Initial and Maintenance Therapy of Wegener

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Initial and maintenance therapy of Wegener's granulomatosis and microscopic

polyangiitis

Author

John H Stone, MD, MPH

Andre A Kaplan, MDBurton D Rose, MD Section Editor

Gerald B Appel, MD Deputy Editors

Alice M Sheridan, MD

Last literature review version 16.1: January 2008 | This Topic Last Updated: September 24,

2007 (More)

INTRODUCTION Wegener's granulomatosis (WG) and microscopic polyangiitis

(MPA) are related systemic vasculitides. Both are associated with anti-neutrophil

cytoplasmic antibodies (ANCA), have similar features on renal histology (eg, a focalnecrotizing, pauci-immune glomerulonephritis), and have similar outcomes.

The management of WG and MPA are discussed in this review. The clinical manifestationsand diagnosis of these diseases and the roles of agents other than cyclophosphamide,

glucocorticoids, methotrexate azathioprine, and plasma exchange are discussed elsewhere.

(See "Clinical manifestations and diagnosis of Wegener's granulomatosis and microscopic

polyangiitis" and see "Alternative agents in the treatment of Wegener's granulomatosis andmicroscopic polyangiitis" and see "Resistant and relapsing disease in Wegener's

granulomatosis and microscopic polyangiitis").

INITIAL THERAPY

Daily cyclophosphamide and glucocorticoids Many physicians favor daily oralcyclophosphamide-glucocorticoid combination therapy in the initial treatment of all

patients diagnosed with WG. Once remission is induced (which requires a minimum of

three to six months for most patients), several regimens that substitute less toxicimmunosuppressive agents for cyclophosphamide have been employed. (See "Maintenance

therapy" below).

The use of such aggressive immunotherapy is justified because survival in untreatedgeneralized WG is extremely poor, with up to 90 percent of patients dying within two

years, usually due to respiratory or renal failure [1] . However, mortality has markedly

diminished with the introduction of cyclophosphamide-glucocorticoid therapy.

A response to therapy is defined as partial or complete resolution of the inflammatory

manifestations. This definition is important because many patients have persistentabnormalities that are not due to active disease but reflect permanent damage due to the

effects of disease or treatment. As an example, a patient in whom the systemic symptoms


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and signs resolve and the urinalysis becomes inactive is considered to be in remission, even

if there is persistent or even slowly worsening renal insufficiency which, in this setting,

probably reflects irreversible injury induced during the active phase of the disease.Similarly, late progression of the renal disease is often due to factors other than active

disease. (See "Clinical manifestations and diagnosis of Wegener's granulomatosis and

microscopic polyangiitis").

One of the largest nonrandomized prospective single center studies reported the outcomes

of 158 patients with WG treated with varying regimens at the National Institutes of Health[1] . "Standard" low-dose cyclophosphamide plus prednisone, low-dose cyclophosphamide

alone, non-cyclophosphamide cytotoxic agents plus steroids, or glucocorticoids alone were

administered to 133, 8, 6, and 10 patients, respectively. Cyclophosphamide wasadministered for a mean of two years.

The following outcomes were reported at a mean follow-up of eight years (range of 6

months to 24 years): Survival was 80 percent, with most deaths due to WG, side effects oftherapy, or both. Significant clinical improvement was observed in more than 90 percent of

patients, with 75 percent achieving complete remission. Among the 98 patients followed for

more than five years, nearly one-half experienced remissions of greater than five years inlength.

Similar findings have been noted in other studies, as the combination of oralcyclophosphamide and glucocorticoids induces remission in 85 to 90 percent of patients,

with approximately 75 percent experiencing complete remission [2-8] .

Time to remission Reasonable estimates of the mean time to remission with commontreatment regimens were provided by CYCAZAREM (Cyclophosphamide versus

azathioprine for the maintenance of remission), a trial of 155 patients with ANCA-

associated vasculitis [7] , and WGET (Wegener's Granulomatosis Etanercept Trial), a trialof 180 patients with WG [8] . Overall, 93 percent of patients in the CYCAZAREM trial

achieved remission, within three months in 77 percent and between three and six months in

an additional 16 percent. Similarly, more than 90 percent of patients in WGET achieveddisease remissions, although only 50 percent maintained remissions for the duration of the

trial.

Persistent disease-related morbidity Nearly 90 percent of patients had clinically

important morbidity from the disease, despite adequate therapy. Common extrarenal

complications included hearing loss (35 percent), cosmetic and functional nasal deformities

(28 percent), and tracheal stenosis (13 percent). Forty-two percent of patients eventuallydeveloped permanent renal insufficiency; the median plasma creatinine concentration in

this subset was 2.6 mg/dL (229 mol/L) at an average follow-up of seven to eight years,

with segmental sclerosis of previously active glomerular lesions being the most commonfinding on renal biopsy. Eleven percent progressed to end-stage renal disease.

Alternative regimens Because of the toxicity associated with the prolongedadministration of oral cyclophosphamide, several different regimens have been evaluated


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for initial therapy. None has supplanted the oral daily cyclophosphamide-glucocorticoid

regimen for initial therapy.

Monthly intravenous cyclophosphamide To lower the overall cumulative dose of

cyclophosphamide, monthly intravenous pulses of cyclophosphamide have been evaluated

as a possible alternative strategy. The role of this regimen, which has been primarily usedin lupus, is incompletely defined. Both equal and decreased efficacy, when compared to

daily oral cyclophosphamide, have been described in patients with WG [3,6,9,10] . (See

"Therapy of diffuse or severe focal proliferative or severe membranous lupus nephritis").

One possible explanation for the conflicting results with pulse cyclophosphamide is

different patient populations. One report of 43 patients, for example, found that 58 percentdid not respond to pulse cyclophosphamide [11] . The nonresponders had more severe

disease, as evidenced by more frequent involvement of the heart and central nervous

system. However, some patients have an incomplete response to pulse therapy even when

used as initial treatment; in this setting, switching to a daily oral regimen may be associatedwith complete remission of the disease.

Direct comparisons between oral and intravenous cyclophosphamide have also beenperformed in small, prospective, randomized trials [12-14] . A meta-analysis published in

2001 based upon three prospective randomized studies of a total of 143 patients found that

intravenous and oral cyclophosphamide had similar efficacy in terms of inducing remission[15] . Intravenous therapy was associated with less toxicity but a higher relapse rate.

The results of the CYCLOPS trial, which directly compared pulse intravenous versus oral

cyclophosphamide, are awaited. Preliminary results suggest no difference in efficacy orshort term safety, but the cumulative dose of cyclophosphamide is lower with intravenous

therapy.

Methotrexate In view of its beneficial effect in rheumatoid arthritis, low-dose weekly

oral methotrexate has been tried in patients with WG without severe disease [16-19] . An

initial study of 42 patients without immediately life-threatening disease suggested possiblebenefit from methotrexate and glucocorticoids and provided the rationale for a randomized

trial [17,18] . Active renal disease was present in 21 at baseline (mean serum creatinine 1.4

mg/dL [124 mol/L], only one with a serum creatinine 2.0 mg/dL [221 mol/L]). Twentyof these patients achieved renal remission, and only one patient eventually had a rise in

serum creatinine to above 2.0 mg/dL (221 mol/L) at a median follow-up of 76 months.

The efficacy of methotrexate was directly examined in the randomized (NORAM) trial thatcompared methotrexate and cyclophosphamide for both induction and remission of ANCA-

associated vasculitis without significant renal involvement (mean serum creatinine 1.0

mg/dL [85 mol/L] and microscopic hematuria in only 28 percent) [19] . The trial enrolled89 patients with newly diagnosed WG and 6 with MPA, all of whom had "early generalized

disease." The exclusion criteria were signs of potentially severe systemic disease as

manifested by a serum creatinine greater than 1.7 mg/dL (150 mol/L), red blood cell casts,severe hemoptysis, cerebral infarction due to vasculitis, orbital pseudotumor, or rapidly

progressive neuropathy.


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The patients were assigned to methotrexate (20 to 25 mg per week orally) or

cyclophosphamide (2 mg/kg per day orally); all received prednisolone. Therapy wasgradually tapered and withdrawn by 12 months.

The following findings were noted: At six months, 90 and 94 percent of patients in themethotrexate and cyclophosphamide arms, respectively, achieved remission, although time

to remission was two months longer in the methotrexate group. Among the patients who

achieved remission, the relapse rate at 18 months was significantly higher withmethotrexate (70 versus 47 percent with cyclophosphamide). Two patients in each group

died. There was a higher incidence of leukopenia among those treated with

cyclophosphamide and a higher incidence of liver function test abnormalities among thosetreated with methotrexate.

Thus, methotrexate was as effective as cyclophosphamide for the induction of remission in

patients with mild disease, but was associated with a significantly higher relapse rate.Given the high relapse rate, methotrexate should probably be used only for non-renal

limited disease or for patients truly intolerant of cyclophosphamide.

Given the risk of toxicity in those with renal dysfunction, methotrexate should not be

administered to patients with a serum creatinine concentration above 2.0 mg/dL (177

mol/L). (See "Major side effects of methotrexate").

