Wegener Granulomatosis Treatment & Management

  • Author: Patricia J Papadopoulos, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: May 9, 2012
 

Approach Considerations

The mainstay of treatment for Wegener granulomatosis (WG) is a combination of corticosteroids and cytotoxic agents.

Treatment should be tailored to appropriately treat WG manifestations while minimizing long-term toxicities to the patient.

Untreated generalized or severe Wegener granulomatosis (WG) typically carries a dismal prognosis, with up to 90% of patients dying within 2 years, usually of respiratory or renal failure. Even non-renal WG carries a mortality rate of up to 40%.[34]

Outcomes for this previously fatal disease improved dramatically with the introduction in the 1970s of cyclophosphamide, which is administered in combination with corticosteroids.[4] Approximately 90% of patients with WG respond to cyclophosphamide, with approximately 75% experiencing complete remission. However, 30%-50% of those who initially respond experience at least one relapse, requiring another course of therapy. In general, limited disease does not require as aggressive therapy as does severe disease. Additionally, treatment recommendations are different for induction of remission and maintenance of remission.

Grading

Current treatment recommendations in WG depend on the severity and activity of disease. The European Vasculitis Study Group recommends grading disease severity of the AAVs into the following 5 categories[47] :

  • Localized - Upper and/or lower respiratory tract disease without any other systemic involvement or constitutional symptoms
  • Early systemic - Any, without organ-threatening or life-threatening disease
  • Generalized - Renal or other organ-threatening disease, serum creatinine level less than 5.6 mg/dL
  • Severe - Renal or other vital-organ failure, serum creatinine level exceeding 5.6 mg/dL
  • Refractory - Progressive disease unresponsive to glucocorticoids and cyclophosphamide

Activity

Contact sports are to be avoided for 1 month following a kidney biopsy. Otherwise, activities are as tolerated. Because patients are immunosuppressed, they should attempt to minimize exposure to ill contacts.

Consultations

WG is a multisystem disease that requires a multidisciplinary approach to management, involving rheumatologists, pulmonologists, nephrologists, and otolaryngologists (ear, nose, and throat specialists). In addition, a baseline ophthalmologic examination should be considered.

Deterrence/prevention

No known deterrents prevent the development of WG.

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Remission Induction

Cyclophosphamide

Generalized or severe disease generally requires aggressive therapy. Since introduced by Fauci et al in the 1970s, oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion standard for induction of remission in AAV.

Eventually, intravenous cyclophosphamide was investigated as an alternative to oral cyclophosphamide in an effort to decrease treatment-associated toxicities, and, while the emphasis has been placed on optimizing treatment by minimizing exposure to cyclophosphamide and seeking alternative comparable therapies, the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for induction of remission in generalized/severe Wegener granulomatosis (WG) for years.[47]

In 2011, however, the US Food and Drug Administration (FDA) approved the use of rituximab (a monoclonal antibody that targets B cells), in combination with glucocorticoids, as an alternative to cyclophosphamide for induction of remission in AAV (WG and microscopic polyangiitis).

Cyclophosphamide can be given either by a daily oral route or intermittent intravenous route in combination with high-dose glucocorticoids. The recommended daily oral dose of cyclophosphamide is 2mg/kg/day (not to exceed 200mg/day). Pulsed (intravenous) cyclophosphamide (15mg/kg every 2 weeks for the first 3 pulses, then every 3 weeks for the next 3-6 pulses) is an alternative to daily oral cyclophosphamide; it results in less cumulative exposure to cyclophosphamide and, therefore, theoretically causes fewer adverse effects.

