Glomerular and Vascular Diseases: Systemic and renal vasculitis plus Membrane Disease
Does this patient have antineutrophil cytoplasmic antibody disease or antiglomerular basement membrane disease?
What tests to perform?
- How should patients with glomerular and vascular diseases be managed?
- What happens to patients with glomerular and vascular disease?
How to utilize team care?
Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this patient have antineutrophil cytoplasmic antibody disease or antiglomerular basement membrane disease?
Antineutrophil cytoplasmic antibody (ANCA) disease is associated with four clinical phenotypes: Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiits (MPA), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg Strauss syndrome) and pauci-immune necrotizing and crescentic glomerulonephritis without clinical extra-renal manifestations of vasculitis (NCGN- sometimes referred to as "renal limited disease"). ANCA diseases are clinical presentations of pauci immune small vessel vasculitis. Small vessel vasculitis is necrotizing inflammation of predominently venules and capillaries (especially glomerular capillaries) but arterioles, arteries and veins can be affected.
The major types of ANCA have specificity for proteinase 3 (PR3-ANCA) and for myeloperoxidase (MPO-ANCA) by enzyme-linked immunosorbent assay (ELISA). On indirect immunofluorescence microscopy assay PR3-ANCA usually causes cytoplasmic staining of neutrophils (c-ANCA) and MPO-ANCA usually causes perinuclear staining (p-ANCA). PR3 c-ANCA is classically associated with GPA and MPO p-ANCA with MPA but there is a significant ammount of cross over in these relationships. The majority of patients with pauci-immune NCGN have circulating MPO-ANCA. About 40% of patients with EGPA have circulating MPO-ANCA.
Manifestation of ANCA disease in the kidney is most frequently a glomerulonephritis, but focal papillary necrosis from medullary angiitis can occur. Glomerular lesions in ANCA disease begin with segmental fibrinoid necrosis that leads to crescent fromation. Immunoglobulins are typically not distinctly detected in vascular walls in ANCA disease.
Dermal leukocytoclastic venulitis and necrotizing inflammation of arteries in many tissues including but not limited to peripheral nerves, skeletal muscle, gut, liver, pancreas and skin are also features of ANCA disease. Lung involvement may be manifested as hemorrhagic alveolar capillaritis (in MPA, GPA and EGPA), or present as pulmonary nodules and cavities more characteristic of GPA. Patients with EGPA have severe reactive airway disease.
Patients with renal limited pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) present with hematuria, non-nephrotic proteinuria, and decreased GFR without other clinical signs or symptoms of systemic (extra-renal) vasculitis.
Microscopic polyangiitis is a systemic pauci immune small vessel vasculitis that can effect the kidneys, lungs, skin, nerves, muscles, joints, gastrointestinal tract or other systems in the body. MPA patients do not have evidence for necrotizing granulomatous inflammation or asthma.
Granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis) is characterized by granulomatous inflammation, usually in the upper or lower respiratory tract. These lesions can be documented as radiographic demonstration of cavitary lung nodules (in the absence of infection) or lytic bone lesions in the nasal septum. The granulomatous inflammation is often accompanied by a systemic pauci immune small vessel vasculitis that can affect the kidneys, lungs, skin, nerves, muscles, joints, gastrointestinal tract or other systems in the body. It is possible to have a granulomatous upper respiratory tract disease in the absence of systemic small vessel vasculitis referred to as respiratory granulomatosis. GPA is not classically accompanied by asthma.
Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg Strauss syndrome) is diagnosed in patients with peripheral eosinophila, asthma and systemic pauci immune small vessel vasculitis that can affect the kidneys, lungs, skin, nerves, muscles, joints, gastrointestinal tract or other systems in the body. Granulomatous inflammation in the respiratory tract can be present in EGPA.
Presenting symptoms of ANCA disease reflect the location of the vasculitis. Low grade fever, fatigue, weight loss, malaise, myalgias, migratory polyarthralgias are common presenting complaints. Scleritis, polychondritis, mucocutaneous ulcers, and vasculitic rash including palpable purpura, petechiae, ecchymosis, ulceration, nodules, livido reticularis and urticaria can also be seen. Patients with renal involvement of disease may note brown "tea-colored" or "cola-colored" urine, but the hematuria is frequently microscopic. Flank pain is uncommon and could signify necrosis from arteriolitis or renal vein thrombosis. Deep vein thrombosis occurs in about 10% of patients with ANCA disease.