Glucocorticoids alone Glucocorticoid monotherapy is not generally considered for

remission induction, since the reported remission rate is much lower than in

combination with cyclophosphamide (56 versus 85 percent), and the rate of relapse

much higher [3] . This is particularly true for patients with severe disease

manifestations, such as glomerulonephritis. Among 57 patients evaluated at the NIH

who were initially treated with prednisone alone, none of those with renal disease (45

patients) experienced sustained improvement, and 55 of the 57 (96 percent) eventually

required cytotoxic therapy [20] .

Role of plasma exchange Several controlled trials of patients with WG or the related

disorder focal necrotizing glomerulonephritis have demonstrated no overall benefit for the

renal disease from plasma exchange, with the possible exception of patients who aredialysis-dependent at presentation [4,21-27] . In a randomized trial, for example, 48

patients were assigned to immunosuppressive therapy with or without plasma exchange

[21] . The following findings were noted: No difference in outcome was observed among

the 17 patients with a serum creatinine concentration of less than 5.7 mg/dL (500 mol/L)or the 12 with higher creatinine concentrations but in whom dialysis was not required.

Plasma exchange appeared to be of benefit among patients who required dialysis [21] . As

noted below, benefit was also noted in this subgroup in another trial [27] .

There are three subsets of patients with ANCA-associated vasculitis who may benefit from

plasma exchange: those with concurrent anti-GBM antibody disease, those with severepulmonary hemorrhage, and those who present with severe renal disease. Given the paucity

of data, the use of plasma exchange in these settings is empiric, and the risks of plasma


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exchange (eg, large intravenous catheter, infection) must be weighed against any potential

benefits. Concurrent anti-GBM antibodies Based entirely upon benefits observed in

retrospective studies among patients with anti-GBM antibodies alone, plasma exchange isusually used in combination with immunosuppressive agents in patients with ANCA-

associated vasculitis who also have anti-GBM antibodies [28,29] . (See "Treatment of anti-

GBM antibody (Goodpasture's) disease").

Some of these patients (12 of 39 in one study) have anti-GBM antibodies and linear IgG

staining with antibodies that bind to components of the GBM other than the alpha-3 chainof type IV collagen (the Goodpasture antigen) [28] . These antibodies are not considered

pathogenic, but this distinction cannot be made at most centers. Pulmonary hemorrhage

Although no controlled studies have been performed, patients with pulmonary hemorrhageshould be treated with plasma exchange [29,30] . This strategy is based upon the theoretical

benefit of removing ANCA by plasma exchange and the observed efficacy of plasma

exchange in patients with pulmonary hemorrhage due to anti-GBM antibody disease.

Benefits with plasma exchange in this setting were suggested in a retrospective review of

20 patients who presented between 1995 and 2001 at the University of North Carolina with

diffuse alveolar hemorrhage (DAH) and ANCA-associated small vessel vasculitis [30] . Inaddition to evidence of pulmonary hemorrhage in all patients, 14 presented with abnormal

renal function, with the average serum creatinine concentration being 4.7 mg/dL (415

mol/L).

All patients underwent daily full plasma volume plasma exchange until DAH improved,

which was then changed to alternative day apheresis therapy until the DAH resolved. The

replacement fluid was 5 percent albumin and two units of fresh frozen plasma at the end ofapheresis. All patients also received intravenous methylprednisolone (7 mg/kg per day) for

three days, and all but two received intravenous cyclophosphamide (0.5 g/m2 of body

surface area). Additional therapy included ventilatory support and hemodialysis for nineand seven patients, respectively.

DAH resolved in all 20 patients, with the mean number of apheresis treatments being 6.15(range of 4 to 9). There were no complications due to apheresis. One patient died because

of a pulmonary embolism. Among the 13 non-dialysis dependent patients, only one did not

achieve disease remission and required chronic therapy.

The results of this study must be interpreted in light of its retrospective design and lack of a

control group. In addition, because all patients in the review received conventional

therapies (generally cyclophosphamide and glucocorticoids) in addition to plasmaexchange, independent effects of plasma exchange are impossible to delineate. Patients

with severe renal disease during the acute phase The potential efficacy of plasma

exchange among patients with ANCA-associated vasculitis and severe renal disease duringthe acute phase has been examined in several case series. Some found no benefit [29,30] ,

while others suggested improved outcomes [21,27] .

The role of plasma exchange in patients with severe renal disease was addressed in the

randomized Methylprednisolone versus Plasma Exchange (MEPEX) trial [27] . This trial


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enrolled 137 patients with a new diagnosis of WG or MPA, pauciimmune

glomerulonephritis, and a serum creatinine concentration above 5.8 mg/dL (500 mol/L).

The patients were assigned randomly to receive either seven sessions of plasma exchange

over the first two weeks after diagnosis (n = 70) or methylprednisolone 1 g/day for three

days (n = 67). In addition to these therapies, patients received prednisolone (1 mg/kg perday, tapered over six months) and cyclophosphamide (2.5 mg/kg per day for three months),

followed by azathioprine for remission maintenance.

The major results of the MEPEX trial are as follows: Plasma exchange was associated with

a significantly higher likelihood of being alive and having independent renal function at

three months. At this point, 69 percent of patients treated with plasma exchange were aliveand independent of dialysis, compared with only 49 percent of the methylprednisolone

group. Plasma exchange was associated with a significant reduction in the risk of

progression to end-stage renal disease at one year (43 and 19 percent). The numbers of

deaths were high in both groups. Twenty-seven percent of patients in the plasma exchangegroup died, compared with 24 percent of those in the methylprednisolone group. The

majority of deaths occurred in the first three months of treatment. Of the 35 deaths in the

trial, 19 were related to infection, 6 to pulmonary hemorrhage, and 4 to cardiovascularevents.

The MEPEX trial had several important shortcomings, including the following: The trialwas not blinded. Neither group received the most intensive therapy possible. A more ideal

trial design would have provided pulse methylprednisolone to both treatment groups at the

outset of therapy and then randomized patients to either plasma exchange or sham plasma

exchange. As the trial was designed and conducted, neither treatment arm accuratelyreflects the type of intensive therapy that could be provided to patients in this setting. The

plasma exchange regimens varied significantly from site to site. The number of deaths in

the trial appear excessive compared to other studies, even allowing for the fact that patientsin the MEPEX study likely had more severe disease at baseline compared to patients in

other trials.

Despite these limitations, the results of the MEPEX trial support the notion that the addition

of plasma exchange to cyclophosphamide and glucocorticoid therapy may enhance the

recovery of renal function among patients who present with advanced renal dysfunctionduring the acute phase of disease.

Treatment-associated toxicity The cyclophosphamide plus glucocorticoid regimen is

associated with important toxicity and does not reverse tissue necrosis. (See "Prognosis"below). In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus.

(See "Pregnancy in women with underlying renal disease" and see "Use of

immunosuppressive drugs in pregnancy and lactation" and see "The use ofcyclophosphamide in rheumatic and renal disease: General principles").

In the NIH study, cyclophosphamide therapy resulted in a 57 percent incidence ofamenorrhea lasting more than one year or inability to become pregnant; gonadal function in

men was not evaluated. Other reported toxicities were: cystitis (50 percent), bladder cancer


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(5.6 percent), myelodysplasia (2 percent), and lymphoma (0.7 percent) [1] . (See

"Mechanism of action and general toxicity of cyclophosphamide and chlorambucil in

inflammatory diseases", for a detailed discussion of the measures available to minimizetoxicity associated with this regimen).

Reported toxicities of extended glucocorticoid in the NIH study were cataracts (21 percentin the NIH study), diabetes mellitus (8 percent), osteopenia, fractures (11 percent), and

aseptic necrosis of bone (3 percent). In addition, severe gastritis may develop and result in

gastrointestinal bleeding in patients at increased risk. (See "Major side effects of systemicglucocorticoids").

Pneumocystis carinii (jiroveci) pneumonia (PCP) and other opportunistic infections arepotentially deadly complications of immunosuppressive therapy in WG [31] .

Trimethoprim-sulfamethoxazole (160/800 mg three times weekly) prophylaxis may be both

cost-saving and life-prolonging in this setting, but must not be used in conjunction with

methotrexate [32] . (See "Pneumocystis carinii (P. jiroveci) pneumonia in non-HIV infectedpatients").

Recommendations We recommend combination cyclophosphamide-glucocorticoidtherapy in the initial treatment of most patients with WG or MPA. This is particularly

indicated in those with life-threatening disease, including patients with a serum creatinine

concentration greater than 2.0 mg/dL (177 mol/L), pulmonary involvement resulting inhypoxemia, CNS disease, and/or bowel perforation/infarction.

There are only limited data comparing the efficacy of oral and intravenous

cyclophosphamide regimens. There is lack of agreement among experts and among theauthors of this topic. Either daily oral or monthly intravenous cyclophosphamide is

effective in inducing remissions in most patients with WG or MPA. The critical point in the

management of patients on cyclophosphamide is close clinical follow-up and regularlaboratory testing to avoid neutropenia. (See "The use of cyclophosphamide in rheumatic

and renal disease: General principles").