Pulsed cyclophosphamide has been shown to be as effective as daily oral cyclophosphamide in inducing remission.[48] A study found, however, that there was a trend toward higher relapse rates with pulsed cyclophosphamide later in the maintenance phase of treatment. Nonetheless, this study was not intended to detect a difference between the 2 groups; more studies are needed.[47, 48]

Cyclophosphamide doses are reduced as needed for renal function and age. Cyclophosphamide therapy is usually continued until there is significant disease improvement or remission, typically 3-6 months. The patient is then transitioned to a less toxic medication for maintenance of remission. Cyclophosphamide toxicity manifests as hemorrhagic cystitis (in 15-43% of cases after oral treatment), bladder cancer (30-fold increased incidence as compared with controls), increased risk of other malignancies, cytopenias, infertility, and opportunistic infections, typically occurring during cyclophosphamide-induced leukopenia.

Patients receiving pulse cyclophosphamide should also be given oral or intravenous 2-mercaptoethanesulfonate sodium (Mesna), which binds to acrolein, the toxic metabolite of cyclophosphamide responsible for hemorrhagic cystitis. Once bound to acrolein, the toxic metabolite can no longer bind to cell-surface proteins in the bladder, limiting the risk of local cyclophosphamide-associated toxicity. Mesna may also be beneficial in patients receiving continuous oral cyclophosphamide.

The recommended IV dosing of mesna is equal to 20% (weight/weight) of the IV cyclophosphamide dose, divided into 3 equal doses. The first dose of IV mesna is administered 15-30 minutes prior to IV cyclophosphamide. The 2 remaining doses are then given 4 hours and 8 hours following IV cyclophosphamide. Peak urinary concentrations with IV mesna dosing occur in 1 hour.[49]

The dose of oral mesna should be equal to 40% of the cyclophosphamide doses (oral or IV), based on a 50% oral bioavailability, and divided into 3 equal doses. The first dose of oral mesna should be given 2 hours before cyclophosphamide (oral or IV). The second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing. The bioavailability is not affected by food intake, and peak urinary concentrations occur in 3 hours.[49]

Frequent urinalyses should be performed while the patient is receiving either intravenous or oral cyclophosphamide, and should also be performed throughout the patient’s life to screen for the development of bladder cancer. Urine cytology can also be considered. Additionally, complete blood count (CBC) monitoring should be performed every 1-2 weeks throughout the course of daily oral cyclophosphamide to detect and prevent leukopenia. CBC counts should be performed on day 10 and 14 after each intravenous pulse and immediately before the next intravenous dose as well.

Finally, infertility may be of great concern to both male and female patients who desire future childbearing. A study of 42 women in the WGET trial, aged 14 to 46 years (mean age 35 years), found that daily oral cyclophosphamide, even when administered for less than 6 months, was associated with diminished ovarian reserve, as evidenced by decreased anti-Müllerian hormone (AMH).[50] If there is time prior to the initiation of cyclophosphamide therapy, men may wish to pursue sperm banking and women of childbearing age should consider oral contraceptives and gonadotropin-releasing hormone analogues (ie, leuprolide) to help preserve fertility.[51]

Rituximab

Rituximab combined with high-dose glucocorticoids represents an alternative to cyclophosphamide for induction of remission in WG; it is the first treatment ever approved by the FDA for AAV.

The evidence for this approval came from the Stone et al's RAVE (Rituximab in Antineutrophil Cytoplasmic Antibody ̶ Associated Vasculitis) trial.[12] Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that induces apoptosis of B cells, with the exception of plasma cells and pre-B cells. Infusion of rituximab typically causes a 6-month depletion of circulating B cells and therefore may decrease the production of autoantibodies such as ANCAs.

The RAVE trial, which showed the noninferiority of rituximab compared with the cyclophosphamide control group, suggested that rituximab may be better for induction of relapsing disease. There were no significant differences between the treatment groups in the number or severity of adverse events.

The RITUXVAS trial, by The European Vasculitis Study Group (EUVAS), examined the use of rituximab in severe WG with renal involvement in older patients and found rituximab was not superior to cyclophosphamide and was associated with a similar number of adverse events, although the rituximab group also received cyclophosphamide.[13] Both studies confirmed the efficacy and superiority of rituximab over cyclophosphamide in reducing ANCA positivity.[52]

Following the FDA approval, questions surfaced regarding the potential for rituximab as maintenance therapy for AAV, its optimal dosing frequency, and whether other immunosuppressive medications should be continued while patients are also receiving rituximab.