Pulmonary involvement of disease may manifest as dyspnea, hemoptysis, chest pain or non productive cough. Sinus congestion, clear rhinorhea or bloody/crusty nasal discharge is common in MPA and GPA. Otitis media, hearing loss, tinnitus, mastoiditis, vertigo and loss of balance can also be manifestations of small vessel vasculitis.
GPA patients may have destruction of the cartilagenous nasal bridge and present with saddle nose deformity or subglottic stenosis with hoarseness, dyspnea and stridor. Peripheral neuropathies, mononeuritis multiplex, are common. Patients may have focal, usually asymetric parasthesias or weakness such as foot drop. Cranial nerve involvement may also occur, presenting with acute (unilateral) hearing loss or vertigo. Central nervous system vasculitis presenting as head aches or seizures have been reported. Gastrointestinal complaints ranging from nausea to severe abdominal pain are present in one third of patients as well. Rarely, patients present signs of gastrointestinal bleeding.
ANCA disease has a vast array of presentations. Emergent organ- or life-threatening presentations include dyspnea and stridor from subglottic stenosis, respiratory failure due to diffuse alveolar hemorrhage, central nervous system vasculitis, severe abdominal pain from bowel infarct, and renal failure.
Medications and drugs have been implicated in the development of ANCA disease in some patients. Of these, the association of propothiouracil (PTU) is the most frequently reported, and the best studied association with ANCA. Methimazole, carbimazole, hydralazine, minocycline, allopurinol, phenytoin, and penicillamine have all been reported as possibly linked to the development of ANCA disease. Cocaine and/or levamisole used for cutting cocaine have recently been implicated in the development of ANCA (among other autoantibodies) and vasculitis.
On physical exam, hypertension may or may not be present. Mild temperature elevation is not uncommon. Depending on respiratory status from pulmonary capillaritis tachypnea and tachycardia can be present. Scleral injection or "red eyes" can be noted. A slit lamp evaluation will likely be required for detailed evaluation of ocular vasculitis.
Examining the ears, nose, and throat is particularly important for ANCA disease. Cloudy tympanic membranes, inflamed ear canals, nasal septal perforation, saddle nose deformity, crusty/bloody nasal discharge, boggy nasal turbinates, hoarseness and stridor all can be components of the physical exam for a patient with upper respiratory tract manifestations of ANCA. Laryngoscopic exam is usually necessary for a complete assessment of vasculitis on this part of the body
Examination of the chest may reflect rhonchi or crackles (inspiratory or expiratory), wheezing, or dullness from pleural effusion. Patients with bronchial lesions or alveolar hemorrhage may present with hemoptysis. However, the absence of hemoptysis does not exclude the diagnosis of alveolar hemorrhage, which is best diagnosed by bronchoalveolar lavage in the proper clinical setting. Severe diffuse alveolar hemorrhage may be associated with bright red blood on the laryngoscopy or seen coming from the endotracheal tube in ventilated patients.
Rash including palpable purpura, petechiae, ecchymosis, ulceration, nodules, livido reticularis and urticaria can also be seen on the extremities or trunk. Abdominal tenderness or tenderness over muslces or joints, including frank arthritis with synovitis may be noted.Edema is somewhat rare but can be seen. Sensory or strength deficits, foot drop, and gait abnormalities may be present.
ANCA disease can be differentiated from other forms of systemic vasculitis. Takayasu's arteritis and giant cell arteritis fall into the category of large vessel vasculitis with reduced pulses, headache, blindness, deafness, tongue dysfunction, vascular bruits, claudication and renovascular hypertension. It is noteworthy that temporal artery inflammation can occur in GPA, making large vessel vasculitis a potential differential diagnosis for ANCA disease.Usually necrosis is noted on temporal artery biopsy in GPA and not giant cell arteritis. Large vessel vasculitides do not cause a glomerulonephritis.
The medium sized vessel vasculitides, polyarteritis nodosa and Kawasaki's disease, are characterized by pseudoaneurysms caused by necrotizing lesions of medium sized arteries leading to major viscera. In the kidneys, medium vessel vasculitis may effect the interlobar and arcuate arteries, less frequently the main renal artery and interlobular arteries.