Daily oral cyclophosphamide-glucocorticoid regimen Cyclophosphamide is given orally

in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is

induced, which is usually achieved within three to six months. The white blood cell count(WBC) must be closely monitored and the cyclophosphamide dose adjusted to avoid severe

leukopenia (WBC should remain above 3000/mm3 and absolute neutrophil count above

1500/mm3). (See "The use of cyclophosphamide in rheumatic and renal disease: General

principles", section on Monitoring).

When initiating glucocorticoid therapy, there is disagreement among experts and among the

authors as to whether therapy should be begun with pulse methylprednisolone (7 to 15mg/kg to a maximum dose of 500 to 1000 mg/day for three days) in all patients or only in

those with necrotizing or crescentic glomerulonephritis or more severe respiratory disease.

Oral glucocorticoid therapy, either from day 1 or day 4 if pulse methylprednisolone is

given, typically consists of 1 mg/kg per day (maximum of 60 to 80 mg/day) of oral


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prednisone (or its equivalent). A variety of prednisone tapering schemes have been

employed. In general, the initial high dose should be continued for two to four weeks. If

significant improvement is observed at this time, the dose of prednisone may be taperedslowly, with the goal of reaching 20 mg of prednisone per day by the end of two months

and an overall glucocorticoid course of between six and nine months. Alternate day

glucocorticoid regimens, once recommended in WG, are not generally employed now.

Monthly intravenous cyclophosphamide An alternative to daily oral cyclophosphamide

is intravenous monthly pulse cyclophosphamide therapy. Monthly cyclophosphamide istypically administered in doses of 0.5 to 1.0 g/m2 body surface area for three to six months,

until a stable remission is induced. Prednisone is given concurrently with monthly

intravenous cyclophosphamide, using similar regimens as with daily oralcyclophosphamide. (See "The use of cyclophosphamide in rheumatic and renal disease:

General principles", for a discussion of dosing of cyclophosphamide).

Prophylaxis Given the toxicities of cyclophosphamide, prophylactic therapy should beprovided for Pneumocystis pneumonia (trimethoprim sulfamethoxazole [which should not

be used by patients also taking methotrexate]), amenorrhea in women of child-bearing age

(leuprolide), and bladder cancer (hydration and mesna) [31-35] . (See "Pneumocystis carinii(P. jiroveci) pneumonia in non-HIV infected patients", section on PCP prophylaxis, and see

"The use of cyclophosphamide in rheumatic and renal disease: General principles" and see

"Mechanism of action and general toxicity of cyclophosphamide and chlorambucil ininflammatory diseases", sections on Prevention of gonadal toxicity and Prevention of

bladder toxicity).

Given the toxicities of prolonged glucocorticoid use, prophylactic treatments should beprovided for oropharyngeal fungal infections (nystatin), gastritis (H2 blocker or proton

pump inhibitor for patients at increased risk for gastrointestinal bleeding), and bone loss

(calcium and vitamin D or bisphosphonate). (See "Prevention and treatment ofglucocorticoid-induced osteoporosis").

Methotrexate A methotrexate-based regimen, in conjunction with glucocorticoids, is anoption in patients with mild disease. This primarily includes those with pulmonary nodules

or infiltrates without respiratory compromise, and/or ocular disease. Although this regimen

can be used to treat patients with glomerulonephritis and normal or near-normal serumcreatinine, it is not recommended given the high rate of relapse. If the regimen is used,

patients require close follow-up.

A methotrexate-based regimen may be particularly attractive in such patients who havelimited bone marrow reserve from past cyclophosphamide use, a history of

cyclophosphamide-induced bladder injury, or concerns relating to major cyclophosphamide

toxicity. Methotrexate should not be administered to patients with a serum creatinineconcentration above 2.0 mg/dL (177 mol/L) given the increased risk of toxicity in those

with renal dysfunction, and patients should not receive concurrent trimethoprim-

sulfamethoxazole. (See "Mechanism of action and general toxicity of cyclophosphamideand chlorambucil in inflammatory diseases" and see "Major side effects of methotrexate").


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One regimen consists of oral methotrexate at an initial dose of 0.3 mg/kg (but not

exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose

of 20 to 25 mg/week [26] . Since methotrexate is a structural analogue of folic acid that cancompetitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate

reductase (DHFR), folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 24

hours after methotrexate) should be given concurrently to reduce potential toxicity.

Glucocorticoids are administered concurrently with methotrexate. The dosing regimen for

prednisone is the same as that previously described for prednisone when used with dailyoral cyclophosphamide therapy. (See "Daily oral cyclophosphamide-glucocorticoid

regimen" above).

Plasma exchange We suggest plasma exchange in selected groups of patients with WG

or MPA, given the high morbidity and mortality associated with these specific clinical

settings: Patients with anti-GBM antibodies as well as ANC Patients with severe pulmonary

hemorrhage on presentation (as defined radiographically or by arterial oxygen saturation)or those with worsening pulmonary hemorrhage despite the combination of high-dose

glucocorticoids and cyclophosphamide Patients who have advanced renal dysfunction at

presentation, as defined by a serum creatinine level above 5.8 mg/dL (500 mol/L) and/ordialysis dependence [21,27]

The potential morbidity associated with plasma exchange must be strongly consideredbefore pursuing this modality given the uncertainty regarding its benefits. (See

"Prescription and technique of therapeutic plasma exchange" and See "Complications of

therapeutic plasma exchange").

The method and duration of plasma exchange vary with the response to therapy and the

clinical presentation. Among patients with ANCA-associated vasculitis who present with

advanced renal dysfunction, we suggest seven sessions of plasma exchange over two weeks(60 mL/kg at each session) [27] . A more prolonged regimen is used in patients with anti-

GBM disease. (See "Treatment of anti-GBM antibody (Goodpasture's) disease").

In general, albumin can be used as the replacement fluid. However, if the patient has had a

recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen

plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors. (See "Prescription and technique of therapeutic

plasma exchange").

If a severe infection develops in the setting of plasma exchange, a single infusion ofintravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish

antibody levels [36] .

MAINTENANCE THERAPY Patients will often require continued immunosuppression

following attainment of a clinical remission to reduce the risk of relapse, with the notable

exception of patients with drug-induced ANCA-associated vasculitis. The duration ofmaintenance therapy varies. (See "Initial therapy" above and see "Duration of maintenance

therapy" below).


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Long-term cyclophosphamide has significant treatment-related toxicity [1,6] ; thus, a

switch to non-cyclophosphamide maintenance regimens is advisable. The preferred drugsfor maintenance therapy are methotrexate and, particularly in patients with renal

insufficiency, azathioprine.

Patients should be switched to either methotrexate or azathioprine as soon as a stable

remission is attained, which is generally within three to six months. Patients in whom

remission is not attained for more than six months may be maintained oncyclophosphamide for a few months after remission unless toxicity is limiting.

Glucocorticoids do not appear to provide additional benefit during maintenance, and shouldbe tapered once there is a significant response, which usually occurs after one month. The

median duration of glucocorticoid therapy is less than six to eight months [8,18] .

The possible efficacy of other agents is discussed elsewhere. (See "Alternative agents in thetreatment of Wegener's granulomatosis and microscopic polyangiitis").

In patients who present with or develop dialysis-dependent kidney failure, and in whomthere is no evidence of return of kidney function after two to three months of

immunosuppressive drug therapy, excess immunosuppression should be avoided to

minimize morbidity and mortality [37] . This issue is discussed separately. (See "Resistantand relapsing disease in Wegener's granulomatosis and microscopic polyangiitis").

Methotrexate Weekly methotrexate can be used for maintenance therapy after induction

of remission with three to six months of cyclophosphamide [38] . The potential efficacy ofthis approach was illustrated in a series of 42 patients in whom remission was induced in all

patients with cyclophosphamide and glucocorticoids (at a median period of three months).

Methotrexate was started within one to two days of the last cyclophosphamide dose at adose of 0.3 mg/kg per week (maximum dose 15 mg) [39,40] . If tolerated, the dose was

increased in 2.5 mg increments each week to a dose of 20 to 25 mg per week. Patients were

also treated with leukovorin (5 to 10 mg) once per week given 24 hours after methotrexate.If remission was sustained for two years or longer, methotrexate was tapered by 2.5 mg

each month until discontinuation. The following findings were reported, at a median

follow-up of 32 months [39,40] : One patient died from a cause unrelated to vasculitis, twowere withdrawn for methotrexate pneumonitis, and one was lost to follow-up. Relapse

occurred in 22 (58 percent) of the remaining 38 patients. Among 16 patients with a renal

relapse, only four had elevations in serum creatinine concentration, all of whom returned to

baseline kidney function following treatment. Of the 16 patients who did not relapse, 15were in remission a median period of 16 months after all immunosuppressive therapy had

stopped. The remaining patient was being tapered off methotrexate after two years of

remission.

The effectiveness of methotrexate in maintaining remission is lower in patients who are not

treated initially with cyclophosphamide. In the previously described randomized NORAMtrial comparing methotrexate and cyclophosphamide for both induction and remission in

patients with early clinical disease, treatment with methotrexate orally for 12 months was


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associated with a significantly higher relapse rate at 18 months (70 versus 47 percent with

cyclophosphamide for 12 months) [19] .