A recent retrospective review evaluated the relapse rate and tolerance of rituximab maintenance therapy in 28 AAV patients (4 with microscopic polyangiitis, 24 with granulomatosis with polyangiitis). The patients received a median of 4 rituximab infusions of differing dose and frequency over 38 months. Combined treatment included corticosteroids and other immunosuppressives (azathioprine, mycophenolate mofetil, methotrexate, leflunomide) at the time of the first rituximab maintenance infusion, although most had their immunosuppressive medication held for an average of 8 months after their first infusion. Results suggest that rituximab effectively maintained remission with a good safety profile, confirming previous reports.[53, 54]

A prospective trial (MAINRITSAN) has been started for patients with AAV who have achieved remission with conventional cyclophosphamide-based therapy to better determine if the low relapse rate was due to rituximab maintenance therapy or if concomitant immunosuppressive therapy played a role. Patients in the MAINRITSAN trial will be enrolled at remission and randomized to receive maintenance therapy with either rituximab (1 systematic infusion every 6 mo for 18 mo) or azathioprine (for 21 mo).[55]

Further studies may address whether rituximab is effective for limited disease, which is typically associated with more granulomatous features than vasculitic ones. Rituximab is typically thought to be more effective in the vasculitic phase rather than the granulomatous phase, but small studies have shown good results even in limited disease.[56, 57]

Adverse effects associated with rituximab include infusion reactions, mucocutaneous reactions, increased risk of infections (to include opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy. In rheumatoid arthritis patients, hypogammaglobulinemia before rituximab seemed to be more closely associated with risk of infection than during or after rituximab.[58] Whether rituximab-associated hypogammaglobulinemia is associated with risk of infection in AAV remains to be determined, although a retrospective study did not show an association.[53] Late-onset neutropenia has also been associated with rituximab in WG; appropriate laboratory monitoring should be considered.[59]

Corticosteroids

Historically, glucocorticoid monotherapy prolonged median survival in WG by only 7.5 months. There have been no clinical trials evaluating the role or dosing of glucocorticoids in AAV, but every clinical trial has used glucocorticoids in combination with other immunosuppressants. Thus, corticosteroids remain the cornerstone of treatment for AAV, especially for the induction of remission.[47]

One meta-analysis sought to answer the question of comparing glucocorticoid regimens in AAV. The authors found that studies with a longer course of glucocorticoids (ie, nonzero target dose) were associated with fewer relapses. Another retrospective study by McGregor et al found that once remission is reached for at least 1 month, glucocorticoid therapy beyond 6 months was associated with a greater risk of infection without a significantly reduced risk of relapse.[60] Further studies are still needed to define the best regimen with respect to glucocorticoid dose and duration of therapy.[33]

Glucocorticoids are usually given orally, but, if a rapid response is needed, such as in the case of rapidly progressive glomerulonephritis and/or alveolar hemorrhage, intravenous pulse methylprednisolone (0.5-1 g/day for 3 consecutive days) can be used and then followed by oral prednisone. Initial high-dose glucocorticoids (1 mg/kg/day) should be continued for at least 1 month. Doses should not be reduced to less than 15 mg/day within the first 3 months. The dose should then be slowly tapered to a maintenance dose of 10 mg/day or less during remission.[47] Methods to prevent glucocorticoid-induced osteoporosis should be followed.

Trimethoprim-sulfamethoxazole

Pneumocystis pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with WG, especially with prolonged lymphocytopenia.

Prophylaxis against Pneumocystis (carinii) jiroveci pneumonia should be instituted while patients are taking cyclophosphamide and corticosteroids (particularly high-dose corticosteroids). Typically, TMP-SMZ at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100mg daily can be substituted. Pneumocystis prophylaxis has also been recommended during rituximab treatment and for at least 6 months following the last rituximab infusion.

