Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a form of granulomatous necrotizing vasculitis of small and medium-sized vessels. It can be restricted to the the respiratory tract, or may involve additional organs, primarily the kidneys, and it most commonly occurs in adults around 40 years of age, with slight male predilection. Diagnosis is achieved through biopsy, and treatment includes corticosteroids and immunosuppressants.
Symptoms of GPA may appear abruptly, but an insidious onset is documented as well, and the full symptomatology usually takes years to develop. Several organs may be affected, but the most common symptoms are related to the upper and lower respiratory tract . Sinusitis, often chronic in nature, epistaxis, nasal chondritis that is often accompanied by pain and swelling, and may lead to septal perforation. Secondary infections by Staphylococcus aureus are reported, and in severe inflammatory reactions, subglottic stenosis can occur, leading to symptoms such as hoarseness, dyspnea, stridor, wheezing and severe pain. Symptoms of lower respiratory tract occur as a result of inflammation of the bronchial tree, and include chest pain, dyspnea, development of pneumonia, and productive cough. In severe cases, potentially life-threatening alveolar hemorrhage may occur.
The kidneys are most commonly affected in addition to the respiratory tract, with the development of glomerulonephritis that may be rapidly progressive, and symptoms include hematuria, hypertension and edema.
Apart from the respiratory tract and the kidneys, other organs may be affected:
The diagnosis of GPA comprises a full workup, including laboratory tests, imaging studies, and often tissue biopsy to confirm the diagnosis.
Laboratory tests should include a complete blood count (CBC), and findings may include eosinophilia, thrombocytosis and anemia may be present. Serum albumin and total protein content are decreased, while creatinine values are increased, as a result of poor kidney function. Urinalysis may reveal proteinuria, as well as dysmorphic RBCs. Inflammatory markers, such as ESR and CRP are elevated.
Serologic detection of ANCA antibodies should be performed in all patients with clinical criteria, and in addition to ANCA, anti-PR3 antibodies should be evaluated as well. Positive ANCAs are usually highly suggestive of GPA, but patients with bacterial endocarditis, tuberculosis, as well as other inflammatory conditions, may have positive ANCAs. For these reasons, imaging studies, and eventual tissue biopsy is necessary to confirm the disease.
A plain chest X-ray usually reveals multiple pulmonary nodules that may be cavitating, as well as parenchymal infiltration that may be bilateral. X-ray of the sinuses may also reveal chronic inflammation. CT scan may provide a more specific view of the lungs and sinuses, and is preferred in establishing the lesions .
Tissue biopsy should be performed in patients with clear diagnostic criteria, and biopsy should be performed on affected organs, which are the lungs and the kidneys in the majority of cases. In addition to biopsy and microscopic examination, culture of the material should be obtained, to exclude possible infections (such as tuberculosis).
The choice of treatment depends on the severity of the disease at the time of diagnosis, and organ-specific involvement.
The recommended regimen for patients with severe, and possibly life-threatening manifestations, such as rapidly progressive glomerulonephritis and alveolar hemorrhage, is the administration of high-dose corticosteroids together with immunosuppressive therapy, such as cyclophosphamide. Corticosteroid therapy usually lasts for several months, until patients reach remission, and in the next few years, the goal of therapy is to gradually eliminate the use of corticosteroids, as well as the use of less potent immunosuppressants. Treatment options include methylprednisolone 15mg/kg or 1g q24h in the first few days, together with oral prednisone 1mg/kg q24h for several weeks. Then, the dose is slowly tapered, usually by 10mg per week until the patients reach the dose of 40mg q24h. Then the dose is reduced by 5mg every 14 days until it reached 10mg q24h, and eventually reducing the dose by 1mg each month until the cessation of therapy is indicated. However, changes in therapy may occur in the case of relapses, or if patients develop complications. Cyclophosphamide is a potent immunosuppressant, and is used as a first-line therapy together with corticosteroids in severe cases of GPA, in doses of 2mg/kg q24h per os, for at least 3 months, or more, until remission is reached. Because this drug may cause severe leukopenia, WBC counts must be monitored, while Pneumocystis jirovecii pneumonia may also be a potentially adverse effect, which is why patients are often given trimethoprim-sulfamethoxazole in prophylactic regimens. Rituximab, which is a form of monoclonal antibody targeted against B cell activity, has shown good results in patients with relapsing disease .