Thus, methotrexate appears to be reasonably effective in maintaining a remission in

patients with no or mild renal disease who are initially treated with cyclophosphamide,

however, prolonged treatment is required. Treatment with methotrexate as induction andmaintenance agent is associated with a higher relapse rate.

Given the risk of toxicity in those with renal dysfunction, methotrexate should not beadministered to patients with a serum creatinine concentration above 2.0 mg/dL (177

mol/L), and trimethoprim-sulfamethoxazole should not be given concurrently. (See

"Major side effects of methotrexate").

Azathioprine Maintenance of remission can also be achieved with oral azathioprine

[7,41,42] . This was best shown in a European study of 155 patients who received induction

therapy with oral cyclophosphamide (2 mg/kg per day) plus prednisolone (initial 1 mg/kgper day and tapered to 0.25 mg/kg per day by twelve weeks), which was administered for a

minimum period of three months (CYCAZAREM) [7] . Among those in whom remission

was achieved (77 and 16 percent in three months and between three and six months,respectively), patients were randomly assigned to either continued cyclophosphamide (1.5

mg/kg per day) or azathioprine (2 mg/kg per day); prednisolone was also given at 10

mg/day in each regimen. At one year, both groups were given azathioprine (1.5 mg/kg perday) plus prednisolone (7.5 mg/day). At follow-up at 18 months, the following results were

reported: The rates of relapse were not significantly different between the two groups (15.5

versus 13.7 percent in the azathioprine and cyclophosphamide groups, respectively).

During the remission phase, both groups had a similar number of severe adverse events(eight and seven patients, respectively).

By comparison, the Wegener's Granulomatosis Etanercept Trial (WGET) found thatmaintenance therapy consisting of azathioprine or methotrexate (with methotrexate being

administered to those with a serum creatinine concentration less than 2.0 mg/dL [177

mol/L]) was associated with a much higher rate of severe relapse (22 percent) or relapseof any severity (57 percent) than that observed in the European study (7 and 15 percent

respectively) [8] . This well designed study of 180 patients evaluated the effectiveness of

etanercept versus placebo to enhance the ability of standard therapy to maintain remission.(See "Alternative agents in the treatment of Wegener's granulomatosis and microscopic

polyangiitis", for details concerning this study).

Possible explanations for the higher rates of relapse with WGET versus that observed in theEuropean study (CYCAZAREM) included the following: A relapse in WGET required

only one minor manifestation, but three minor manifestations were defined as a relapse in

the European study. Microscopic polyangiitis, a form of the disease that is less likely torelapse than WG, comprised a higher percentage of patients (approximately one-third) in

CYCAZAREM, whereas WGET focused on WG. The WGET study follow-up was 27

months, compared to only 18 months in CYCAZAREM. Patients continued to receive 7.5mg/day of prednisolone in CYCAZAREM. In contrast, glucocorticoid therapy was


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terminated after six months in the WGET study, provided that patients were in clinical

remission.

Recommendations We and most investigators recommend a strategy in which the

induction of remission is first accomplished with cyclophosphamide (daily therapy) in

combination with glucocorticoids and, in selected patients, plasma exchange [7] .

Once complete remission is achieved, which usually occurs within three to six months,

cyclophosphamide is discontinued and either methotrexate (which is an option only amongthose with a serum creatinine concentration 2.0 mg/dL [177 mol/L]) OR azathioprine is

initiated (which is preferred by most physicians in patients with glomerulonephritis)

[5,43] . Azathioprine is administered at an initial dose of 2 mg/kg per day in most patients.The dose can be lowered to 1.5 mg/kg per day at one year from the time of initiation of

induction therapy [7] . If methotrexate is used, one regimen consists of oral methotrexate at

an initial dose of 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5

mg each week to a maximum dose of 20 to 25 mg/week [40] . Because methotrexate is astructural analogue of folic acid that can competitively inhibit the binding of dihydrofolic

acid (FH2) to the enzyme dihydrofolate reductase (DHFR), folic acid (1 to 2 mg/day) or

folinic acid (2.5 to 5 mg/week, 24 hours after methotrexate) should be given concurrently toreduce potential toxicity. Given the risk of toxicity in those with renal dysfunction,

methotrexate should not be administered to patients with a serum creatinine concentration

above 2.0 mg/dL (177 mol/L). (See "Major side effects of methotrexate").

We and many experts prefer these regimens to long-term cyclophosphamide therapy, which

is associated with significantly greater toxicity (see "Prognosis" below).

Duration of maintenance therapy Maintenance therapy is usually continued for 12 to 18

months after stable remission has been induced [7] . For patients who have experienced

serial disease relapses following the discontinuation of maintenance therapy, long-termmaintenance therapy should be continued, particularly for those who remain ANCA-

positive during clinical remission.

Slow tapering of glucocorticoids is initiated once there is a significant response, which

usually occurs after one month. Some physicians, however, maintain a low-dose, possibly

alternate day regimen for as long as immunosuppressive therapy is continued. In theEuropean trial, the maintenance dose was 7.5 mg/day of prednisolone (equivalent to

approximately 10 mg/day of prednisone) [7] . (See "Daily oral cyclophosphamide-

glucocorticoid regimen" above).

PROGNOSIS Overall, the morbidity and mortality associated with WG and microscopic

polyangiitis results from the combined effects of the following factors: Irreversible organ

dysfunction because of inflammatory injury occurring before and the early phase ofeffective therapy The consequences of prolonged and/or aggressive immunosuppressive

therapy, whether utilized for initial disease, maintenance of remission, or management of

relapse The natural history of the disease


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Morbidity Some of the consequences of irreversible damage and prolonged aggressive

immunosuppressive therapy have been reviewed previously, particularly the findings

reported in the NIH study [1] . The principal adverse nonfatal outcomes includedglucocorticoid toxicity, an increased risk of malignancy (5.6 percent for bladder cancer),

sterility and progressive organ failure. In the WGET, 89 percent of enrolled patients had at

least one sustained adverse effect from either the disease or treatment within one year ofenrollment [8] . The most common manifestations of disease-related damage were partial

hearing loss (25 percent) and persistent proteinuria (19 percent). (See "Treatment-

associated toxicity" above)

The risk of venous thrombotic events, including deep venous thromboses or pulmonary

emboli, also appears to be increased in ANCA-associated vasculitis. In the WGET trial, 29percent experienced a venous thrombotic event during the trial or had reported an event

before enrollment in the trial [44] .

Other studies utilizing cyclophosphamide therapy have reported similar findings,particularly the association with malignancy [45] . The incidence of bladder cancer,

myelodysplasia, and lymphoma due to prolonged cyclophosphamide therapy may be even

higher than reported, given the prolonged latent period associated with the development ofmalignancy.

An increased risk of skin cancer is another concern with long-term immunosuppression.The standardized incidence rate of cutaneous squamous cell carcinoma for patients is

approximately seven-fold higher than for individuals without WG [45] . The risk of skin

cancer has been correlated with use of azathioprine and with use of glucocorticoids for

more than four years [46] .

Renal outcomes Given that the kidney is a frequent target organ, progressive renal

failure is commonly observed in patients with WG. End-stage renal disease eventuallyoccurs in approximately 20 to 25 percent of patients [47-49] . In a retrospective analysis of

108 patients, the two- and five-year renal survival was 86 and 75 percent, respectively

[48] .

However, renal failure severe enough to require dialysis during the acute phase of the

disease does not preclude a good initial response to therapy. Between 55 and 90 percent ofthese patients will recover enough function to come off dialysis [3,4,22,37] , with 40 to 70

percent being maintained off dialysis for three years or more [3,50] .

Overall, the principal determinants of a relatively poor renal outcome include more severerenal dysfunction at presentation, lack of response to initial treatment, and an enhanced

amount of fibrotic changes, such as interstitial fibrosis and glomerulosclerosis on initial

renal biopsy [1,51,52] . By comparison, improved renal function over time andresponsiveness to immunosuppressive therapy can be observed among those with

predominantly active renal lesions at disease presentation.

Mortality The long-term survival in patients with WG has improved dramatically since

the addition of cyclophosphamide to the therapeutic regimen. Untreated patients have a 90


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percent mortality rate within two years. In comparison, some cyclophosphamide studies

have reported mortality rates of 20 to 28 percent at five years and 35 percent at 10 years

[1,2,53-55] , while others have noted even better survival rates (80 percent at eight years [1]and 88 percent at 12 years [56] ).

The major causes of death in WG are complications from the underlying disease (renalfailure and pulmonary failure, and less often from heart failure and myocardial infarction)

and complications that may have been due to therapy (infection and malignancy). Higher

mortality rates are observed among the elderly and those who present with florid organfailure, such as patients with diffuse pulmonary hemorrhage requiring ventilatory support

or advanced renal dysfunction [54] .

MANAGEMENT OF UPPER AIRWAY INVOLVEMENT The consequences of upper

airway involvement are often not improved by immunosuppressive therapy and are not

considered resistant disease.