Reports have examined TMP-SMZ use in isolation without other immunosuppressive medications in the induction phase of treatment in patients with very limited disease; however, prospective trials of TMP-SMZ as monotherapy have been disappointing.

In adults, TMP-SMZ has been shown to prevent relapses of WG in remission.[11] This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.

Plasma exchange

Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function.[47] Additionally, plasma exchange, along with aggressive immunotherapy, may be helpful in DAH.[61] PLEX is used with daily oral cyclophosphamide and glucocorticoids, usually pulse methylprednisolone.

Plasma exchange has not been shown to improve overall survival rates or relapse rates but has been associated with improved long-term survival, free of hemodialysis.[62, 63]

Jayne et al reported improved renal outcomes in adults with Wegener granulomatosis or microscopic polyangiitis with severe renal failure (creatinine >5.8 mg/dL) who were treated with plasma exchange, when compared with intravenous methylprednisolone.[63] The patients in this multicenter European trial were also treated with oral prednisone and oral cyclophosphamide at the time of enrollment.

The proposed mechanism of action of plasma exchange in AAV includes removal of pathologic circulating factors (eg, ANCA, activated lymphocytes), removal of excess physiologic factors (eg, complement, coagulation factors, cytokines/chemokines), replacement of deficient plasma factors, and other, less well-defined mechanisms. Potential adverse events associated with plasma exchange include electrolyte disturbances, anaphylaxis, hemorrhage, and transfusion-related lung injury.[64]

Methotrexate

Localized, milder disease generally requires less aggressive therapy. A combination of methotrexate (oral or subcutaneous) and glucocorticoids can be considered as a less-toxic alternative to cyclophosphamide for the induction of remission of non–organ-threatening or non–life-threatening WG.[47]

Methotrexate (20-25 mg/wk, oral or subcutaneous) can be used in patients with normal renal function. It may take longer to reach remission with methotrexate than with cyclophosphamide, but methotrexate has been shown to be equal to cyclophosphamide in terms of its capacity to induce remission in early AAV.[65] Daily folic acid 1 mg/day is recommended to lessen some of the adverse effects of methotrexate.

Azathioprine for induction of remission has not been shown to be effective.[2]

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Remission Maintenance

Once induction of remission has occurred, maintenance of remission should be continued for at least 18 months, often longer. Agents that can be used in remission maintenance include azathioprine, methotrexate, and leflunomide.[47] Long-term oral cyclophosphamide has been used for remission maintenance but results in significant toxicity, making it unattractive.

Azathioprine

Azathioprine has been proven inferior to cyclophosphamide during the induction phase of treatment. However, as shown by the CYCAZAREM (Cyclophosphamide Versus Azathioprine During Remission in ANCA-Associated Vasculitis) trial, azathioprine (2 mg/kg/day) is safer and as effective as cyclophosphamide in maintaining remission.[66] Azathioprine impairs leukocyte proliferation by inhibiting purine synthesis. It results in somewhat higher relapse rates than cyclophosphamide, especially if the patient is still PR3-ANCA–positive at the time of the switch from cyclophosphamide to azathioprine.[66, 67, 68]

Study data have raised the question as to whether the induction treatment phase can be shortened to 3 months with transition from cyclophosphamide to azathioprine. The European Vasculitis Study Group analyzed a group of 144 patients with ANCA-associated vasculitis (Wegener granulomatosis and microscopic polyangiitis) who achieved remission with induction therapy of prednisolone and cyclophosphamide (2 mg/kg/day) for 3 months.

After a 3-month induction phase, patients were randomized to cyclophosphamide (1.5 mg/kg/day) or azathioprine (2 mg/kg/day). Remission rates and adverse effects were similar in both groups. The authors concluded that once remission is achieved with a 3-month course of prednisolone and cyclophosphamide, patients can be safely switched from cyclophosphamide to azathioprine to reduce the exposure to cyclophosphamide.

