Granulomatosis with Polyangiitis (GPA)

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Granulomatosis with polyangiitis (GPA), (previously Wegener's Granulomatosis) is an autoimmune disorder characterized by granulomatous necrotizing vasculitis that typically affects small and/or medium sized blood vessels in the orbit, respiratory tract (sinuses, nose, throat, lungs), and kidneys.

Disease Entity

Vasculitis, the inflammation of blood vessels, can lead to necrosis of the vessel and resultant poor organ perfusion. Eventually, this inflammation can lead to the vessel becoming completely occluded. Different diseases affect different sized blood vessels. Chronic inflammation can lead to the formation of granulomas, and ultimately, organ necrosis. Granulomatosis with polyangiitis (GPA) is an autoimmune disorder that typically affects small and/or medium sized blood vessels (arterioles, venules, capillaries, and small arteries) in the orbit, sinuses, nose, throat, lungs, and kidneys. The skin, joints, and nerves can also be affected, but this is less commonly reported. Patients can present with any number of these symptoms across a spectrum of severity. GPA belongs to a group of diseases that are associated with antineutrophil cytoplasmic antibody (ANCA). Microscopic polyangiitis (MPA) and Churg-Strauss Syndrome (CSS) also belong to this family of diseases, though they are less common than GPA.[1]

Disease History

GPA was first described by Heintz Klinger in 1931 but was formally identified by Dr. Friedrich Wegener in 1936 as an official syndrome, thus it was originally named “Wegener’s granulomatosis”.[2] Early study of this disease process determined three criteria were required for diagnosis:

  1. Granuloma formation in the upper respiratory tract
  2. Necrotizing vasculitis
  3. Glomerulonephritis


Over time, this diagnostic criteria has evolved, and GPA has been grouped with other small-medium vessel diseases. See Diagnosis below for more detailed information.

Etiology

The cause of GPA is unknown, but it is thought to be autoimmune. There may be environmental contributing factors such as dust, exposure to silica, smoke, or chemicals.[3] Certain medications may also contribute to the development of the disease. Hydralazine, phenytoin, sulfasalazine, antithyroid medication, and allopurinol have been potentially implicated.[3]

Of the three ANCA-associated vasculitides, GPA is the most common.[1] The annual incidence is about 8–10 cases per million and the prevalence of GPA is estimated to be 3 cases per 100,000 people.[4] These numbers vary by continent but GPA is typically more common in colder climates. Men and women are affected equally. Patients are usually caucasian and in their 40s-50s but GPA can occur in any age or race. Ocular disease, one of the earliest possible disease manifestations, is seen in at least 15% of cases of GPA, and is much less frequently associated with MPA or CSS.[1]

General Pathology

GPA involves the partial, and possibly complete, occlusion of blood vessels which results in the formation of microabscesses that develop into granulomas over time, ultimately leading to necrosis, thus a necrotizing granulomatous vasculitis. Unlike in tuberculosis or sarcoidosis, the granulomas in GPA are poorly defined and consist of giant cells surrounded by lymphocytes, plasma cells, and dendritic cells.[5] The presence of these cells damages the submucosa and can eventually penetrate surrounding cartilage and bone. This can manifest clinically as boney erosion and collapse of the nasal bridge, often referred to as a ‘saddle-nose’ deformity.

Pathologically there can be seen the triad of 1) vasculitis, 2) granulomatous inflammation +/- giant cells, 3) tissue necrosis. Clinically usually only 1 or 2 of these features are seen on extra-pulmonary biopsy. Biopsy of orbital tissues may lack frank necrotizing vasculitis on histopathologic exam and therefore make diagnosis difficult without respiratory or renal involvmenet.[6]

Pathophysiology

The cause of GPA has not been fully identified. Formation of the granulomas in GPA begins with the formation of neutrophilic microabscesses. While the initial cause is not completely understood, it is thought that autoantibody development to myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA) is key in the development of GPA. In persistent GPA, humoral immunity, specifically CD4+ T cells produce IL-17 and IL-23 which contribute to organ injury, particularly in the kidneys.[7] Microbes such as S. aureus could also be involved in the disease process via superantigen stimulation of B and T cells. Molecular mimicry by S. aureus is thought to lead to the development of PR3-ANCA.[7]

Diagnosis

History

Granulomatosis with polyangiitis (GPA) can present in many different ways. GPA may be broadly categorized into a limited form and a systemic form. The limited form is defined by the absence of renal involvement and is largely isolated to the upper and lower respiratory tracts. The systemic form may involve the kidneys as well as other organs outside of the respiratory tract. There is no gender predilection for the disease, although women are more likely to have the limited form of the disease. Patients are typically in their fourth or fifth decade at the time of diagnosis, and very rarely occur in those under the age of 18.[8]

