Medication Summary

Rituximab in combination with glucocorticoids is favored over cyclophosphamide for remission inductionin patients with active, severe granulomatosis with polyangitis (GPA). However, the use of cyclophosphamide with lower cumulative doses than previous regimens, which results in less toxicity, remains an option and should be guided by the patient's preferences and values, according to 2021 American College of Rheumatology/Vasculitis Foundation guidelines.^[7]

Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide or rituximab and corticosteroids (particularly high-dose corticosteroids) and for at least 6 months following these medications. Typically, trimethoprim-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.

Class Summary

Corticosteroids have immunosuppressant and anti-inflammatory action used to reduce activity of systemic vasculitis. High-dose methylprednisolone is used to halt pulmonary hemorrhage and reverse crescentic glomerulonephritis.

Prednisone

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Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders and vasculitis. By reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, it may decrease inflammation.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

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Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Class Summary

These agents have improved the prognosis of GPA. Cyclophosphamide is initiated with high-dose corticosteroids but is continued for at least 3-6 months (until there is significant disease improvement and/or remission).

Cyclophosphamide

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Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, cyclophosphamide's mechanism of action of active metabolites may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells. Complete blood cell (CBC) counts should be checked every 1-2 weeks while taking daily oral cyclophosphamide and at days 10 and 14 of each intravenous cyclophosphamide pulse to monitor for bone marrow suppression.

Class Summary

These agents are useful in patients who experience significant adverse effects with cyclophosphamide induction therapy, as induction therapy in mild to moderate disease, and, most commonly, for maintenance of remission. The immunosuppressive drug is generally started at a lower dose and gradually increased over time. The onset of effect generally takes several weeks; therefore, the use of these drugs in induction therapy for severe disease is not advised.

Azathioprine (Imuran, Azasan)

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Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting the synthesis of DNA, ribonucleic acid (RNA), and proteins. Its effects may decrease the proliferation of immune cells and result in lower autoimmune activity.

Methotrexate (Rheumatrex, Trexall)

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Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. This agent ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Class Summary

Rituximab gained FDA approval for GPA in adults in 2011 and for children aged 2 years or older in 2019. It is an alternative to cyclophosphamide for induction of remission.

Rituximab (Rituxan)

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Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. It is indicated in combination with glucocorticoids for treatment of adult and pediatric patients aged 2 years or older with granulomatosis with polyangiitis (GPA; Wegener granulomatosis) or microscopic polyangiitis (MPA).

Class Summary

Trimethoprim-sulfamethoxazole (TMP-SMZ) is recommended for prophylaxis against Pjiroveci pneumonia, typically as a daily dose, with single-strength dosing, or a dose of 3 times weekly with double-strength dosing. It is continued for as long as the patient is on immunosuppressive therapy. Data show that TMP-SMZ may be beneficial in decreasing relapses during maintenance therapy of GPA. Twice-daily dosing should not be combined with methotrexate, if possible, due to the risk of pancytopenia.

Additionally, in adults, TMP-SMZ has been shown to prevent relapses of GPA in remission.^[18]This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.

Trimethoprim-sulfamethoxazole (Septra DS, Bactrim, Bactrim DS)

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TMP-SMZ inhibits the bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, inhibiting folic acid synthesis. This results in the inhibition of bacterial growth. The antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Questions

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Media Gallery

Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.
Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.
Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.
Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.
Granulomatosis with polyangiitis. 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 granulomatosis with polyangiitis.
Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.
Granulomatosis with polyangiitis. 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 granulomatosis with polyangiitis. Image courtesy of the US Government.
Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. 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).
Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.
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.

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Author

Christopher L Tracy, MD Associate Program Director, Rheumatology Fellowship Program, Walter Reed National Military Medical Center

Christopher L Tracy, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Patricia J Papadopoulos, MD Staff Rheumatologist, MultiCare Rheumatology Specialists

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

Disclosure: Own small amount of stock for: Amazon, Johnson & Johnson, Proctor & Gamble, Cigna Corp, Pfizer.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; 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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Acknowledgements

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