, need for intravenous line insertion.

Physical/speech therapy

Physical therapy plays an important role in patients with peripheral orcentral nervous system involvement, debilitated patients, and patientswith pulmonary impairment.

Special points The degree of recovery from neurologic involvement varies from patientto patient and longstanding impairment can occur. Early physicaltherapy is critical to optimize the potential for recovery, with instruc-tion of exercises that the patient can perform on their own over thetime.

Pediatric considerations

GPA can occur in children, although this is uncommon. There isevidence that there is a higher frequency of subglottic disease inpatients with disease onset at age 18 years or younger, but thespectrum of organ involvement, severity, and the rate of relapse ap-pear comparable with adults [47, 48]. Treatment approaches to GPAin children are similar to adults. The potential for teratogenicity mustbe recognized in therapeutic decisions in adolescents. Care must betaken to acknowledge the potential psychological impact of GPA andglucocorticoids on children and adolescents. FDA approval of ritux-imab was limited to adults with GPA.

DisclosureC.A. Langford was an investigator in the Rituximab in ANCA-Associated Vasculitis trial (RAVE). Genentechand Bristol-Myers Squibb provided study drug for clinical trials in which Dr. Langford was an investigator.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Walton E. Giant cell granuloma of the respiratorytract (Wegener's Granulomatosis). Brit Med J.1958;2:265–70.

2. Hollander D, Manning RT. The use of alkylatingagents in the treatment of Wegener's granulomatosis.Ann Intern Med. 1967;67:393–8.


3. Fauci A, Wolff S. Wegener's granulomatosis: studiesin eighteen patients and a review of the literature.Medicine. 1973;52:535–61.

4. Fauci A, Haynes B, Katz P, Wolff S. Wegener's gran-ulomatosis: prospective clinical and therapeutic ex-perience with 85 patients for 21 years. Ann InternMed. 1983;98:76–85.

5. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegenergranulomatosis: an analysis of 158 patients. AnnIntern Med. 1992;116:488–98.

6. De Groot K, Rasmussen N, Bacon PA, et al. Ran-domized trial of cyclophosphamide versus metho-trexate for induction of remission in early systemicantineutrophil cytoplasmic antibody-associated vas-culitis. Arthritis Rheum. 2005;52:2461–9.

7. Langford CA, Talar-Williams C, Barron KS, et al. Astaged approach to the treatment of Wegener's gran-ulomatosis: induction of remission with glucocorti-coids and daily cyclophosphamide switching tomethotrexate for remission maintenance. ArthritisRheum. 1999;42:2666–73.

8. Jayne D, Rasmussen N, Andrassy K, et al. A ran-domized trial of maintenance therapy for vasculitisassociated with antineutrophil cytoplasmic autoan-tibodies. N Engl J Med. 2003;349:36–44.

9.• Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolatemofetil vs azathioprine for remission maintenance inantineutrophil cytoplasmic antibody-associated vas-culitis: a randomized controlled trial. JAMA.2010;304:2381–8.

This study compared azathioprine to mycophenolate mofetilfor remission maintenance. Mycophenolate mofetil was as-sociated with a higher rate of relapse than azathioprine buthad a comparable rate of adverse events.10.•• Stone JH, Merkel PA, Spiera R, et al. Rituximab versus

cyclophosphamide for ANCA-associated vasculitis. NEngl J Med. 2010;363:221–32. This randomizedblinded trial of 197 patients compared rituximab tocyclophosphamide for remission induction of severeGPA and MPA.

This randomized blinded trial of 197 patients comparedrituximab to cyclophosphamide for remission induction ofsevere GPA and MPA. Rituximab was found to be as effectiveas cyclophosphamide for remission induction. This was apivotal trial that formed the basis for FDA approval of rit-uximab for GPA and MPA in 2011.11.•• Jones RB, Tervaert JW, Hauser T, et al. Rituximab

versus cyclophosphamide in ANCA-associated renalvasculitis. N Engl J Med. 2010;363:211–20.

This trial randomized 44 patients at a 3:1 ratio to receiveintermittent cyclophosphamide or rituximab following 2doses of intermittent cyclophosphamide. The trial did notmeet its primary endpoint of superiority of rituximab,?although rituximab appeared as effective as cyclophospha-mide. A high mortality rate was seen likely reflecting theolder age and renal insufficiency in the study population.12.• Holle JU, Gross WL, Latza U, et al. Improved out-

come in 445 patients with Wegener's granulomatosis

in a German vasculitis center over four decades.Arthritis Rheum. 2011;63:257–66.