In milder cases, corticosteroid therapy is used together with methotrexate or azathioprine, which are less potent immunosuppressants, and they are used to maintain remission . Careful monitoring of WBC count should be monitored in these patients as well.
In most severe cases, when kidney function cannot be maintained with therapy and even dialysis, kidney transplantation is indicated, and the risk of relapse is significantly reduced, due to concomitant use of potent immunosuppressive drugs.
Prognosis of patients with GPA depends on the time of diagnosis, and the magnitude of the disease (organ involvement and damage). Renal involvement has shown to be a valid indicator of outcome, as 5-year survival rates are 100% for patients without renal disease, compared to 70% for patients with glomerulonephritis .
The outcome is quite good if this disorder is treated promptly, with the majority of patients going into long-term remission. Renal function may be significantly improved with intensive immunosuppressive therapy, and more than half of patients may be dialysis-independent . However, relapses are common in patients with GPA, and more than 50% of patients develop relapses within the first several years of treatment.
Overall 10-year survival rates range between 75-88%, and poor outcomes are related to older age, multiorgan involvement, and delayed therapy.
The cause of GPA is not completely understood, but genetic, immune, as well as infectious factors have been proposed in the pathogenesis of this disorder .
The genetic basis of the disease is supported by findings that associate major histocompatibility complex (MHC) abnormalities, notably HLA-DP, and genes encoding anti-PR3 antibodies, alpha-1 antitrypsin, and ANCA antibodies . Cell-mediated hypersensitivity, supported by the presence of granulomas and rapid remission of symptoms and the disease to immunosuppressive therapy, has been hypothesized as a factor in the development of this disorder as well. Infectious agents have been implied in the pathogenesis of this disorder, including chronic nasal carriage of Staphylococcus aureus , but without solid conclusions.
The rates of GPA vary across the globe, and prevalence rates in the United States are estimated to be 3 per 100,000 individuals, although rates may be higher . Prevalence rates in Nordic countries include 160 per million , but in general, this disease develops in approximately 1 in 25,000 individuals.
The onset of GPA most commonly occurs around age 40, and it is seen in all ethnic groups, although Caucasians comprise the majority of cases. This disorder affects males more commonly than females, for unknown reasons.
The hallmark of GPA is granulomatous inflammation of both tissues and blood vessels. Typically, granulomas form with epitheloid and giant cells, while the presence of various leukocytes, including neutrophils, lymphocytes, and eosinophils, has been observed. Granulomatous inflammation is accompanied by tissue and vessel necrosis, which can result in the formation of ulcerative lesions in the nasopharynx and nose, while severe patterns of necrosis may result in the development of cavitary lesions in the lungs.
Anti-neutrophilic cytoplasmic antibodies (ANCA) are present in the vast majority of patients with GPA , and their involvement implicated activation of the immune system in the pathogenesis of the disorder. The role of B cells in the development of this diseases, including antibody and cytokine production, as well as antigen presentation, has been reported . On the other hand, T-cell involvement is the presumable mechanism of granuloma formation, and autoreactive PR3-specific cells have been described.
Kidney damage occurs due to focal glomerular necrosis as a result of intense inflammation, while more severe lesions lead to crescentic glomerulonephritis, in which diffuse necrosis and proliferation of parietal cells occur. These events may progressively lead to kidney failure if not treated early with immunosuppressive therapy.
Prevention of GPA is currently not achieved, but recognizing the disease in its early stages may provide a significantly better outcome for patients, which is why a timely diagnosis and prompt treatment is essential for patients suffering from this disease.