Methotrexate

Methotrexate (20-25 mg weekly, oral or subcutaneous) has been used for the maintenance of remission if the serum creatinine level is less than 1.5 mg/dL. Methotrexate has been shown to be similar to azathioprine in terms of adverse effects, efficacy in maintaining remission, and rates of relapse.[69] The rate of relapse with methotrexate ranges from 37-58%.[70, 71, 72, 73]

Leflunomide

Leflunomide (20-30 mg/day) is as effective as methotrexate, but it is associated with more adverse effects.[74] Leflunomide targets T cells by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase and thus limits pyrimidine synthesis. It is used in the treatment of rheumatoid arthritis. Leflunomide is metabolized by the liver and thus may be used in patients with renal insufficiency.

Because leflunomide has been reported to be associated with increased peripheral neuropathy symptoms, physicians should be aware that the development of neurologic symptoms could represent either a disease flare or an adverse medication effect.[41]

Other considerations

The glucocorticoid dose should be tapered to prednisone 10mg/day (or less) during remission. The dose can be tapered gradually after 6-18 months, depending on the patient’s response.

The addition of TMP-SMZ (800/160 mg twice daily) to standard maintenance therapy may reduce the rate of relapse in WG.[75]

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Alternative or Promising Therapies

Intravenous immunoglobulin

IVIG may be effective by interfering with ANCAs and thus inhibiting ANCA-mediated neutrophil activation.[76] Good results were reported in a study of 22 patients with AAV given IVIG as an adjunct to immunosuppressants and/or glucocorticoids.[77]

Mycophenolate mofetil

Mycophenolate mofetil (MMF) (2 g/day) is a derivative of the fungus Penicillium stoloniferum that, similar to azathioprine, limits purine synthesis. MMF is primarily used for immunosuppression in transplant patients and suppresses B and T cells. Because of its favorable side-effect profile and clinical potency, MMF is being increasingly used in the management of systemic connective-tissue disorders and is typically used in combination with prednisone.

A study of microscopic polyangiitis, an MPO-ANCA ̶ associated vasculitis, suggested that MMF may be an alternative to cyclophosphamide in mild-to-moderate microscopic polyangiitis.[78] MMF has been used in small series of refractory WG cases, for both induction and maintenance, with varying responses.[79, 80]

Nowack et al reported a good outcome in a study using MMF during the maintenance phase of treatment in 11 adult patients with ANCA-associated systemic vasculitis (9 patients with WG, 2 patients with microscopic polyangiitis).[81] Patients were started on a regimen of MMF and low-dose oral corticosteroids after a 14-week induction period with steroids and oral cyclophosphamide. Outcome was assessed only to 15 months but was very good. Only 1 patient relapsed 14 months into the maintenance treatment phase. MMF was well tolerated at a dose of 2 g/day, with minimal adverse effects.

Joy et al evaluated MMF in patients with non–life-threatening recurrent or cyclophosphamide-resistant ANCA (+) small-vessel vasculitis.[79] A 24-week treatment period in conjunction with corticosteroids resulted in a marked reduction in disease activity as assessed by the Birmingham Vasculitis Activity Scoring system. Thus, MMF may be useful in this setting to avoid recurrent treatment with alkylating agents.

However, a European Vasculitis Study Group trial (IMPROVE, International Mycophenolate Mofetil to Reduce Outbreaks of Vasculitides) reported that MMF was less effective than azathioprine in the maintenance of remission of AAV.[82] Further studies are needed.

Etanercept

Etanercept is a dimeric, recombinant human fusion protein with 2 soluble p75 tumor necrosis factor ̶ alpha (TNF-α) receptors linked to the Fc region of human IgG1. The initial pilot study showed good response when etanercept was added to standard therapy.[83]

The larger Wegener Granulomatosis Etanercept Trial (WGET), which subsequently assessed the efficacy of etanercept in the treatment of WG, suggested that etanercept does not improve AAV relapses and likely contributes to increased risk of infection and malignancy. Etanercept or placebo was added to standard therapy (corticosteroids plus cyclophosphamide or methotrexate). No improvement was found in the primary endpoint of sustained remission; moreover, more solid cancers were found in the etanercept group.[9] Additionally, the combination of anti-TNF therapy with an alkylating agent (ie, cyclophosphamide) may increase risk of solid tumors.