Lesions of the tracheobronchial tree can cause a variety of problems. The most serious

complications include tracheal or bronchial stenosis that can lead to respiratory failure or

postobstructive pneumonia. Treatment options for these problems include airway dilationwith or without stenting. For subglottic stenosis, intralesional injection of glucocorticoids in

combination with endoscopic dilation may avoid the need for more invasive surgical

procedures [57,58] .

Tracheostomy should be avoided whenever possible. For patients in whom tracheostomy is

necessary, most patients are able to have the tracheostomy tube removed. This was

illustrated in a retrospective report of 27 patients with ANCA positive disease of whom 11(41 percent) required tracheostomy but only 3 (11 percent) could not be decannulated [59] .

(See "Overview of the management of central airway obstruction").

Stenosing lesions of the nasal passages and destructive lesions of the nasal cartilage and

bones may cause discomfort, be disfiguring, or both. In these patients, reconstructive

surgery may provide a functional airway and can restore a more nearly normal appearingnose [60] . Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone,

or dura have been used with varying success.

MANAGEMENT IN PREGNANCY There are only limited reports of pregnancy

complicated by WG [61,62] . One report of two patients with a review of eight others found

the following [63] : Either de novo or recurrent WG can occur during pregnancy or in the

postpartum period. As with active disease in nonpregnant patients, prednisone alone isrelatively ineffective while combined therapy with cyclophosphamide induced remission.

Women with significant active disease during pregnancy can undergo therapeutic abortion

prior to cyclophosphamide which can be teratogenic, particularly in the first trimester. (See"Use of immunosuppressive drugs in pregnancy and lactation"). However, one woman

delivered an apparently healthy baby despite being treated with cyclophosphamide.

INFORMATION FOR PATIENTS Educational materials on this topic are available for

patients. (See "Patient information: Vasculitis"). We encourage you to print or e-mail this


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topic, or refer patients to our public web site www.uptodate.com/patients, which includes

this and other topics.

Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease

AuthorCharles D Pusey, MD

Raghu Kalluri, PhD Section Editor

Richard J Glassock, MD, MACP Deputy EditorsAlice M Sheridan, MD

Last literature review version 16.1: January 2008 | This Topic Last Updated: June 5,

2007 (More)

INTRODUCTION Anti-GBM antibody disease is a disorder in which circulating

antibodies are directed against an antigen intrinsic to the glomerular basement membrane(GBM), thereby resulting in acute or rapidly progressive glomerulonephritis that is

typically associated with crescent formation [1,2] . Goodpasture's syndrome (also called

Goodpasture syndrome) and Goodpasture's disease are often used synonymously to refer toanti-GBM antibody-mediated disease, which typically presents with the syndrome of

glomerulonephritis and pulmonary hemorrhage, but may present with glomerulonephritis

alone. However, some also use the term Goodpasture syndrome in referring to the clinical

constellation of glomerulonephritis and pulmonary hemorrhage, regardless of theunderlying pathogenesis [2] . (See "Acute glomerulonephritis and pulmonary

hemorrhage"). The term Goodpasture's disease is often reserved for those patients with

glomerulonephritis, pulmonary hemorrhage and anti-GBM auto-antibodies.

The pathogenesis, clinical presentation, and diagnosis of anti-GBM disease will be

reviewed here. The treatment of this disorder, and other renal conditions with pulmonaryinvolvement, are discussed separately. (See "Treatment of anti-GBM antibody

(Goodpasture's) disease" and see "Acute glomerulonephritis and pulmonary hemorrhage").

The differential diagnosis of glomerular disease and the approach to the patient with

suspected kidney disease are discussed in detail elsewhere. (See "Differential diagnosis of

glomerular disease" and see "Diagnostic approach to the patient with acute or chronic

kidney disease").

PATHOGENESIS There is short-lived production of circulating autoantibodies in

response to an unknown inciting stimulus, which are directed against an antigen intrinsic tothe glomerular basement membrane (GBM) [3] . The principal target for the anti-GBM

antibodies (which are typically IgG, but sometimes IgA or IgM) is the NC1 domain of the

alpha-3 chain of type IV collagen (alpha-3(IV) chain), one of six genetically distinct geneproducts found in basement membrane collagen [4-6] . The specific epitopes are localized

to the globular NC1 domain of the alpha-3(IV) chain [7-9] . These antibodies represent


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about 1 percent of the circulating IgG in these patients [10] . Antibodies may also be

directed against other alpha chains; this appears to represent a secondary response to

common epitopes in the different chains, and may be non-pathogenic [4] .

The cDNA for the alpha-3(IV) chain was cloned, and its chromosomal location identified

(q35-37 region of the long arm of chromosome 2) [11,12] . Cells transfected with the alpha-3(IV) chain cDNA make the protein that binds anti-GBM antibodies, thereby proving that

the alpha-3(IV) chain is the target antigen in this disorder [13,14] .

The pathogenicity of anti-GBM antibodies has been demonstrated by passive transfer

experiments in which antibodies obtained from the plasma or eluted from the glomeruli of

patients with this disorder produced glomerulonephritis when infused into animals. Theability of these antibodies to bind rapidly and tightly to the GBM may underlie the typically

fulminant nature of this disease [15] .

Experimental models and clinical studies suggest that autoreactive T cells may contribute tothe development of anti-GBM antibody disease [8,16-20] : T cells isolated from patients

with this disorder, but not from controls, react against the alpha-3 chain of type IV

collagen, the same molecule against which the anti-GBM antibodies are directed [8,21] .Regulatory T cells (CD4+ CD25+) appear to play a role in regulation of the autoimmune

response [17] . The administration of an anti-CD8 monoclonal antibody or an anti-CD154

antibody could prevent and/or treat experimental crescentic glomerulonephritis [16,18] .Similarly, regulatory T cells (CD4+CD25+), which counter the effects of autoreactive T

cells, reduced the severity of glomerular lesions in murine anti-GBM glomerulonephritis

[20] . A T cell epitope inducing anti-GBM disease in experimental models has been

characterized [22,23] . Certain microbial peptides have similarities to this T cell epitope,and elicit production of anti-GBM antibody and severe glomerulonephritis [24,25] .

Epitope spreading may explain immune responses to other regions of the alpha-3 chain and

to the alpha-4 chain [26] .

These observations suggest that autoreactive T cells, in addition to enhancing B cell

function and antibody production, may have a direct causative role in the glomerular andalveolar injury. Furthermore, there is experimental support for the observation that some

cases of anti-GBM disease appear to be associated with infections (see "Associated factors"

below).

The epitope of type IV collagen specifically recognized by anti-GBM antibodies may

correlate with the prognosis of the disease. This was illustrated in a review of 77 patients in

whom anti-GBM antibodies recognized multiple epitopes of the alpha-3(IV)chain [27,28] .Titers of antibodies directed against the N-terminus of the NC1 domain correlated with

renal survival; in contrast, renal prognosis was unrelated to the titers of antibodies directed

against other areas of the NC1 domain.

The variable pathogenicity of different anti-GBM antibodies is consistent with reports that

antibodies against the alpha-3(IV) chain exist in normal individuals without evidence ofrenal disease [29] . In this report, the anti-GBM titers and avidity were substantially lower,

and of a different IgG subclass distribution, than seen in patients with anti-GBM disease.


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EPIDEMIOLOGY There are no good data on the population incidence and prevalence.

Acute glomerulonephritis due to anti-GBM antibody disease is rare, estimated to occur infewer than one case per million population [3] . In case series published before the 1980s,

anti-GBM antibody disease accounted for fewer than 20 percent of cases of rapidly

progressive glomerulonephritis [30,31] . Anti-GBM disease may be present in up to 50percent of patients presenting with concomitant severe pulmonary involvement [32,33] .

The prevalence among patients presenting for evaluation of potential glomerular disease islower. Crescentic glomerulonephritis due to anti-GBM antibody disease accounted for

fewer than three percent of all kidney biopsies done over the course of 10 years in one

region of the United States [3,30,34] .

The diagnosis of anti-GBM disease is made in older children, as well as in adults of all ages

[3,35] . However, younger patients (50 years) with isolated glomerulonephritis [35,36] . There appears to be a slight

male predominance in the younger age group, and a female predominance in the older age

group.

PROGNOSIS OF UNTREATED PATIENTS The prognosis of untreated acute

glomerulonephritis due to anti-GBM antibody disease is extremely poor. In the previouslydescribed case series of 67 patients, death or dialysis ensued in over 90 percent of patients

[30] . In another review of 32 patients with Goodpasture's syndrome, 29 progressed to renal

failure, most of them in less than six months [34] . Among patients with isolated anti-GBM

antibody glomerulonephritis, the prognosis was slightly better: 11 progressed to renalfailure within six months, seven progressed to renal failure nine months to 22 years later,

and three were alive with normal kidney function one to seven years after diagnosis.

Prognosis is improved following treatment, with recovery more likely if there is less severe

renal disease [30] . Since antibody production is short-lived, due to T cell regulatory

mechanisms, relapses are rare. These issues, and recurrence after kidney transplantation arediscussed separately. (See "Treatment of anti-GBM antibody (Goodpasture's) disease" and

see "Anti-GBM antibody disease: Recurrence after transplantation").