GPA is a form of necrotizing vasculitis, usually consisting of three principal components: necrotizing granulomatous inflammation (most commonly in the upper or lower respiratory tract), granulomatous vasculitis of small and medium-sized vessels, including arteries, arterioles, capillaries and venules; and kidney disease (focal glomerulonephritis, often with necrosis and crescent formation) . The cause and pathogenesis of this disorder presumably include autoimmune mechanisms that lead to formation of granulomas consisting of lymphocytes, plasma cells, neutrophils, and eosinophils, and inflammation targets both tissues and vessels. Prevalence rates vary across the world, but averages about 1 in 30,000 individuals, with males being affected more commonly than women. The onset of disease is most commonly around 40 years of age, and Caucasian race is affected in the majority of cases. Clinical presentation depends on the site of disease, but the principal target is the upper respiratory tract including the sinuses and nasopharynx. Chronic sinusitis, epistaxis, and secondary infections due to Staphylococcus aureus, are commonly encountered signs and symptoms, while hoarseness, dyspnea, and wheezing may occur in severe forms of disease in which subglottic stenosis develops. In addition to both upper and lower respiratory tract, the ears, eyes, heart, kidneys, musculoskeletal and nervous system can be affected, depending on the severity of the disease. The course of disease may be abrupt or it may take a prolonged period of time to develop, up to several years, but in more severe forms with multiorgan involvement the onset is acute, and may pose significant morbidity, which is why prompt identification and treatment must be conducted. The diagnosis of GPA is achieved through laboratory tests, such as evaluation of inflammatory markers (sedimentation rate, C-reactive protein), proteins, albumin, and urinalysis, while anti-neutrophil cytoplasmic antibodies (c-ANCA), together with anti-proteinase-3 (PR-3) antibodies and clinical findings are highly suggestive of GPA. A definite diagnosis is achieved by obtaining a biopsy of the affected tissue, and is most commonly performed on the lungs and kidneys. If patients are timely treated, the majority will enter complete remission, but relapses are not uncommon, particularly in patients who stopped treatment. Treatment principles include immediate treatment with corticosteroids, together with cyclophosphamide (in severe forms) or methotrexate (for milder forms), and in most severe cases, dialysis and kidney transplantation is indicated. If left untreated, the disease is fatal in the majority of patients.
Granulomatosis with polyangiitis (GPA) is a disease which results in inflammation of small blood vessels and tissues. The exact cause of this disorder is not known, but it presumably involves autoimmune mechanisms, which lead to inflammation and formation of granulomas, which are masses containing blood cells, inflammatory cells, and can cause significant damage in organs in which they develop. The onset of this disease is most commonly around 40 years of age, and occurs in males more commonly than females, for unknown reasons. The principal organs that are targeted in this disease are the lungs and the upper respiratory tract, with symptoms such as nose bleeding, pain and recurrent secondary infection of the sinuses, cough, and difficulty breathing are commonly reported. In addition to the lungs, the kidneys are also affected in a substantial number of patients, and manifests as the presence of blood in urine (hematuria) and increased blood pressure. Many other organs may be affected, most notably the nervous system and the eyes, but the heart, musculoskeletal system, and the skin may be affected in patients suffering from GPA. The diagnosis is achieved by performing blood tests that confirm the presence of inflammation in the body, evaluation of kidney function, while a vast majority of patients test positive for anti-neutrophil cytoplasmic antibodies (ANCAs), which are one of the main features of this disease. Chest and sinus X-rays, as well as computed tomography (CT scan) can be helpful in assessing the damage caused by inflammatory events, while a definite diagnosis is obtained by performing a biopsy, which includes obtaining a sample of the affected organ. In most cases, either the lungs or the kidneys are favorable sites for obtaining biopsy material. Because the prognosis is not good in patients with untreated disease, prompt diagnosis and treatment is necessary, as the majority of patients enter remission with good treatment strategies. Treatment includes the use of drugs that suppress inflammation, including corticosteroids and drugs such as methotrexate and cyclophosphamide, although they should be used with caution, as they can have significant adverse effects. Overall, survival rates are very high with proper therapy, but relapses of the disease may occur.