Granulomatosis with Polyangiitis (GPA, formerly Wegener Granulomatosis) Treatment & Management

The mainstay of treatment for granulomatosis with polyangiitis (GPA) is a combination of corticosteroids and cytotoxic agents. Treatment should be tailored to appropriately treat GPA manifestations while minimizing long-term toxicities to the patient. Untreated generalized or severe GPA typically carries a dismal prognosis, with up to 90% of patients dying within 2 years, usually of respiratory or renal failure. Even non-renal GPA carries a mortality rate of up to 40%. ^[42]

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 GPA 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 GPA depend on the severity and activity of disease. The European Vasculitis Study Group recommends grading disease severity of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) into the following 5 categories ^[6] :

• 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 - Kidney or other organ-threatening disease, serum creatinine level less than 5.6 mg/dL
• Severe - Kidney 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

GPA 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 GPA.

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 (eg, prednisone 1 mg/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 GPA for years. ^[6]

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 (GPA 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 2 mg/kg/day (not to exceed 200 mg/day). Pulsed (intravenous) cyclophosphamide (15 mg/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. ^[62]  One study found a trend toward higher relapse rates with pulsed cyclophosphamide later in the maintenance phase of treatment, but this study was not intended to detect a difference between the 2 groups; more studies are needed. ^{[6, 62]}

Cyclophosphamide doses are reduced as needed for kidney function and age. Cyclophosphamide therapy is usually continued until significant disease improvement or remission occurs, typically 3-6 months. The patient is then transitioned to a less toxic medication for maintenance of remission. Cyclophosphamide toxicity includes the following:

• 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
• 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. ^[63]

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. ^[63]

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). ^[64] 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. ^[65]

Rituximab

Rituximab combined with high-dose glucocorticoids represents an alternative to cyclophosphamide for induction of remission in GPA; it is the first treatment ever approved by the FDA for AAV. ^[66]

The evidence for this approval came from the Stone et al's RAVE (Rituximab in Antineutrophil Cytoplasmic Antibody ̶ Associated Vasculitis) trial. ^[19] 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 treatment 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 GPA with kidney 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. ^[20] Both studies confirmed the efficacy and superiority of rituximab over cyclophosphamide in reducing ANCA positivity. ^[67]

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. ^{[68, 69]}

The long-term safety of rituximab in GPA was documented in a phase IV, open-label, prospective 4-year observational registry of adult patients with GPA or microscopic polyangiitis. The safety profile of rituximab proved consistent with that of shorter-term treatment and with rituximab's known safety profile in other autoimmune diseases. ^[70]

Adverse effects associated with rituximab include infusion reactions, mucocutaneous reactions, increased risk of infections (including opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy. In rheumatoid arthritis patients, the presence of hypogammaglobulinemia before rituximab treatment seemed to be more closely associated with risk of infection than hypogammaglobulinemia  during or after rituximab. ^[71] 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. ^[72] Late-onset neutropenia has also been associated with rituximab in GPA; appropriate laboratory monitoring should be considered. ^[73]

Corticosteroids

Historically, glucocorticoid monotherapy prolonged median survival in GPA by only 7.5 months. There have been no clinical trials evaluating the role 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. ^[6]

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. ^[74] Further studies are still needed to define the best regimen with respect to glucocorticoid dose and duration of therapy. ^[41]

Glucocorticoids are usually given orally. If a rapid response is needed, however, 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. ^[6] Methods to prevent glucocorticoid-induced osteoporosis should be followed.

In the PEXIVAS trial, which compared two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (GPA or microscopic polyangiitis), a reduced-dose regimen proved noninferior to a standard-dose regimen with respect to the risk of death or end-stage kidney disease, and resulted in a lower risk of serious infections in the first year of treatment. The reduced-dose regimen in PEXIVAS provides approximately 55% of the standard-dose regimen over the first 6 months. ^[5]  American College of Rheumatology/Vasculitis Foundation guidelines conditionally recommend a reduced-dose glucocorticoid regimen over a standard-dose regimen for remission induction in GPA and microscopic polyangiitis. ^[7]

Trimethoprim-sulfamethoxazole

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

Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide and corticosteroids (particularly high-dose corticosteroids). Typically, trimethopim-sulfamethoxazole (TMP-SMZ) at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100 mg 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 GPA in remission. ^[18] This effect 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. ^[6] Additionally, plasma exchange, along with aggressive immunotherapy, may be helpful in patients with diffuse alveolar hemorrhage. ^[75] Plasma exchange 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. ^{[76, 77]}

Jayne et al reported improved renal outcomes in adults with GPA or microscopic polyangiitis with severe kidney failure (creatinine >5.8 mg/dL) who were treated with plasma exchange, when compared with intravenous methylprednisolone. ^[77] 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. ^[78]

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 GPA. ^[6]

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. ^[79] 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]

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, rituximab, and leflunomide. ^{[6, 80]} 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. ^[8] 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. ^{[8, 81, 82]}

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 (GPA 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. ^[83] For example, 10-year follow-up of 97 patients with GPA who were enrolled in the WEGENT trial showed no significant difference in overall survival and relapse-free survival rates between the azathioprine and methotrexate arms. ^[84] The rate of relapse with methotrexate ranges from 37-58%. ^{[85, 86, 87, 88]}

Leflunomide

Leflunomide (20-30 mg/day) is as effective as methotrexate, but it is associated with more adverse effects. ^[9] 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 kidney 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. ^[50]