This study examined the experience with cyclophosphamidein GPA over four decades and described the evolution of useof this agent and the lessons learned regarding safety andefficacy over time.13.•• de Groot K, Harper L, Jayne DR, et al. Pulse versus daily

oral cyclophosphamide for induction of remission inantineutrophil cytoplasmic antibody-associated vascu-litis: a randomized trial. Ann Intern Med.2009;150:670–80.

This study compared intermittent to daily cyclophospha-mide. A similar rate of remission induction was seen al-though intermittent dosing appeared to be associated with ahigher relapse rate. Daily cyclophosphamide had a higherfrequency of leukopenia that occurred at times of decreasedblood count monitoring. Intermittent cyclophosphamideprovided a lower cumulative dose over time. This studysuggested that both approaches are acceptable and providedguidance regarding blood count monitoring and cyclo-phosphamide duration.14. Talar-Williams C, Hijazi YM, Walther MM, et al. Cy-

clophosphamide-induced cystitis and bladder cancerin patients with Wegener granulomatosis. Ann InternMed. 1996;124:477–84.

15. Le Guenno G, Mahr A, Pagnoux C, et al. Incidenceand predictors of urotoxic adverse events in cyclo-phosphamide-treated patients with systemic necro-tizing vasculitides. Arthritis Rheum. 2011;63:1435–45.

16. Monach PA, Arnold LM, Merkel PA. Incidence andprevention of bladder toxicity from cyclophospha-mide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum. 2010;62:9–21.

17. Hoffman GS, Leavitt RY, Kerr GS, et al. The treatmentof Wegener's granulomatosis with glucocorticoidsand methotrexate. Arthritis Rheum. 1992;35:6112–8.

18. Sneller M, Hoffman G, Talar-Williams C, et al.Analysis of 42 Wegener's granulomatosis patientstreated with methotrexate and prednisone. ArthritisRheum. 1995;38:608–13.

19. de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapyfor the maintenance of remission in sixty-fivepatients with generalized Wegener's granulomatosis.Methotrexate versus trimethoprim/sulfamethoxa-zole. Arthritis Rheum. 1996;39:2052–61.

20. Langford CA, Talar-Williams C, Sneller MC. Use ofmethotrexate and glucocorticoids in the treatment ofWegener's granulomatosis. Long-term renal outcomein patients with glomerulonephritis. Arthritis Rheum.2000;43:1836–40.

21. Villa-Forte A, Clark TM, Gomes M, et al. Substitutionof methotrexate for cyclophosphamide in Wegenergranulomatosis: a 12-year single-practice experience.Medicine (Baltimore). 2007;86:269–77.

22. Langford CA, Talar-Williams C, Barron KS, et al. Useof a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's


granulomatosis: extended follow-up and rate of re-lapse. Am J Med. 2003;114:463–9.

23. Pagnoux C, Mahr A, Hamidou MA, et al. Azathio-prine or methotrexate maintenance for ANCA-asso-ciated vasculitis. N Engl J Med. 2008;359:2790–803.

24. Tukova J, Chladek J, Nemcova D, et al. Methotrexatebioavailability after oral and subcutaneous dminis-tration in children with juvenile idiopathic arthritis.Clin Exp Rheumatol. 2009;27:1047–53.

25. van Roon EN, van de Laar MA. Methotrexate bio-availability. Clin Exp Rheumatol. 2010;28:S27–32.

26. Langford CA, Talar-Williams C, Sneller MC. Myco-phenolate mofetil for remission maintenance in thetreatment of Wegener's granulomatosis. ArthritisRheum. 2004;51:278–83.

27. Nowack R, Göbel U, Klooker P, et al. Mycophenolatemofetil for maintenance therapy of Wegener's gran-ulomatosis and microscopic polyangiitis: a pilotstudy in 11 patients with renal involvement. J AmSoc Nephrol. 1999;10:1965–71.

28. Silva F, Specks U, Kalra S, et al. Mycophenolatemofetil for induction and maintenance of remissionin microscopic polyangiitis with mild to moderaterenal involvement–a prospective, open-label pilottrial. Clin J Am Soc Nephrol. 2010;5:445–53.

29. Specks U, Fervenza FC, McDonald TJ, et al. Responseof Wegener's granulomatosis to anti-CD20 chimericmonoclonal antibody therapy. Arthritis Rheum.2001;44:2836–40.