CLINICAL PRESENTATION The presentation of anti-GBM antibody disease is

similar to that of other forms of rapidly progressive glomerulonephritis: relatively acute

renal failure with a urinalysis showing proteinuria (which is usually not in the nephrotic

range), and a nephritic sediment characterized by dysmorphic red cells, white cells, and redcell and granular casts.

Pulmonary involvement, generally consisting of alveolar hemorrhage, affectsapproximately 60 to 70 percent of patients; such patients are considered to have

Goodpasture's syndrome. In rare cases, pulmonary disease predominates [37] . Pulmonary

manifestations include shortness of breath, cough, sometimes overt hemoptysis, pulmonaryinfiltrates on chest x-ray, and an increased carbon monoxide diffusing capacity (DLCO)

due to the presence of hemoglobin in the alveoli. Iron deficiency anemia, possibly due to


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prolonged pulmonary bleeding, may be seen. (See "The diffuse alveolar hemorrhage

syndromes").

Patients with and without alveolar hemorrhage appear to have similar auto-antibodies

against the alpha-3 chain [4] . The variable presence of pulmonary disease appears to

reflect a general lack of access of the circulating anti-GBM antibodies to the alveolarbasement membrane. Thus, patients with pulmonary involvement often have underlying

pulmonary injury due to smoking, or less frequently, infection, cocaine inhalation, or

hydrocarbon exposure [1,38-40] .

Systemic complaints and signs, such as malaise, weight loss, fever, or arthralgia, are

typically absent. The presence of such signs suggests that the patient has a concurrentvasculitis [41] (see "Anti-neutrophil cytoplasm antibodies" below).

The general limitation of injury to the glomeruli and alveoli appears to reflect the tissue

distribution of the alpha-3 chain. In comparison to the more widespread distribution of thealpha-1 and alpha-2 chains of type IV collagen, expression of the alpha-3 chain is highest in

the glomerular and alveolar basement membranes, lower in the renal tubular basement

membranes, detectable in the choroid plexus, cochlea and retina, and virtually absent inmany other tissues, such as the small intestine and placenta [42] .

A relatively mild degree of renal involvement may be more common than previouslyappreciated in patients with anti-GBM antibody disease. A retrospective review from one

center in Australia found that 5 of 14 patients (36 percent) with this disorder had hematuria

and/or proteinuria, but a normal creatinine clearance or serum concentration of creatinine

[43] . Other series have found that 15 to 35 percent of patients have "normal" renalfunction, which is variably defined as a normal urinary sediment or no evidence of a fall in

glomerular filtration rate [43] . However, such cases clearly have the potential to progress

rapidly.

Associated factors Anti-GBM antibody disease is most often idiopathic, although it can

occasionally follow pulmonary infections, or can be associated with pulmonary injury [1] .The association with infections may lead to clustering of cases [2] .

One hypothesis to explain the association of pulmonary involvement with smoking orpulmonary infections is that ensuing damage reveals an epitope that incites an immune

response [2] . A similar explanation has been made for the association of anti-GBM renal

disease with urinary tract obstruction and lithotripsy [2,44] . Another possibility is that

damage to alveolar capillaries that occurs in these settings allows access of existingcirculating anti-GBM antibodies to antigen in the alveolar basement membrane.

One interesting setting in which this disorder can occur is in 5 to 10 percent of renaltransplants in patients with underlying hereditary nephritis [45] . These patients most

commonly have an abnormality in the alpha-5 chain of type IV collagen, although alpha-3

and alpha-4 chain abnormalities may occur. This leads to defective organization of thealpha-5, -4 and -3 collagen chains in the basement membrane, and altered Goodpasture

antigen in the alpha-3 chain, so it is not recognized by anti-GBM antibodies. In


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comparison, the Goodpasture antigen is normal in the donor kidney, potentially initiating an

immune response against this previously "unseen" antigen in the transplanted kidney [45] .

The antibody produced, however, recognizes a different epitope than the IgG antibody inGoodpasture's disease. (See "Hereditary nephritis (Alport syndrome)").

Genetic susceptibility There is increasing evidence that genetic factors affect thesusceptibility to anti-GBM antibody disease. Patients with HLA-DR15 and DR4 appear to

be at increased risk, while those with DR1 and DR7 are at lesser risk [46] . More specific

molecular analysis of DR chains has found that a particular six amino acid motif commonto DRw15 and DR4 may confer disease susceptibility [47] . This motif is not seen in DR1

and is uncommon in blacks who also have a lower incidence of anti-GBM antibody disease.

The importance of genetic factors in determining the development of anti-GBM antibody

disease is supported by findings in rodent models. In mice immunized with alpha-

3(IV)NC1, the emergence of crescentic glomerulonephritis and lung hemorrhage was

restricted to mice with MHC haplotypes H-2s, b, or d [48] . The nephritogenic response inH-2s maps more specifically to the Ab/Aa region. Organ inflammation was also associated

with the emergence of an IL-12/Th1-like T cell phenotype, a finding consistent with a role

for T cells as mentioned above. In rats with experimental anti-GBM glomerulonephritis,susceptibility was determined by copy number variation in the Fcgr3 gene [49] .

DIAGNOSIS The presence of anti-GBM antibody disease should be suspected in anypatient with acute glomerulonephritis, particularly if accompanied by rapid progression

and/or pulmonary (alveolar) hemorrhage. Pulmonary hemorrhage can also be seen with

other acute nephritides due to pulmonary edema, or to lung involvement in ANCA positive

and other forms of systemic vasculitis, and lupus [1,38] . In one report of 45 such patients,as an example, 8 had anti-GBM antibody disease while 25 had a systemic vasculitis [38] .

(See "Acute glomerulonephritis and pulmonary hemorrhage").

The diagnosis of anti-GBM antibody disease requires the demonstration of anti-GBM

antibodies either in the serum or the kidney. Renal biopsy should be performed, unless

there is a contraindication, because the accuracy of serologic assays is variable. In addition,renal biopsy provides important information regarding the activity and chronicity of renal

involvement that may help guide therapy.

Renal biopsy Light microscopy usually shows crescentic glomerulonephritis (although

milder cases do occur), whereas immunofluorescence microscopy demonstrates the

virtually pathognomonic finding of linear deposition of IgG along the glomerular

capillaries and occasionally the distal tubules (show histology 1A-1E). In rare cases, theantibody may be IgA or IgM [50] .

In some cases, the tubular staining reflects distinct circulating anti-tubular basementmembrane (TBM) antibodies. The observation that the associated tubulointerstitial disease

(interstitial infiltrate and fibrosis, tubular atrophy) is more severe in patients with anti-TBM

antibodies is consistent with these antibodies being pathogenetically important [51] .However, alpha-3(IV)NC1 is present in a proportion of tubules (distal), so tubular deposits

may reflect increased access of anti-GBM antibody to the TBM.


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There are two other disorders in which linear IgG staining can be seen in the glomeruli:

diabetic nephropathy and fibrillary glomerulonephritis [52,53] . In the former and perhapsin the latter, the IgG is nonspecifically absorbed onto the highly permeable glomerular

capillary wall and onto the fibrils, respectively. Staining is rarely as strong as with anti-

GBM disease. (See "Glomerular diseases due to nonamyloid fibrillar deposits"). In diabeticnephropathy, there is also linear deposition of albumin and other plasma proteins [54] .

Diabetic nephropathy and fibrillary glomerulonephritis can be easily distinguished fromanti-GBM disease on both clinical and histopathologic grounds. Circulating anti-GBM

antibodies are absent in both disorders and crescents are not seen in diabetic nephropathy.

The history of diabetes, the finding of diabetic glomerulosclerosis on light microscopy, and,in fibrillary glomerulonephritis, the presence of the characteristic fibrils on electron

microscopy are also helpful.

Serologic testing The diagnosis can usually be rapidly established (particularly whenbiopsy cannot be performed or will be delayed), either by indirect immunofluorescence or

by serum assay for anti-GBM antibodies using a direct enzyme-linked immunoassay

(ELISA) with purified or semi-purified antigens. Neither method is completely reliable;thus a renal biopsy to confirm the diagnosis is recommended unless contraindicated.

Indirect immunofluorescence is rarely performed, and requires an experienced renalpathologist. This test involves incubation of the patient's serum with normal renal tissue.

Fluorescein-labeled anti-human IgG is then added to see if IgG deposition has occurred,

and the results are compared to those obtained with normal serum. The test has a high false

negative rate, possibly as high as 40 percent. However, if performed appropriately and inthe proper clinical setting (eg, severe acute glomerulonephritis), a positive test is probably

diagnostic, although rigorous studies have not been performed.

A more common approach is the detection of anti-GBM antibodies in serum using a direct

enzyme-linked immunoassay (ELISA); the specificity of the antibody can be confirmed by

Western blot [55] . High antibody titers are usually found in those with rapidly progressivedisease [56,57] . The sensitivity varies depending upon the commercial kit used, ranging

from 63 to nearly 100 percent [57,58] . False negative results may occur in those with low

antibody titers [56] , and in some patients with Alport syndrome who develop post-transplant anti-GBM disease, with antibodies directed against the alpha-5(IV) chain [59] .

