Granulomatosis with polyangiitis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief:Amandeep Singh M.D.[2]Cafer Zorkun, M.D., Ph.D. [3]
Overview
Granulomatosis with polyangiitis is a form of vasculitis that affects the lungs, kidneys and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term immune suppression. Granulomatosis with polyangiitis is part of a larger group of vasculitic syndromes, all of which feature the presence of an abnormal type of circulating antibody termed ANCAs (antineutrophil cytoplasmic antibodies) that affect small and medium-size blood vessels. Apart from granulomatosis with polyangiitis, this category includes Churg-Strauss syndrome and microscopic polyangiitis. Although granulomatosis with polyangiitis affects small and medium-sized vessels, it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several hypothesizes have been made to identify possible links associated with this disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction. The genetic component of granulomatosis with polyangiitis is not fully known. However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis. Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.The incidence of granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year. The prevalence in the United States is 3 per 100,000 persons. The mean age of diagnosis of granulomatosis with polyangiitis is 58 years. The disease most commonly presents in patients that are either middle aged or elderly. The mean age of diagnosis in children is between the ages of 4 to 17. Males are more commonly affected with granulomatosis with polyangiitis. The overall male to female ratio is approximately 1.2 to 1. In children females are more commonly seen with the disease. Granulomatosis with polyangiitis typically affects Caucasians. Common risk factors in the development of granulomatosis with polyangitis (GPA) are age group of 40-65 years and presence of variant HLA-DPB1*0401 with ANCA. If left untreated, granulomatosis with polyangiitis may progress to morbidity and mortality. Complications of granulomatosis with polyangiitis include, vision loss, subglottic manifestations, hearing loss, renal failure and increased infections with prolonged immunosuppressant therapy. Determination of ANCAs can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. Cytoplasmic staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with granulomatosis with polyangiitis. If the patient has renal failure or cutaneous vasculitis, these are the most logical organs to obtain a biopsy from. Rarely, thoracoscopic lung biopsy is required. The symptomatology depends on the system involved. The disease involve ear, nose and throat and cause symptoms of sinusitis, nasal crusting, otitis media, otorrhea, epistaxis. Patients with history of lung involvement presents with hoarseness, Cough, Dyspnea, Stridor, Hemoptysis. Renal involvement presents with cloudy urine with hematuria, edema.The important physical exam findings are ulcerations, palpable purpura and subcutaneous nodules in the skin; conjunctivitis, uveitis, sinusitis, purulent exudate from nares, saddle nose deformity, reduced hearing in the head and neck; pleuritic chest pain and signs of atelectasis in lung examination; and signs of mononeuritis multiplex on neural exam. Laboratory findings consistent with the diagnosis of granulomatosis with polyangiitis include, anti-neutrophil cytoplasmic antibody, elevated blood urea nitrogen, elevated creatinine serum, erythrocyte sedimentation rate, C reactive protein, proteinuria, microscopic hematuria, and red blood casts. An x-ray may be helpful in the diagnosis of granulomatosis with polyangiitis. Findings on an x-ray suggestive of granulomatosis with polyangiitis include 4 patterns as multiple nodules with or without cavitation; pulmonary hemorrhage as airspace opacities; reticulations and nodules and wedge-like consolidation in periphery. In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes glucocorticoids, cyclophosphamide, Rituximab, Methotrexate, Azathioprine and when needed with plasmapheresis.
Historical Perspective
Granulomatosis with polyangiitis was first discovered by Peter McBride, a Scottish otolaryngologist, in 1897 when describing a case of rapid destruction of the nose and face. In 1907, Heinz Karl Ernst Klinger added information regarding the anatomical pathology of the disease. However, the full presentation of the disease was later discovered in 2 separate reports in 1936 and 1939 by a German pathologist, Friedrich Wegener. The disease was called pathergic granulomatosis. This led to some confusion with lethal midline granuloma and lymphomatoid granulomatosis. In 1954, it was called as Wegener's granulomatosis, named after a German pathologist, Friedrich Wegener who described the disease in his detailed report published in 1936. As of November 7, 2010, the name Wegener's granulomatosis has been changed to Granulomatosis with polyangiitis by the American College of Rheumatology, American Society of Nephrology, and the European League Against Rheumatism. The association between ANCA and Granulomatosis with polyangiitis was made in 1982.