Infliximab

Infliximab is a chimeric monoclonal antibody to TNF-α that consists of murine antigen recognition sites bound to human Fc regions. The results in various studies and/or case reports have been mixed, so it is not currently possible to comment on the efficacy of infliximab.[84, 85] The safety of infliximab therapy in patients with WG, similar to the results in trials with etanercept, seems to be the limiting factor, as there were increased serious infections in the infliximab group.[86] Further studies are needed.

15-Deoxyspergualin

The drug 15-deoxyspergualin (0.5 mg/kg/day subcutaneous or intravenous) is a synthetic derivative of spergualin, a protein from Bacillus laterosporus that is capable of preventing T-cell and B-cell maturation. The medication is licensed in Japan for recurrent kidney transplant rejection. In addition, 15-desoxyspergualin has been used with some success in refractory WG cases and in patients with contraindications to cytotoxic therapy.[87, 88, 89] It may offer a safer alternative to cyclophosphamide for induction therapy but is not yet supported for routine clinical use.[85]

Antithymocyte globulins

Antithymocyte globulins are polyclonal antibodies targeted against T-lymphocyte antigens. Infusion of antithymocyte globulin causes a deep, rapid depletion of T lymphocytes. It has been investigated for use in severe refractory WG.[90] However, severe adverse effects, including death, may occur. Thus, antithymocyte globulin’s use is not clinically supported.[76, 85]

Alemtuzumab

Anti-CD52 therapy (alemtuzumab) is a humanized monoclonal antibody to CD52 that selectively depletes lymphocyte and macrophage populations. Its use in WG is considered experimental.[91]

Abatacept

Abatacept is a soluble, cytotoxic T-lymphocyte Ag-4 immunoglobulin that binds CD28, in that way inhibiting T-cell activation. Abatacept has been used with some success to prevent disease progression in an animal model of crescentic glomerulonephritis.[92]

Stem cell transplantation

Hematopoietic stem cell transplant evidence is limited.[85]

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Summary of Treatments

Induction of remission in severe or generalized Wegener granulomatosis

Cyclophosphamide (EITHER oral OR intravenous dosing):

  • Oral dosing - 2 mg/kg/day (max 200 mg/day); adjust dose as needed for elderly age or renal insufficiency; also adjust dose as needed to keep white blood cells (WBCs) >3.5 and/or absolute neutrophil count (ANC) >1.5; should be taken in the morning with forced dieresis and empty bladder before bedtime
  • Intravenous (pulse) dosing - 15 mg/kg every 2 weeks times 3, then every 3 weeks
  • Given with high-dose glucocorticoids (see below)
  • Typically given for 3-6 months, until significant improvement in disease activity or remission
  • Recommended IV dosing of mesna is equal to 20% (weight/weight) of the IV cyclophosphamide dose, divided into 3 equal doses. The first dose of IV mesna is administered 15-30 minutes prior to IV cyclophosphamide. The 2 remaining doses are then given 4 hours and 8 hours following IV cyclophosphamide. Peak urinary concentrations with IV mesna dosing occur in 1 hour.[49]
  • Dose of oral mesna should be equal to 40% of the cyclophosphamide doses (oral or IV), based on a 50% oral bioavailability, and divided into 3 equal doses. The first dose of oral mesna should be given 2 hours before cyclophosphamide (oral or IV). The second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing. The bioavailability is not affected by food intake, and peak urinary concentrations occur in 3 hours.[49]
  • Pneumocystis (carinii) jiroveci pneumonia prophylaxis recommended
  • Required laboratory monitoring - CBC, creatinine (Cr), liver function tests (LFTs), urinalysis (UA), +/- urine cytology

