What is Wegener’s Granulomatosis, and what are the mortality implications?
The disorder called Wegener’s Granulomatosis was renamed in 2011 by the American College of Rheumatology and the European League against Rheumatism. They suggest the new name of granulomatosis with polyangiitis (GPA). GPA is a rare disease with an estimated prevalence in the United States of 3 per 100,000 people. The prevalence in the U.K. is estimated at 25 per 100,000. Ninety percent of cases occur in persons of northern European descent. There is a male to female ratio of approximately 1.5 to 1. Patients with GPA typically present between the ages of 35-55 years; however, it can occur at any age, even in children.
GPA is considered to be one of a family of small vessel vasculitides that are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). Other disorders in this group include microscopic polyangiitis (MPA) (including renal-limited vasculitis (RLV)) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). In addition to the ANCA association, these disorders share a similar renal histology characterized by a focal, crescentic glomerulonephritis.
The pathology of the vasculitis associated with MPA, GPA and EGPA is indistinguishable. EGPA may be associated with asthma and eosinophilia, is the least common of the ANCA-associated vasculitides and has a different prognosis. It is beyond the scope of this discussion.
People with GPA or MPA often present with fatigue, fever, weight loss and anorexia. Prior to the development of ANCA testing the diagnosis of Wegener’s was based on clinical criteria such as oral or nasal inflammation characterized by ulcers or bloody nasal discharge; abnormal chest x-ray showing granulomas (nodules) or cavitations; microscopic hematuria and proteinuria; and biopsy evidence of granulomatous inflammation of a small artery. The inflammation in the nose can destroy underlying supporting structures and result in a characteristic saddle deformity (Figure 1). In theory MPA is differentiated from GPA by the lack of granulomatosis; however, biopsies can miss areas of involvement. There is often overlap in clinical findings, and even progression from MPA to GPA has been noted.
Figure 1 - A characteristic saddle deformity of the nose can occur in up to 28% of people with GPA
About 90% of people with GPA will have detectable ANCA; for patients with MPA the number is closer to 70%. The subtype of ANCA can also be used to differentiate MPA from GPA. There are two primary neutrophil autoantigens; Myeloperoxidase (MPO) found in approximately 10% of ANCA positive patients and Proteinase 3 (PR3) found in 80-90% of ANCA positive patients. With cellular staining, the MPO antigens are found in a perinuclear pattern (P-ANCA), while PR3 antigens are in the cytosol (C-ANCA). PR3-ANCA is primarily associated with GPA, while MPO-ANCA is associated with MPA.
There is some evidence that the type of ANCA may be more predictive of outcome than the diagnosis of GPA or MPA. There are various guidelines of diagnostic criteria and algorithms to establish the diagnosis of GPA, and there is currently a large multi-national study to better define all of the vasculitides. But, elevated titres of PR3-ANCA and biopsy or typical imaging evidence of granulomatous inflammation on medium to small arteries are generally accepted as diagnostic of GPA.
Treatment & Prognosis
Early treatment is important for preventing organ damage and be life-saving, but skin, lung or kidney biopsy confirmation remains the most definitive method to establish the diagnosis.
The natural history of GPA was grim prior to the advent of effective therapy. The mean survival was approximately five months. Eighty-two percent died within the first year and a cumulative 90% died after two years. Treatment with corticosteroids only added a little more than a year to overall survival.
Current treatment of GPA is immunosuppressive therapy, initially cyclophosphamide or rituximab and glucocorticoids to induce remission. Patients with severe renal or pulmonary involvement at presentation may also undergo plasma exchange in addition to supportive therapy. Most remissions occur in two to six months, and studies have shown percent remission rates in the high 80s to low 90s.
Once in remission, maintenance therapy with azathioprine, methotrexate or rituximab may be continued for 12 to 24 months to prevent relapse. Relapse rates after first remission vary widely, possibly due to differences in treatment, time to remission and even differences in definitions of relapse. Different studies report relapse rates of 14-40%. In patients who have had multiple relapses maintenance therapy may be continued indefinitely.
While the mortality associated with GPA has improved greatly with recent therapy, it is still higher than the general population and the insured population. In a study of 273 patients with MPO and PR3 ANCA associated vasculitis in which 22% did not have renal involvement, the average age was 52 for those without renal involvement and 58 for those with renal involvement. They reported overall survival at 1, 5 and 10 years as 90%, 83% and 74%, respectively. They also found survival to be significantly better in those who were PR3 ANCA positive as opposed to MPO ANCA positive. Those patients with renal failure were at a significant survival disadvantage.
Another study of GPA compared to general population mortality found a Mortality Risk Ratio (MRR) of 3.8 (95% CI 2.6 to 5.6), MMR 4.0 for men (95% CI 2.5 to 6.3), MRR 3.4 for women (95% CI 1.6 to 7.2). Factors adversely affecting survival include older age and end organ damage (especially renal damage). Causes of death associated with GPA include infections, renal failure, pulmonary failure and cardiovascular disease.
There is also an increased risk of cancer with this disease. A study of the Swedish inpatient register linking Wegener’s to cancer for up to 26 years found a two-fold overall increased risk for cancer in the cohort. The increase was most pronounced for bladder cancer (SIR 4.8; 95% CI 2.6–8.1), squamous cell skin cancer (SIR 7.3; 95% CI 4.4–12), leukemias (SIR 5.7; 95% CI 2.3–12) and for malignant lymphomas (SIR 4.2; 95% CI 4.2–8.3).
Returning to the Case
Given the high rate of relapse of GPA it would be prudent to postpone for some time after the completion of treatment. When reconsidering, special attention should be paid to renal function, urinalysis and any end organ (lungs, heart) damage that may have occurred.
DeJoode A et al, “Renal Survival in Proteinase 3 and Myeloperoxidase ANCA-Associated Systemic Vasculitis”, Clin J Am Soc Nephrol 2013;8:1709–1717.
Mukhtyar C, et al. “Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force.” Ann Rheum Dis 2008;67:1004–1010.
Knight A, et al, “Cancer Incidence in a Population-Based Cohort of Patientswith Wegener’s Granulomatosis,” Int. J. Cancer 2002;100:82–85.
Hogan J, et al, “Is Newer Safer? Adverse Events Associated with First-Line Therapies for ANCA-Associated Vasculitis and Lupus Nephritis,” Clin J Am Soc Nephrol 2014;9:1657–1667.
Goceroglu A, et al, “ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse,” PLoS ONE 2016 11(12): e0165402, doi:10.1371/journal.pone.0165402
Up To Date: Last Accessed 3/1/2017.