GPA granulomatosis with polyangitis Wegener

Granulomatosis with Polyangiitis

Epidemiology and Pathophysiology

Granulomatosis with polyangiitis (GPA) is the most common ANCA-associated vasculitis, with an incidence of 7 to 12/million/year. It is more prevalent in Nordic countries and White persons. Typical age of onset is between 45 and 60 years.

Clinical Manifestations and Diagnosis

GPA affects the upper and lower airways, kidneys, eyes, and ears. At least 50% of patients have constitutional symptoms. More than 95% of patients are ANCA positive, overwhelmingly (>90%) directed against proteinase 3 (anti-PR3 antibodies; c-ANCA).

GPA has two forms: systemic and localized. Systemic is more common, involves major organs, and is anti-PR3 positive. Localized has more granulomatous inflammation, has less vasculitis, and is less likely to be anti-PR3 positive. Patients in the localized group are more likely to be younger and female; have mainly ear, nose, and throat involvement; and be more prone to relapse.

The entire triad (upper airway disease, lower respiratory tract disease, and glomerulonephritis) may not be present initially.  Upper respiratory tract symptoms include epistaxis, sinusitis, otitis media, and hoarseness.  The associated granulomatous inflammation can lead to oral ulcers (as seen in this patient), nasal septal perforation, saddle nose deformity, and tracheal stenosis.  Lung involvement may lead to pulmonary nodules, cavitary defects, infiltrates, or pleural effusion.  Renal involvement occurs in approximately 70% of patients and is characterized by rapidly progressive glomerulonephritis.  Constitutional symptoms such as fatigue, fever, and weight loss are common.  Ocular involvement also occurs frequently.

In the setting of a classic clinical presentation and positive c-ANCA/anti-PR3, diagnosis of GPA is straightforward. However, because of significant risks of treatment, biopsy of involved tissue is usually recommended. Histopathology of most tissues demonstrates pauci-immune necrotizing granulomatous vasculitis; pauci-immune necrotizing glomerulonephritis without granulomas is seen on kidney biopsy.

Anti–glomerular basement membrane (GBM) disease (also known as Goodpasture disease) presents with hemoptysis and glomerulonephritis; however, a markedly elevated sedimentation rate is unusual.  Constitutional symptoms (eg, malaise, weight loss, fever, arthralgia) are not typically present, and their presence is more suggestive of vasculitis.  In addition, chest x-ray in anti-GBM disease reveals patchy basilar infiltrates, not the cavitation seen in this patient.

Management

For induction of remission in severe organ-threatening or life-threatening disease, treatment of GPA consists of high-dose glucocorticoids plus cyclophosphamide or rituximab.

Initial immunosuppressive therapy typically consists of cyclophosphamide and prednisone, with plasma exchange added in cases, such as this one, with organ-threatening disease, such as pulmonary hemorrhage or deteriorating renal function.

Maintenance therapy includes azathioprine, mycophenolate mofetil, or rituximab for at least 12 to 24 months after stable remission has been achieved. Glucocorticoids alone are insufficient to control GPA. Patients with nonsevere forms of GPA (such as arthropathy or upper airway disease) without organ-threatening disease can be treated with glucocorticoids plus either methotrexate or mycophenolate mofetil; such patients should be carefully monitored for treatment failure or the development of renal or other organ-threatening disease, necessitating the more aggressive regimen. Using these approaches, GPA mortality has declined from 90% to around 10%.

The RAVE (Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis) trial demonstrated that rituximab is superior to cyclophosphamide in the subgroup of patients with relapse. In this study, remission without prednisone at 6 months was observed in 67% of rituximab-treated patients compared with 42% of cyclophosphamide patients (P = 0.01; NNT = 4). Rituximab was also as effective as cyclophosphamide in the treatment of patients with kidney disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.

In trials of etanercept treatment for GPA, patients manifested an increased risk for the development of solid malignancies, especially if they had previously been treated with cytotoxic drugs. Therefore, etanercept is not considered first-line treatment for GPA.

Corticosteroids such as prednisone are not considered adequate single-drug maintenance therapy in GPA. The addition of corticosteroids to another agent used for maintenance therapy is not recommended, as trials suggest that it results in a greater number of infections but not a decreased risk of GPA relapse.

Mycophenolate mofetil appears inferior to azathioprine for maintenance therapy after remission has been achieved in GPA, and it offers no advantages over azathioprine in terms of the frequency of adverse medication events.

Cyclophosphamide and azathioprine appear to be equally efficacious for GPA maintenance therapy; however, concerns regarding an increased risk of secondary malignancy when cyclophosphamide is used make the drug a less optimal choice than azathioprine for maintenance therapy.

Methotrexate is inadequate as induction therapy for severe disease; it can be used alone either as maintenance therapy after induction, or for mild and limited disease.

Relapses are common (>50% 5 years after initial remission) and may respond better to rituximab than to cyclophosphamide.

This patient has evidence of a non–organand non–life-threatening relapse of his granulomatosis with polyangiitis (GPA) after discontinuation of his maintenance therapy. In this situation, it is most appropriate to restart his prior rituximab maintenance therapy, usually in combination with a short course of glucocorticoids. In addition to rituximab, other common agents that could be used for GPA maintenance monotherapy include azathioprine, methotrexate, and mycophenolate.

While cyclophosphamide is useful as an induction agent in combination with glucocorticoids, the toxicity of the drug makes it a poor choice for maintenance therapy, and this patient does not have an organor life-threatening relapse that requires reinduction therapy that could include cyclophosphamide. If his relapse were associated with organor life-threatening disease, or if a non–organand non–life-threatening relapse occurred during ongoing maintenance therapy and did not respond to higher doses of the maintenance agent, full reinduction therapy with glucocorticoids and either cyclophosphamide or rituximab would have been indicated.

Both cyclosporine and leflunomide have immunomodulatory effects; however, neither has an established role in the treatment of GPA.

Kidney failure and infection are the main causes of mortality.1

Footnotes

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