Rituximab:

  • 375 mg/m2 weekly times 4
  • Given with high-dose glucocorticoids (see below)
  • Pneumocystis (carinii) jiroveci pneumonia prophylaxis recommended
  • Required laboratory monitoring - CBC, Cr, LFTs

Glucocorticoids:

  • Severe disease, consider pulse methylprednisolone 500-1000 mg intravenous daily times 3 days
  • Otherwise recommend prednisone 1 mg/kg/day for at least 1 month, followed by taper (doses should not be reduced to less than 15 mg/day within the first 3 months; slowly taper to maintenance dose of 10 mg/day or less during remission
  • Recommend baseline evaluation of bone mineral density
  • Recommend daily calcium and vitamin D supplementation
  • Recommend consideration of bisphosphonate therapy to prevent glucocorticoid-induced osteoporosis, depending on renal function

Induction of remission in localized or milder WG (ie, non-organ- or non-life-threatening disease)

Methotrexate:

  • 20-25 mg weekly, oral or subcutaneous
  • Must have normal renal function (ie, Cr < 1.5mg/dL)
  • Given with folic acid 1mg/day to lessen some adverse effects
  • Required laboratory monitoring - CBC, Cr, LFTs

Glucocorticoids:

  • See above
  • Likely pulse methylprednisolone not needed
  • Reasonable to consider faster taper than in severe or generalized WG
  • Recommend baseline evaluation of bone mineral density
  • Recommend daily calcium and vitamin D supplementation
  • Recommend consideration of bisphosphonate therapy to prevent glucocorticoid-induced osteoporosis

Maintenance of remission

Immunosuppressive medications (azathioprine, methotrexate or leflunomide) that replace cyclophosphamide or rituximab and should be continued for at least 18mo. Glucocorticoids should also be continued in remission.

Azathioprine:

  • 2 mg/kg/day
  • Required laboratory monitoring - CBC, Cr, LFTs
  • Consider checking thiopurine methyltransferase (TPMT) enzyme activity before starting

Methotrexate:

  • 20-25 mg weekly, oral or subcutaneous
  • Must have normal renal function (ie, Cr < 1.5mg/dL)
  • Required laboratory monitoring - CBC, Cr, LFTs

Leflunomide:

  • 20-30 mg/day
  • Required laboratory monitoring - CBC, Cr, LFTs

Glucocorticoids:

  • Prednisone should be tapered to 10 mg/day or less during remission.
  • The prednisone dose can be tapered gradually after 6-18mo depending on the patient’s response
  • Recommend baseline evaluation of bone mineral density
  • Recommend daily calcium and vitamin D supplementation
  • Recommend consideration of bisphosphonate therapy to prevent glucocorticoid-induced osteoporosis, depending on renal function

Adjunctive therapies

  • TMP-SMZ 160/800 mg 3 times weekly (typically Mondays, Wednesdays, Fridays) for Pneumocystis (carinii) jiroveci pneumonia prophylaxis; may be continued during remission to help prevent flares
  • Plasma exchange for patients with rapidly progressive renal disease (Cr >5.65mg/dL) and/or diffuse alveolar hemorrhage
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Surgical Indications

The natural history of Wegener granulomatosis (WG) is such that inflammation may lead to tissue necrosis and damage to the nose, subglottic areas, trachea, and bronchi caused by fibrosis. Surgical intervention can be considered in these situations.