Classification
According to the American College of Rheumatology (ACR) Granulomatosis with polyangiitis is classified using 4 criteria.
Pathophysiology
The pathogenesis of granulomatosis with polyangiitis is currently unknown. However, several hypothesizes have been made to identify possible links associated with this disease, such as bacterial infections, failure of B-cells to downregulate, and T cell dysfunction. The genetic component of granulomatosis with polyangiitis is not fully known. However, there seems to be a strong correlation between HLA-DPB1 and HLA-DPB2 with granulomatosis with polyangiitis.
Differentiating Xyz from Other Diseases
Granulomatosis with polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.
Epidemiology and Demographics
The incidence of granulomatosis with polyangiitis in children ranges form 0.03 to 3.2 per 100,000 per year. The prevalence in the United States is 3 per 100,000 persons. The mean age of diagnosis of granulomatosis with polyangiitis is 58 years. The disease most commonly presents in patients that are either middle aged or elderly. The mean age of diagnosis in children is between the ages of 4 to 17. Males are more commonly affected with granulomatosis with polyangiitis. The overall male to female ratio is approximately 1.2 to 1. In children females are more commonly seen with the disease. Granulomatosis with polyangiitis typically affects Caucasians.
Risk Factors
Common risk factors in the development of granulomatosis with polyangitis (GPA) are age group of 40-65 years and presence of variant HLA-DPB1*0401 with ANCA.
Natural History, Complications, and Prognosis
If left untreated, granulomatosis with polyangiitis may progress to morbidity and mortality. Complications of granulomatosis with polyangiitis include, vision loss, subglottic manifestations, hearing loss, renal failure and increased infections with prolonged immunosuppressant therapy.
Diagnosis
Diagnostic Study of Choice
Determination of ANCAs can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. Cytoplasmic staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with granulomatosis with polyangiitis. If the patient has renal failure or cutaneous vasculitis, these are the most logical organs to obtain a biopsy from. Rarely, thoracoscopic lung biopsy is required.
History and Symptoms
The symptomatology depends on the system involved. The disease involve ear, nose and throat and cause symptoms of sinusitis, nasal crusting, otitis media, Otorrhea, epistaxis. Patients with history of lung involvement presents with hoarseness, cough, dyspnea, stridor, hemoptysis. Renal involvement presents with cloudy urine with hematuria, edema.
Physical Examination
The important physical exam findings are ulcerations, palpable purpura and subcutaneous nodules in the skin; conjunctivitis, uveitis, sinusitis, purulent exudate from nares, saddle nose deformity, reduced hearing in the head and neck; pleuritic chest pain and signs of atelectasis in lung examination; and signs of mononeuritis multiplex on neural exam.
Laboratory Findings
Laboratory findings consistent with the diagnosis of granulomatosis with polyangiitis include, anti-neutrophil cytoplasmic antibody, elevated blood urea nitrogen, elevated creatinine serum, erythrocyte sedimentation rate, C reactive protein, proteinuria, microscopic hematuria, and red blood casts.
X-ray
An x-ray may be helpful in the diagnosis of granulomatosis with polyangiitis. Findings on an x-ray suggestive of granulomatosis with polyangiitis include 4 patterns as multiple nodules with or without cavitation; pulmonary hemorrhage as airspace opacities; reticulations and nodules and wedge-like consolidation in periphery.
CT scan
On chest CT scan, granulomatosis with polyangiitis is characterized by multiple lung nodules, lung consolidations and ground-glass opacities.
Treatment
Medical Therapy
In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic medicine. It includes glucocorticoids, cyclophosphamide, Rituximab, Methotrexate, Azathioprine and when needed with plasmapheresis.