Physical examination

The physical examination of a patient in whom GPA is suspected should include careful evaluation of the following elements:

  1. Detailed examination of the external eye and orbit, noting for any asymmetry, ptosis, proptosis, or signs of orbital inflammation.
  2. Detailed ophthalmologic examination evaluating visual acuity, pupils (looking for a relative afferent defect), intraocular pressures, and motility examination (looking for ocular misalignment and/or evidence of cranial neuropathies)
  3. Visual fields testing.
  4. A slit lamp, and dilated fundus exam, taking careful note of any signs of eyelid involvement, inflammation in the sclera and conjunctiva, a careful corneal examination for signs of ulceration or keratitis, and any swelling or changes in the optic nerve.

Signs - Ocular Manifestations

Ophthalmic features of Granulomatosis with Polyangiitis can occur in up to 60% of patients with the disease. These manifestations can affect nearly every structure of the eye ranging from the orbit and eyelids, to the retina and optic nerve. Presentations can vary dramatically between patients, and are usually the result of vasculitis of the small vessels supplying the orbit and its structures. Ocular inflammation can lead to severe ocular morbidity resulting in vision loss in up to 8% of patients, but has been reported as high as 37% of patients with inadequately treated disease. In roughly 15% of patients, ocular symptoms can be the first signs of the disease.[3][9][10]

Scleritis is one of the most common and early appearing presentations of GPA and can occur in roughly 50% of patients. This condition typically presents with deep boring pain and erythematous tender eyes which are seen as areas of capillary nonperfusion on ocular examination. Nodular scleritis can also occur in which is depicted in the image below. Episcleritis is also fairly common and runs a milder course which is generally self limiting, although topical glucocorticoids may reduce symptom duration.

Keratitis, especially peripheral ulcerative keratitis, is also a common presentation of GPA. This typically presents with pronounced ocular pain, tearing, photophobia, and reduced vision with corneal stromal infiltration and invading vessels from the limbus being present on examination.

The orbit is commonly involved in GPA often due to contiguous disease in the nasal and paranasal sinuses. Orbital presentations include diplopia, swelling, epiphora, and proptosis due to orbital granuloma. Roughly 20-50% of patients can develop severe visual loss if orbital manifestations are present.[8]

Proptosis is the most common presentation of orbital GPA, and because it is often present concomitantly with respiratory and renal disease, these manifestations together are highly suggestive of the disease.­­ Due to orbital inflammation, patients can present with diplopia as well as pain and restriction with ocular movements. Orbital GPA can also involve the optic nerve resulting in painless optic swelling and ischemic optic neuropathy. This may eventually progress to involve the ocular cranial nerves resulting in painful ophthalmoplegia.

Uveitis may be present with GPA but it is rare and only typically involves roughly 3% of patients. Retinal and choroidal involvement is also relatively uncommon, being seen in 5-12% of patients. Retinal involvement can also be present with manifestations ranging from isolated cotton wool spots or intra-retinal hemorrhages to branch or central retinal artery and vein occlusions. Retinal artery occlusion can also occur due to vasculitis and thrombus formation. Retinitis has been reported as frank retinal vasculitis, chorioretinitis, and macular edema, which can eventually develop neovascularization, vitreous hemorrhage, and neovascular glaucoma.[10]

Eyelid involvement can occur in GPA with a “yellow lid sign” resembling a florid xanthelasma concurrently with orbital inflammation which is especially characteristic of GPA. The conjunctiva are also commonly involved with roughly 16% of patients experiencing ulcerative and necrotic conjunctivitis.

Signs - Systemic Manifestations

Granulomatosis with polyangiitis has the capability to affect nearly any organ system, although the most commonly affected are the sinuses, respiratory tracts and kidneys. The clinical presentation, however, is often nonspecific with varying symptoms from arthralgias to sinusitis. The upper respiratory tract (sinuses, nose, ears, and trachea) is the most often involved system, with up to 85% of patients having disease, and 81% of patients having ENT findings as their initial symptoms. Chronic sinusitis unresponsive to treatment is the most common presentation, with most patients eventually developing lung disease as well.

Renal involvement occurs in 75% of patients with the disease and can present with symptoms of glomerulonephritis. Roughly 60% of patients have musculoskeletal symptoms such as arthralgias, fatigue, and malaise. Gastrointestinal manifestations can occur as well, with intestinal ulcerations involving both the large and small bowels.