(See "Hereditary nephritis (Alport syndrome)").

There are also occasional false positive results with commercial ELISA assays that do notuse purified Goodpasture antigen [55,57,60] . ELISA assays for the detection of anti-GBM

antibodies that use native or recombinant human alpha-3(IV) antigen substrates are much

more sensitive and specific, with reported sensitivity of 95 to 100 percent and specificity of91 to 100 percent [58] .

An alternative is Western blot screening for antibody against the human Goodpastureantigen (alpha-3(IV) NC1) and, as controls, other human alpha chain proteins. Eliminating

false positive results is particularly important if renal biopsy confirmation is not available.


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The patient's a priori probability of having the disease based on clinical grounds must be

strongly considered when interpreting the results of serologic tests.

A case report provides an example in which commercial tests inaccurately suggested that a

patient had anti-GBM antibodies, which was clarified using recombinant human alpha-

3(IV) NC1 proteins [60] . A patient with slowly progressive dyspnea, hematuria, andproteinuria had positive circulating anti-GBM antibodies as detected by standard testing

and, on renal biopsy, trace linear IgG deposits along the GBM. With repeat testing using

standard commercial assays and recombinant human alpha-3(IV) NC1, it was demonstratedthat the patient had antibodies against alpha-2(IV) NC1 and not to the Goodpasture antigen

alpha-3(IV) NC1. When viewed in combination with the atypical clinical and histologic

findings, the positive commercial tests were probably detecting nonspecific cross-reactivityto alpha-3(IV) NC1, and the alpha-2(IV)NC1 antibodies were nonpathogenic bystanders.

Anti-neutrophil cytoplasm antibodies Patients with acute glomerulonephritis with or

without pulmonary hemorrhage also may have Wegener's granulomatosis or microscopicpolyangiitis. Thus, the serum should be tested for antineutrophil cytoplasm antibodies

(ANCA), as well as anti-GBM antibodies. Anti-GBM disease and systemic vasculitis not

only have similar clinical manifestations, but between 10 and 38 percent of patients withanti-GBM antibody disease also test positively for ANCA (almost always anti-

myeloperoxidase, or P-ANCA), and may have signs of a systemic vasculitis or a marked

systemic inflammatory response [61,62] . Even if the patient was negative for ANCA oninitial testing, ANCA serology should be repeated if there are signs of recurrent disease.

(See "Clinical spectrum of antineutrophil cytoplasmic antibodies").

The anti-GBM antibodies in patients who also have ANCA (double-positive) have the sameantigen specificity as those in patients with anti-GBM antibody disease alone [63] .

However, a single center Chinese study found that double-positive patients may have lower

levels, but a broader spectrum of anti-GBM antibodies compared with those with anti-GBMantibodies alone [64] . In addition, ANCA positive patients may develop a relapse of

systemic vasculitis.

The detection of ANCA is clinically relevant, as these patients may be more likely to have

treatable disease than those who have only anti-GBM antibodies. However, this has not

been consistent across all studies [62,65] . (See "Treatment of anti-GBM antibody(Goodpasture's) disease").

SUMMARY AND RECOMMENDATIONS Anti-GBM antibody disease is a disorder

in which circulating antibodies are directed against the NC1 domain of the alpha-3 chain oftype IV collagen, which is highly expressed in the GBM and alveoli.

Patients with anti-GBM antibody disease usually present with rapidly progressiveglomerulonephritis: acute renal failure, nephritic urine sediment and non-nephrotic

proteinuria. Pulmonary involvement (alveolar hemorrhage) is present in 60 to 70 percent of

patients. (See "Clinical presentation" above).


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Systemic complaints and signs are typically absent, and, if present, suggest concurrent

vasculitis. (See "The diffuse alveolar hemorrhage syndromes" and See "Anti-neutrophil

cytoplasm antibodies" above).

The diagnosis requires demonstration of anti-GBM antibodies; thus, we recommend the

following for all patients suspected to have anti-GBM antibody disease: Kidney biopsy,unless contraindicated, since demonstration of linear deposits of IgG (which represent

binding of anti-GBM antibodies to the GBM) in the specimen is diagnostic and activity and

chronicity of renal involvement may help guide therapy. (See "Renal biopsy" above).Serologic testing for anti-GBM antibodies. This may be particularly useful if biopsy cannot

be done or will be delayed, although none of the available tests are completely reliable.

(See "Serologic testing" above).

- We suggest serologic testing using direct enzyme-linked immunoassay (ELISA) kits

that utilize native (eg, bovine) or recombinant human alpha-3(IV) NC1.

- If available, we suggest confirmatory Western blot testing in patients with a positive

ELISA, especially if a kidney biopsy will not be performed. Testing for

antineutrophil cytoplasm antibodies (ANCA), since up to 40 percent of patients withanti-GBM antibody disease also test positive for ANCA and may have a systemic

vasculitis, which may alter treatment decisions and prognosis. (See "Anti-neutrophil

cytoplasm antibodies" above)

Treatment of anti-GBM antibody (Goodpasture's) disease

AuthorAndre A Kaplan, MD

Gerald B Appel, MD

Charles D Pusey, MD Section EditorRichard J Glassock, MD, MACP Deputy Editors

Alice M Sheridan, MD

Last literature review version 16.1: January 2008 | This Topic Last Updated: March 6,2007 (More)

INTRODUCTION Anti-GBM antibody disease is one of the three major forms ofrapidly progressive (or crescentic) glomerulonephritis. Although some patients present with

relatively mild renal insufficiency, this disorder is typically associated with severe renal

injury that, if untreated, progresses quickly to end-stage renal failure.

An important determinant of the response to therapy and long-term prognosis is early

diagnosis [1,2] . There is a direct correlation between the initial plasma creatinineconcentration and the percent of glomeruli with crescents; in particular, crescents are

present in more than 75 percent of glomeruli when the plasma creatinine concentration is


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above 5 mg/dL (442 micromol/L). Avoidance of maintenance dialysis is rare in patients

who require dialysis within 72 hours of presentation, particularly in those who have

crescents involving all glomeruli [3] . In comparison, prevention of end-stage renal diseasecan usually be achieved in less severe cases, although some do progress. The proportion of

preserved glomeruli may be the best determinant of prognosis (see "Selection of patients to

be treated" below).

The treatment of anti-GBM antibody disease is discussed in this review. The pathogenesis,

prognosis and clinical manifestations of this disorder are discussed elsewhere. (See"Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease").

TREATMENT The treatment of choice in anti-GBM antibody disease is plasmapheresiscombined with prednisone and cyclophosphamide [1,3-8] . Plasmapheresis removes

circulating anti-GBM antibodies and other mediators of inflammation (such as

complement), while the immunosuppressive agents minimize new antibody formation.

Initial therapy Most of the reported studies have been uncontrolled. Reviews of available

reports suggest that approximately 40 to 45 percent of patients will benefit by not

progressing to end-stage renal disease or death, when treated with plasmapheresis incombination with immunosuppression [4,5,8] . However, recovery is much more likely in

patients who begin treatment before oliguria ensues, and is rare in patients who require

dialysis or who have 100 percent crescents on biopsy.

Plasmapheresis The only available randomized study evaluated outcomes among 17

patients who were treated with prednisone and cyclophosphamide alone, or with

plasmapheresis [9] . After the end of treatment, two of eight patients who receivedplasmapheresis, compared with six of nine in the immunosuppression alone group, became

dialysis dependent. The authors concluded that, although there may have been some benefit

from plasmapheresis, the percent of crescents on initial renal biopsy and entry plasmacreatinine correlated better with outcome. Regardless of therapy, patients with less than 30

percent crescents and a plasma creatinine below 3 mg/dL (265 micromol/L) did well, while

those with severe crescentic involvement and a plasma creatinine above 4 mg/dL (354micromol/L) did poorly. Potential explanations for the inconclusive results are lack of

adequate power and more severe baseline disease in the patients treated with

plasmapheresis.

Despite the absence of definitive evidence of benefit, plasmapheresis is generally

recommended for the treatment of patients with anti-GBM disease. Two factors are

considered by many experts to justify this recommendation: Improved morbidity andmortality in the era of plasmapheresis compared to historic rates. (See "Pathogenesis and

diagnosis of anti-GBM antibody (Goodpasture's) disease", section on Prognosis).

Biological plausibility of greater amelioration of the consequences of disease with rapidremoval of anti-GBM antibody, compared with a slower reduction in levels seen with

immunosuppressive agents alone.

The recommended initial plasmapheresis prescription is either daily or alternate day 4-liter

exchanges for two to three weeks [1,3,6] . In general, albumin is given as the replacement


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fluid. If, however, the patient has had a recent renal biopsy or has pulmonary hemorrhage,

then one to two liters of fresh frozen plasma should be substituted for albumin at the end of

the procedure to reverse pheresis-induced depletion of coagulation factors [10,11] .

A potential complication with fresh frozen plasma (14 percent citrate by volume) is the

development of metabolic alkalosis. Metabolism of the administered citrate generatesbicarbonate, the excretion of which may be limited by concurrent renal failure. (See

"Complications of therapeutic plasma exchange").