Rituximab

A retrospective review evaluated the relapse rate and tolerance of rituximab maintenance therapy in 28 AAV patients (four with microscopic polyangiitis, 24 with GPA). The patients received a median of four 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. ^{[72, 80]}

Rituximab proved more effective than azathioprine in the prospective Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial. MAINRITSAN included 115 patients with AAV (87 of them with GPA) who had achieved remission with conventional cyclophosphamide-based therapy. At month 28, major relapse had occurred in 29% of patients in the azathioprine group and in 5% of patients in the rituximab group (P=0.002). Severe adverse events occurred at similar frequencies in the two groups. ^[89]

In MAINRITSAN, rituximab was given at a fixed 500-mg intravenous dose on days 0 and 14 after randomization, and then at months 6, 12, and 18. Azathioprine was given at a dosage of 2 mg/kg/day for 12 months, and then 1.5 mg/kg/day for 6 months and 1 mg/kg/day for 4 months. In addition, prednisone was further tapered to a low dose (approximately 5 mg daily), which was maintained for at least 18 months after randomization. ^[89]

On continuation of MAINRITSAN, rituximab maintained its superiority over azathioprine. At month 60, the major relapse-free survival rates were 49.4% with azathioprine and 71.9% with rituximab (P=0.003); minor and major relapse-free survival rates were 37.2% and 57.9%, respectively, (P=0.012), and overall survival rates were 93.0% and 100%, respectively (P=0.045). Cumulative glucocorticoid use was comparable. ^[90]

MAINRITSAN2 found that patients receiving maintenance rituximab on an individually tailored regimen received fewer rituximab infusions, but had did not experience significantly higher rates of relapse, than those receiving fixed-dose therapy. Patients in the tailored-therapy arm received a 500-mg rituximab infusion at randomization, with rituximab reinfusion only when CD19+ B-lymphocytes or ANCA had reappeared or the ANCA titer rose markedly based on testing every 3 months until month 18. Patients in the fixed-dose arm received a 500-mg rituximab infusion on days 0 and 14, then 6, 12, and 18 months after the first infusion. ^[91]

Other considerations

The glucocorticoid dose should be tapered to prednisone 10 mg/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 GPA. ^[92]

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) may be effective by interfering with ANCAs and thus inhibiting ANCA-mediated neutrophil activation. ^[93] Good results were reported in a study of 22 patients with AAV given IVIG as an adjunct to immunosuppressants and/or glucocorticoids. ^[94]

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, a myeloperoxidase (MPO)-ANCA ̶ associated vasculitis, suggested that MMF may be an alternative to cyclophosphamide in mild-to-moderate microscopic polyangiitis. ^[95] MMF has been used in small series of refractory GPA cases, for both induction and maintenance, with varying responses. ^{[96, 97]}

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 GPA, 2 patients with microscopic polyangiitis). ^[98] 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. ^[96] 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. ^[99] 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. ^[100]

The larger Wegener Granulomatosis Etanercept Trial (WGET), which subsequently assessed the efficacy of etanercept in the treatment of GPA, 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. ^[16] 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 tumor necrosis factor–α (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. ^{[101, 102]} The safety of infliximab therapy in patients with GPA, similar to the results in trials with etanercept, seems to be the limiting factor, as there were increased serious infections in the infliximab group. ^[103] 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 GPA cases and in patients with contraindications to cytotoxic therapy. ^{[104, 105, 106]} It may offer a safer alternative to cyclophosphamide for induction therapy but is not yet supported for routine clinical use. ^[102]

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 GPA. ^[107] However, severe adverse effects, including death, may occur. Thus, antithymocyte globulin’s use is not clinically supported. ^{[93, 102]}

Alemtuzumab

Anti-CD52 therapy (alemtuzumab) is a humanized monoclonal antibody to CD52 that selectively depletes lymphocyte and macrophage populations. Its use in GPA is considered experimental. ^[108]

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. ^[109]

Stem cell transplantation

Hematopoietic stem cell transplant evidence is limited. ^[102]

Induction of remission in severe or generalized GPA

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) >1Njiroveci pneumonia prophylaxis recommended

• Required labor atory 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)

• Pneumocystisjiroveci 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 GPA (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 GPA

• 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

See the list below:

• TMP-SMZ 160/800 mg 3 times weekly (typically Mondays, Wednesdays, Fridays) for Pneumocystisjiroveci 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

The natural history of GPA 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 GPA, treatment is typically unresponsive to systemic immunosuppressive therapy. However, rituximab may be beneficial. ^[110]

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. ^{[111, 112]} Patients typically require multiple procedures, but almost all can achieve prolonged airway patency. ^[113]

Other surgical considerations in GPA are as follows:

• Saddle nose deformity - Can be surgically repaired by an otolaryngologist or plastic surgeon, typically using split-calvarial bone  or rib cartilage grafts ^[114] ; 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 transplantation is an option in patients with end-stage renal disease due to GPA, and can significantly decrease all-cause mortality, largely by reducing the risk of death from cardiovsacular disease. ^[115] Glomerulonephritis usually does not affect the transplanted kidney.

Patients with GPA 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 kidney function, erythrocyte sedimentatoin rate (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 GPA 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 GPA. This can be achieved with TMP-SMZ single-strength once daily or double-strength formulation three times per week. Dapsone 100 mg 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.