For subglottic stenosis, which occurs in approximately 20% of patients with WG, treatment is typically unresponsive to systemic immunosuppressive therapy. Surgical interventions are usually required in these patients, including laser treatment, mechanical dilation with injection of long-acting corticosteroids, or resection of the stenotic area with reanastomosis. Dilation-injection therapy is performed most commonly, with good effects.[93, 94]

Other surgical considerations in WG are as follows:

  • Saddle nose deformity - Can be surgically repaired by an otolaryngologist or plastic surgeon, typically using rib cartilage; not usually considered an option until the patient has been in remission for a significant period
  • Obstruction of the nasal lacrimal ducts - Can be corrected surgically
  • Recurrent middle ear infections due to dysfunction of the eustachian tube - Can be treated by introducing ventilating tubes through the tympanic membranes
  • Stenosis of major bronchi - May be treated with dilatation or with silastic stents; intralesional injections of corticosteroids may also be considered
  • Visual impairment caused by stretching or compression of the optic nerve – Urgent surgical decompression of the orbit may be necessary

Renal transplant is an option in patients with renal failure. Glomerulonephritis usually does not affect the transplanted kidney.

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Outpatient Care

Patients with Wegener granulomatosis (WG) should have regularly scheduled follow-up visits with the physician primarily responsible for managing his or her disease. Since recurrences occur frequently, patients should be monitored closely clinically, with radiologic studies and laboratory examinations that include renal function, ESR, ANCA levels, and urinalysis. Visits should also focus on untoward effects of therapeutic agents.

Infection is a major contributor to morbidity and mortality in WG and often mimics a disease flare or manifests as atypical features caused by treatment-related immunosuppression. Providers should have a low threshold for treating suspicious symptoms with antibiotics.

Prophylaxis against Pneumocystis pneumonia is essential while patients are receiving conventional therapy for WG. This can be achieved with TMP-SMZ single-strength once daily or double-strength formulation three times per week. Dapsone 100mg daily can be used in sulfa-allergic patients.

All patients who require long-term glucocorticoid treatment are at risk for glucocorticoid-induced osteoporosis. Baseline bone mineral density should be evaluated. If the density is normal, patients should take daily calcium and vitamin D supplementation. If the density is diminished at baseline or if long-term glucocorticoid use is anticipated, bisphosphonate therapy should be added. Risk versus benefit of bisphosphonate therapy should be discussed with women of childbearing age.

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Contributor Information and Disclosures
Author

Patricia J Papadopoulos, MD  Key Clinical Faculty, Rheumatology Service, Department of Medicine, Walter Reed National Military Medical Center; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences

Patricia J Papadopoulos, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology

Disclosure: Merck Ownership interest Own stock

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Robert John O'Brian, MD Staff Rheumatologist, National Naval Medical Center

Robert John O'Brian, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Girish D Sharma, MD Associate Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center

Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Debbie S Toder, MD Director of Cystic Fibrosis Center, Department of Pediatrics, Division of Pulmonary Medicine, Assistant Professor, Wayne State University and Children's Hospital of Michigan

Debbie S Toder, MD is a member of the following medical societies: American Academy of Pediatrics and American Thoracic Society

Disclosure: Nothing to disclose.

Rudolph P Valentini, MD Director of Dialysis Services, Associate Professor, Department of Pediatrics, Division of Pediatric Nephrology, Wayne State University; Vice Chief of Staff, Children's Hospital of Michigan

Rudolph P Valentini, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government. Additionally, this publication does not imply the Federal or Department of Defense endorsement of any product.

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Lung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Lung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Saddle nose deformity in a 26-year-old man with Wegener granulomatosis. Image courtesy of P. Papadopoulos, MD.
Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis.
C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive. Image courtesy of K. Orr, MD.
P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.
Goodpasture syndrome: Linear deposition of immunoglobulin G and C3 are observed on a renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.
Extensive thickening of the maxillary sinuses in a patient with Wegener granulomatosis. The patient also had intermittent epistaxis.
Wegener granulomatosis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.
This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of Wegener granulomatosis.
Bilateral cavitating nodules in a patient with Wegener granulomatosis.
Wegener granulomatosis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.
Diffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 1. Image courtesy of the US Government.
Diffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 2. Image courtesy of the US Government.
Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7mg/dL and no residual pulmonary disease.
An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.
A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).
 
 
 
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