The patient should be reassessed at the end of this two- to three-week regimen. Further

plasmapheresis may be unnecessary if the patient has improved and there is a marked

decline in serum anti-GBM antibody titers. In comparison, continued pheresis may berequired if the patient still has hemoptysis or antibody titers are still elevated [1] .

Immunosuppressive therapy Plasmapheresis must be accompanied by corticosteroids

and cyclophosphamide [4] . Most patients are given pulse methylprednisolone (15 to 30mg/kg to a maximum of dose of 1000 mg intravenously over 20 minutes) daily for three

doses followed by daily oral prednisone (1 mg/kg per day to a maximum of 60 to 80

mg/day), which can be tapered once remission is induced. The initial cyclophosphamidedose is 2 mg/kg per day orally. It has been suggested that the dose should not exceed 100

mg per day in patients over the age of 60 years to limit toxicity [12] .

Although we recommend oral cyclophosphamide, the relative efficacy of oral and

intravenous cyclophosphamide in anti-GBM disease is not known. Intravenous therapy may

be used in patients who cannot take oral medications, who are unreliable, or who have

severe renal failure and oliguria, a setting in which the bladder toxicity of oralcyclophosphamide may be increased. (See "The use of cyclophosphamide in rheumatic and

renal disease: General principles").

This aggressive regimen is warranted because anti-GBM antibody disease may be fatal and

has a high risk of permanent renal failure.

Duration of therapy The optimal duration of therapy is unknown. Spontaneous cessation

of autoantibody formation can take six to nine months or longer [4,13] . This observation

led to the suggestion that, after remission is induced, maintenance therapy with less toxicdrugs, such as low dose prednisone and azathioprine should be given for six to nine

months.

However, most patients in a large series were treated successfully with two to three weeksof plasmapheresis (daily when possible), approximately three months of cyclophosphamide

and prednisone, and prednisone alone for the subsequent six to nine months (which was

slowly tapered) [1,3] . These results and the low risk of recurrent disease, led some expertsto suggest that the duration of therapy may be as short as two to three months, if anti-GBM

antibody titers (which should be monitored regularly) are persistently negative [1,3] .

Anti-GBM antibody levels should be monitored every one to two weeks until they are

negative on two occasions. We periodically monitor anti-GBM levels for up to six months


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to confirm that remission is maintained or at any time if there are clinical signs suggestive

of recurrence. Recurrent clinical signs, in the presence of positive anti-GBM antibody,

should prompt a further course of plasmapheresis.

If antibody levels remain elevated, the immunosuppressive regimen above should be

continued. If the anti-GBM antibody titers remain positive after three to four months oftherapy with cyclophosphamide, prednisone alone or in combination with azathioprine (1 to

2 mg/kg per day, which is substituted for cyclophosphamide) should be continued for six to

nine months.

In this case, it should be ascertained that the persisting antibodies are directed towards the

pathogenic epitope (the NC1 domain of the alpha-3 chain of type IV collagen). (See"Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease", section on

Pathogenesis).

Selection of patients to be treated In the past, the above regimen was primarily utilizedin patients with a plasma creatinine concentration below 5 to 7 mg/dL (442 to 616

micromol/L) and/or pulmonary hemorrhage, which can be fatal. It is now recognized that

aggressive immunosuppressive therapy may also be beneficial in patients who present withhigher plasma creatinine concentrations.

This was shown in the largest report of long-term outcomes of patients with anti-GBMantibody disease [3] . In this retrospective review of 71 patients treated with plasma

exchange, prednisolone, and cyclophosphamide, patient and renal survival varied with the

severity at presentation: For patients who presented with a plasma creatinine concentration

of less than 5.7 mg/dL (500 micromol/L), patient and renal survival were 100 and 95percent at one year and 84 and 74 percent at last follow-up (median period of 90 months),

respectively. For patients who presented with a plasma creatinine concentration greater than

5.7 mg/dL (500 micromol/L), but who did not require immediate dialysis (within 72 hoursof presentation), patient and renal survival were 83 and 82 percent at one year and 72 and

69 percent at last follow-up, respectively. For patients who required immediate dialysis,

patient and renal survival were 65 and 8 percent at one year and 36 and 5 percent at lastfollow-up, respectively. All such patients who had crescents in all glomeruli on renal

biopsy required long-term maintenance dialysis. By comparison, two patients with

significant acute tubular necrosis plus crescents on biopsy eventually recovered long-termindependent renal function. Among the 42 patients with pulmonary hemorrhage, bleeding

resolved in approximately 90 percent.

Thus, plasmapheresis combined with prednisone and cyclophosphamide should beadministered in the following settings [14] : Patients with pulmonary hemorrhage,

independent of the presence and/or severity of renal involvement. Pulmonary bleeding

appears to occur only in patients who have some concurrent pulmonary injury, since anincrease in alveolar capillary permeability is required for the circulating antibodies to have

access to the alveolar basement membrane [15] . Smoking is the most common cause of

underlying pulmonary disease, although pneumonia and smoke or hydrocarbon inhalationhave also been implicated in selected cases [16,17] . Patients with renal involvement

(including those with plasma creatinine concentrations above 5 to 7 mg/dL [442 to 616


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micromol/L]) who do not require immediate renal replacement therapy [3] . The optimal

therapy in patients who present with less severe disease (variably described as less than 30

to 50 percent crescents on renal biopsy) is uncertain. As described above, these patientsmay do well with pulse methylprednisolone followed by oral prednisone [4,9] . However,

we, and most physicians, treat such patients with the combined regimen, consisting of

plasmapheresis plus prednisone and cyclophosphamide [14] , used for patients with moresevere disease [4] .

In contrast, there is a very low likelihood of a renal response in the patient who presentswith dialysis-dependent renal failure [3] . In this setting, the risk of therapy may exceed the

likelihood of benefit if the patient does not have pulmonary hemorrhage. The recovery of

renal function is particularly unlikely in those who are dialysis-dependent (8 percent renalsurvival at one year) and virtually unknown in dialysis-dependent patients with 100 percent

crescents on renal biopsy.

However, the inability to consistently and accurately identify the dialysis-dependent patientwho may recover renal function has led some investigators to suggest that a short trial of

combined plasmapheresis and immunosuppressive therapy should be considered,

particularly among: Patients with very acute disease, in whom irreversible injury is lesspredictable [18] . Younger patients who are better able to tolerate aggressive

immunosuppression. Patients with anti-GBM antibody disease who have both

antineutrophil cytoplasmic antibodies (ANCA) and clinical signs of a systemic vasculitis[4,19-22] . As an example, findings such as a purpuric rash and arthralgias are suggestive of

a concurrent vasculitis, since they are uncommon in anti-GBM antibody disease alone. (See

"Clinical manifestations and diagnosis of Wegener's granulomatosis and microscopic

polyangiitis" and see "Classification of and approach to the vasculitides in adults", sectionon Clinical manifestations and approach to diagnosis).

Treatment in this setting may be associated with a higher likelihood of a renal response[19,21] . An older report suggested that as many as 40 percent of such patients recover

some function if they are also ANCA positive [19] . This frequency of improvement was

thought to reflect the better renal prognosis seen in Wegener's granulomatosis.

However, a later report found much worse outcomes in double-positive patients who were

dialysis-dependent at presentation [22] . In this retrospective study of 27 double-positivepatients with both anti-GBM antibody and ANCA, renal biopsy showed extensive

glomerular cellular crescents in most patients; among the 17 who were dialysis dependent

at presentation, none recovered renal function despite immunosuppression. However,

treatment was not optimal since not all patients were treated with plasma exchange. Theoverall renal survival rate was only 26 percent at one year. (See "Initial and maintenance

therapy of Wegener's granulomatosis and microscopic polyangiitis").

Complications of therapy There are potentially serious complications of therapy, such as

intercurrent infection [23] , which should be promptly treated since it may exacerbate

disease. If there is a severe infection in the setting of plasmapheresis, a single infusion ofintravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish

antibody levels [24] .


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Cyclophosphamide (oral or intravenous) can cause Pneumocystis jiroveci (carinii)

pneumonia, amenorrhea, and bladder toxicity (cystitis and bladder cancer). Complicationswith high doses of corticosteroids include oropharyngeal fungal infections, gastritis (which

can result in gastrointestinal bleeding in patients at increased risk), and bone loss. These

complications and recommended prophylactic measures are discussed in detail elsewhere.(See "Pneumocystis carinii (P. jiroveci) pneumonia in non-HIV infected patients" and see

"The use of cyclophosphamide in rheumatic and renal disease: General principles" and see

"Mechanism of action and general toxicity of cyclophosphamide and chlorambucil ininflammatory diseases", sections on Prevention of gonadal toxicity and Prevention of

bladder toxicity, and see "Prevention and treatment of glucocorticoid-induced

osteoporosis").

Novel and experimental approaches Preliminary evidence suggests that

immunoadsorption may be effective in anti-GBM antibody disease, even in dialysis

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Initial and Maintenance Therapy of Wegener