EARS: Recurrent otitis media, decrease in hearing

EYES: (see ocular manifestations above) Inflammation throughout all levels of the eye: scleritis, uveitis, orbital pseudotumor - resultant proptosis, ocular pain, and/or vision loss

NOSE: Frequent epistaxis, nasal crusting, erosion and perforation of nasal septum (resultant "Saddle-nose deformity")

SINUSES: Chronic sinus inflammation with destruction of surrounding tissues

TRACHEA: Difficulty breathing due to subglottic stenosis (narrowing of windpipe below vocal cords) - can result in need for emergent tracheostomy

LUNGS: Lung infiltrates with pneumonia-like symptoms, hemoptysis

KIDNEY: Blood and/or protein in the urine due to inflammation (glomerulonephritis), and can result in kidney failure

Symptoms

Ocular symptoms can include eye pain, diplopia, decreased vision, decreased peripheral vision/ visual field, and redness. Systemic symptoms can include rhinitis, epistaxis, collapsed nasal septum, (aka "saddle-nose" deformity) hearing loss, hemoptysis, shortness of breath, joint pain, neuropathy

Clinical diagnosis

WGA should be suspected in any person who is between 64-75 years of age presenting with general symptoms of upper respiratory tract and pulmonary involvement as these are the most common symptoms. In GPA patients[11] pulmonary symptoms and systemic fever malaise weight loss, and myalgia. Upper respiratory symptoms can be sinus pain, nasal ulceration and epistaxis. Pulmonary involvement can manifest as cough, hemoptysis, and pleuritic chest pain. Renal involvement can manifest at presentation in up to 20% of patients as glomerulonephritis, although such cases have been reported as symptomatic and 77% of patients develop glomerular disease within 2 years of dz onset.[12] GPA can present in children under 18 with similar manifestations to the adult GPA, although there exists a female predominance.[13] The American college of Rheumatology has designated a diagnostic criteria for Wegener’s granulomatosis. It involves nasal or oral inflammation characterized by painful/painless oral ulcers, abnormal chest radiographs, urinary sediment with > 5 red blood cells per high power field or red cell casts, and granulomatous inflammation at biopsy with involvement of arterial or arterioles wall.[14][15] The presence of two out of four of these criteria is 88.2% and 92% sensitive and specific, respectively. Most recently the ACR has released a provisional criteria for GPA that is based on a 9 items scale with a score of more than five is needed for GPA classification[14]

American College of Rheumatology (ACR)

1990 classification criteria for ANCA-associated granulomatous vasculitis. Two or more of these criteria have a sensitivity of 88% and a specificity of 92%

Nasal or oral inflammation

  • Painful or painless oral ulcers
  • Purulent or bloody nasal discharge


Lungs (x-ray)

  • Nodules
  • Infiltrates
  • Cavities


Kidneys

  • Hematuria
  • Red cell casts


Biopsy showing granulomatous inflammation

  • Within arterial walls
  • In perivascular areas

Chapel Hill Consensus Conference (CHCC)

1992 Establishing the diagnosis of ANCA-associated granulomatous vasculitis requires:

  • A granulomatous inflammation involving the respiratory tract and
  • A vasculitis of small to medium-sized vessels

Diagnostic procedures

Biopsy findings

Clinical and imaging findings can guide the site of biopsy to confirm the diagnosis of GPA. Any affected organ can be a potential site for biopsy. Lung tissue is the most common biopsies organ. Renal and orbital biopsies have been documented as well in the setting of respective organ involvement.[8]

Lung biopsy is characterized by parenchymal necrosis as neutrophilic microabscesses or areas of visible necrosis surrounded by palisading histiocytes and giant cells and granulomatous inflammation accompanied with neutrophils, lymphocytes, plasma cells and eosinophils.[16]

Renal biopsy can show focal segmental necrotizing glomerulonephritis with proliferation of pauci-immune crescentic formation. It can be associated with microhematuria and proteinuria. [17]

Orbital histopathology can show fat disruption, characterized by fay fat necrosis with free vacuoles, lipid laden-macrophages, as well as giant cells. These findings were accompanied by active or pre-existing fibrosis. There also be granulomatous and acute inflammation with polymorphonuclear cells or eosinophils. Microabscesses were noted in some cases.[18]