30. Keogh KA, Wylam ME, Stone JH, et al. Induction ofremission by B lymphocyte depletion in elevenpatients with refractory antineutrophil cytoplasmicantibody-associated vasculitis. Arthritis Rheum.2005;52:262–8.

31. Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximabfor refractory Wegener's granulomatosis: report of aprospective, open-label pilot trial. Am J Respir CritCare Med. 2006;173:180–7.

32. Flossmann O, Berden A, de Groot K, et al. Long-termpatient survival in ANCA-associated vasculitis. AnnRheum Dis. 2011;70:488–94.

33. Jones RB, Ferraro AJ, Chaudhry AN, et al. A multi-center survey of rituximab therapy for refractoryantineutrophil cytoplasmic antibody-associated vas-culitis. Arthritis Rheum. 2009;60:2156–68.

34. Taylor SR, Salama AD, Joshi L, et al. Rituximab is effec-tive in the treatment of refractory ophthalmic Wegener'sgranulomatosis. Arthritis Rheum. 2009;60:1540–7.

35. Brihaye B, Aouba A, Pagnoux C, et al. Adjunction ofrituximab to steroids and immunosuppressants for re-fractory/relapsing Wegener's granulomatosis: a studyon 8 patients. Clin Exp Rheumatol. 2007;25:S23–7.

36. DeRemee RA, McDonald TJ, Weiland LH. Wegener'sgranulomatosis: observations on treatment with an-timicrobial agents. Mayo Clin Proc. 1985;60:27–32.

37. Stegeman CA, Cohen Tervaert JW, de Jong PE, et al.Trimethoprim-sulfamethoxazole (co-trimoxazole)for the prevention of relapses of Wegener's granulo-matosis. N Engl J Med. 1996;335:16–20.

38. Sneller MC, Hoffman GS, Talar-Williams C, et al. Ananalysis of forty-two Wegener's granulomatosispatients treated with methotrexate and prednisone.Arthritis Rheum. 1995;38:608–13.

39. Ognibene FP, Shelhamer JH, Hoffman GS, et al.Pneumocystis carinii pneumonia: a major complica-tion of immunosuppressive therapy in patients withWegener's granulomatosis. Am J Respir Crit CareMed. 1995;151:795–9.

40. Hernandez-Rodriguez J, Hoffman GS, Koening CL.Surgical interventions and local therapy for Wegen-er's granulomatosis. Curr Opin Rheumatol.2010;22:29–36.

41. Langford CA, Sneller MC, Hallahan CW, et al. Clin-ical features and therapeutic management of sub-glottic stenosis in patients with Wegener'sgranulomatosis. Arthritis Rheum. 1996;39:1754–60.

42. Hoffman GS, Thomas-Golbanov CK, Chan J, et al.Treatment of subglottic stenosis, due to Wegener'sgranulomatosis, with intralesional corticosteroidsand dilation. J Rheumatol. 2003;30:1017–21.

43. Wolter NE, Ooi EH, Witterick IJ. Intralesional corti-costeroid injection and dilatation provides effectivemanagement of subglottic stenosis in Wegener'sgranulomatosis. Laryngoscope. 2010;120:2452–5.

44. Walsh M, Catapano F, Szpirt W, et al. Plasma ex-change for renal vasculitis and idiopathic rapidlyprogressive glomerulonephritis: a meta-analysis. AmJ Kidney Dis. 2011;57:566–74.

45. Casian A, Jayne D. Plasma exchange in the treatmentof Wegener's granulomatosis, microscopic polyan-giitis, Churg-Strauss syndrome and renal limitedvasculitis. Curr Opin Rheumatol. 2011;23:12–7.

46. Jayne DR, Gaskin G, Rasmussen N, et al. Random-ized trial of plasma exchange or high-dosage meth-ylprednisolone as adjunctive therapy for severe renalvasculitis. J Am Soc Nephrol. 2007;18:2180–8.

47. Cabral DA, Uribe AG, Benseler S, et al. Classification,presentation, and initial treatment of Wegener'sgranulomatosis in childhood. Arthritis Rheum.2009;60:3413–24.

48. Rottem M, Fauci AS, Hallahan CW, et al. Wegenergranulomatosis in children and adolescents: clinicalpresentation and outcome. J Pediatr. 1993;122:26–31.


update on the treatment of granulomatosis with polyangiitis (wegener’s)

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