Imaging findings

Chest radiograph: Chest X ray radiographs are usually the first imaging modality to suggest the diagnosis in the setting of upper airways (sinusitis, nasal mucosal ulcer, nasal granulomatous lesions, nasal bridge collapse, and subglottic or tracheal stenosis)[2][15] and lower respiratory tract involvement (cough, wheezing, hemoptysis, and stridor). Radiographic signs reported include nodules, mass lesions, or cavitation.[19] While Radiographs may be the first modality used, it fails to accurately capture the pattern and destruction of the pulmonary and thoracic pathology in a sufficient manner. (https://www.ncbi.nlm.nih.gov/pubmed/15741022)

CT: CT has greater sensitivity and specify for GPA findings.[15] Manifestations are similar to those present on radiographs, but since CT is more sensitive and specific, pulmonary involvement has been studied in greater detail using CT, which are described below. Nodules and masses: most common manifestation in 40-70% of pts. can be single or multiple and can range from millimeters to > 10 cm. Consolidations greater than 3 cm were considered masses. A study by Lorhrmann et al. analyzed CT findings in pts with GPA and found that nodules were bilateral in 70% of patients[20]/ Cavitation has been found in 22% of nodules greater than 2 cm. Cavities can get infected and will be characterized by air fluid levels.[21][20] Lesions greater than 2 cm and they tend to be thick walled with irregular margins. CT imaging can also show areas of consolidation and ground glass opacities in the setting of GPA as a result of alveolar hemorrhage, necrotic alveolar cellular infiltrate. Diffuse alveolar hemorrhage can occur in 10% of patients, and is characterized by bilateral and diffuse consolidation sparing the subpleural lung.[22] This can lead to interlobular septal thickening due to lymphatic’s congestion. These findings may mimic pneumonia, ARDS, TB, or pulmonary edema.

FDG PET/CT: F-fluorodeoxyglucose (FDG) tracer that marks glucose metabolism has been used to provide information regarding tissue metabolism in the setting of cancer and active inflammatory lesions and diseases. A case reports has documented extensive FDG uptake in nasal lung lesions on combined PET/CT. In this case, the anti proteinase 3 ANCA AB were negative at time of pulmonary lesions, but were elevated a year after, allowing a diagnosis 1 yr after. This indicates that FDG uptake on CT/PET scan and ANCA elevation are not mutually exclusive and can show early detection of PGA prior to ANCA elevations.[23] In addition, a study by Frary et al. has shown that FDG PET/CT scan is able to distinguish between actual GPA and concurring comorbidities such as cancer and infection. Diagnostic probability for FDG PET/CT with respect to comorbidity was 90% sensitive and 81% specific, positive predictive and negative predictive values were 75% and 93% respectively. In this study FDG PET/CT scan effectively rules our comorbidities correctly, except for a case of a UTI, which represents a limitation. However, this is an important finding as immunosuppressive therapy is a modality for treatment in GPA and is contraindicated in the setting of a comorbidity such as cancer or infection. This allows ruling out cancer and infection processes in patients with GPA.[19]

Laboratory test

Laboratory findings: One of the most common utilized tests in the diagnosis of GPA is antineutrophil cytoplasmic antibody (ANCA), specifically c -ANCA. ANCA testing has a high diagnostic utility for ANCA-associated vasculitis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPO), and eosinophilic granulomatosis. Antibodies reacting with myeloperoxidase (MPO) and proteinase 3 (PR3) generate specific immunofluorescence that is perinuclear and cytoplasmic, respectively.[24] Although 90% of patients with active disease are ANCA positive, 40% of patients with limited disease can be negative. In addition, p- ANCA (perinuclear) can be positive in GPA patients as well.[25] A meta analysis by Rao et al. has shown the pooled sensitivity and specificity of c-ANCA testing for GPA to be 66% and 98%, respectively.[26]

Measurement of c-ANCA can be done through the conventional antigen specific enzyme-linked immunosorbent assay (ELISA). Newer serological testing methods such as ELiA and Dotblot can provide rapid results, with excellent diagnostic values.[27]

Differential diagnosis

Differential diagnosis is broad due to the varied presentations of the disease. It can include other forms of vasculitis with ANCA association such as Curg Strauss and Microscopic polyangiitis, infections, malignancies, as well as granulomatous and autoimmune disorders.

Table 2. Differential diagnosis of GPA[28]
Other Vasculitides
  • Polyarteritis nodosa
  • Microscopic polyangiitis
  • Churg strauss syndrome
  • Henoch-Schonlein purpura
  • Mixed cryoglobulinemia
  • Goodpasture syndrome
  • Giant cell arteritis
Infections
  • Mycobacterial diseases
  • Fungal infections (histoplasmosis, blastomycosis, coccidiomycosis)
  • Streptococcal pneumonia with glomerulonephritis
Malignancies
  • Nasopharyngeal carcinoma
  • Hodgkin disease
  • Non-Hodgkin lymphoma
  • Angiocentric Lymphoma
  • Castleman disease
Granulomatous Disorders
  • Sarcoidosis
  • Berylliosis
Autoimmune disorders
  • Systemic Lupus Erythematosus
  • Rheumatoid arthritis

Management

The treatment regimen for Granulomatosis with Polyangiitis (GPA) varies based on numerous disease and patient factors and from physician to physician. In choosing treatment, it is advised that one first determines whether the patient has GPA which is life- or organ-threatening or not. After this determination, treatment should be based upon whether it is the initial presentation of the disease, a presentation of refractory disease, of relapsing disease, or if presentation is for maintenance of disease. In patients presenting for the first time with non-life- or organ-threatening GPA, treatment with glucocorticoids in combination with methotrexate is advised. Though cyclophosphamide may be preferred by some, methotrexate is a reasonable option if the disease is mild or if there is little renal involvement.[29] However, treatment with cyclophosphamide in place of methotrexate should be initiated if it is determined that the patient’s disease is more aggressive, if methotrexate is ineffective, or if proteinuria is of serious concern.[29] Alternatively, rituximab can be used in place of cyclophosphamide if there are indications that a patient cannot tolerate methotrexate or cyclophosphamide.[30][31][32] For patients with ocular manifestations of GPA, rituximab should be considered. In a recent study, rituximab was shown to effectively induce remission in treatment-refractory ocular manifestations of GPA.[33] Patients with ocular manifestations that are receiving rituximab should be monitored closely, as exacerbation of symptoms may occur.[34] IVIg has been considered as an alternative for patients with persistent ocular involvement, though there have been no conclusive results supporting or opposing its usage. In a single case, in which the patient had bilateral posterior scleritis and orbital inflammation, IVIg provided resolution of symptoms with no adverse effects.[35] Conversely, in a report of two patients with persistent ocular disease in the setting of controlled systemic disease, IVIg produced no significant improvements.[36] In patients presenting with severe or particularly aggressive disease, or with advanced renal involvement, combination therapy of glucocorticoids, cyclophosphamide or rituximab, and plasma exchange is advised.[37][38] If ocular or orbital involvement is prominent or of particular concern, glucocorticoids with rituximab may be a preferable treatment.[33] While glucocorticoids are a staple of induction therapy, there is currently no consensus regarding use of cyclophosphamide or rituximab and daily oral (DO) cyclophosphamide or pulsed intravenous (IV) cyclophosphamide. With respect to cyclophosphamide, there is similar efficacy between DO and IV administration in remission induction; however, pulsed IV cyclophosphamide may be therapeutically preferred, as it has been associated with lower rates of toxicity when compared to DO cyclophosphamide.[39][40][41] Despite similar efficacy in induction, DO cyclophosphamide is associated with lower relapse rates.[40][41] Between rituximab and cyclophosphamide, rituximab is equally efficacious in achieving and maintaining remission.[30][42][31][32] Furthermore, cyclophosphamide confers a significantly increased risk of malignancy, as well as the potential for infertility and alopecia. [43] Upon achieving a significant response (prior to remission) with the above treatment, one should begin tapering the dose of glucocorticoids. Duration of tapering should continue into remission, but ultimate duration should be tailored to the patient’s condition and with respect to their initial course of glucocorticoid treatment. For maintenance of remission, rituximab, azathioprine, and methotrexate are the recommended options. As cyclophosphamide is associated with significantly increased risk of malignancy, it is not recommended for maintenance.[43] Additionally, rituximab, azathioprine, and methotrexate have all been shown to be as effective as cyclophosphamide in maintaining remission.[30][29][44][42][31][45]Ultimately, which drug is chosen should be determined by the patient’s condition and potential contraindications.

Prognosis

Prior to immunosuppressive therapy, GPA was fatal with a mean survival rate of 5 months, when left untreated. With corticosteroid therapy alone, the mean survival increased to 12.5 months.[9] With the introduction and combination of cytotoxic drugs, however, prognosis has significantly improved. Traditional therapies of combination prednisone and cyclophosphamide result in > 90% of patients experiencing some symptomatic improvement and remission in 75%. There can be as high as a 50% relapse rate, however in patients that experience remission. Once the disease is controlled, it may be possible to transition patients to methotrexate, and there has been some evidence that trimethoprim-sulfamethoxazole may help prevent relapses.[9]

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