Medium vessel vasculitides do not cause glomerulonephritis although they can cause hematuria and renal insufficiency secondary to renal infarction. Likewise, polyarteritis nodosa and Kawasaki's disease by definition are not characterized by pulmonary alveolar capillaritis. The peripheral neuropathy of ANCA disease and polyarteritis nodosa is very similar, however. It is noteworthy, however, that ANCA disease may occasionally involve medium-size arteries and present with aneuryms, ruptures and bleeding. Patients with large or medium size vessel vasculitis do not have circulating ANCA.
The two major categories of small vessel vasculitis include the pauciimmune small vessel vasculitides (ANCA disease) and the immune complex mediated small vessel vasculitides. On the differential diagnosis for ANCA disease is Henoch-Schönlein purpura, cryoglobulinemic vasculitis, lupus vasculitis, and antiglomerular basement menbrane vasculitis. In the immune complex mediated small vessel vasculitides. extensive localization of immunoglobulin and complement in vessel walls can be noted on pathologic examination of tissue. Serologic studies also can help differentiate between pauciimmune and immune complex small vessel vasculitis.
Antiglomerular basement membrane (anti-GBM) disease is an important consideration in the differential diagnosis for ANCA disease. When anti-GBM vasculitis affects the lungs and the kidneys. it is coined Goodpasture's syndrome. Anti-GBM disease can also occur as a renal limited vasculitis then termed anti-GBM glomerulonephritis.
Anti-GBM disease is characterized by circulating antibodies to the glomerular basement membrane and deposition of IgG or rarely IgA along glomerular basement membranes. In anti-GBM disease, the autoantibodies are directed at specific cryptic epitopes of the non-collagenous domain (NC1 domain) of the alpha-3 chain of type IV collagen. Patients presenting with anti-GBM disease may have hematuria, subnephrotic proteinuria, rapidly progressing renal failure and/ or hempotysis.
There are two peaks with respect to sex and age in anti-GBM disease. The first peak is in the second and third decade of life with male predominance and a higher frequency of pulmonary hemorrhage. The second peak is renal limited disease in women in the sixth and seventh decade of life.
About one-third of patients with anti-GBM disease have circulating ANCA, usually to myeloperoxidase (MPO-ANCA). Although patients with anti-GBM disease often present with vasculitis limited to the kidneys and lungs, patients with concominant anti-GBM disease and ANCA may have small vessel vasculitis in multiple organ systems.
Infectious diseases are an important consideration on the differential diagnosis for small vessel vasculitis. GPA in particular can be a mimic for tuberculosis, aspergillous, histoplasmosis and syphillis.
What tests to perform?
When entertaining the diagnosis of small vessel vasculiti, one should order antineutrophil cytoplasmic antibodies (ANCA). The major types of ANCA have specificity for proteinase 3 (PR3-ANCA) and for myeloperoxidase (MPO-ANCA) by enzyme-linked immunosorbent assay (ELISA). On indirect immunofluorescence microscopy assay, PR3-ANCA usually causes cytoplasmic staining of neutrophils (c-ANCA) and MPO-ANCA usually causes perinuclear staining (p-ANCA). PR3 c-ANCA is classically associated with GPA and MPO p-ANCA with MPA but there is a significant amount of cross over in these relationships.
In addition to ANCA, serologic evaluation for anti-GBM, cyroglobulins, hepatitis C or B, antinuclear antibodies (ANA), anti-double-stranded DNA (dsDNA) antibodies, and complement component levels (C3 and C4) help to direct the differential diagnosis.
Laboratory work up should also include chemistry panel, complete blood count,, and urine analysis. C-reactive protein and the erythrocyte sedimentation rate usually are elevated in patients with active vasculitis. Rheumatoid factor levels can also be positive in small vessel vasculitis. Lysosomal membrane protein-2 (LAMP-2) antibodies have been described in patients with small vessel vasculitis, but investigation into these antibodies have not confirmed their specificity for small vessel vasculitis. The role (if any) of anti-LAMP2 antibodies in the diagnosis or pathogenesis of small vessel vasculitis is therefore not established.
Eosinophilia on the differential of the complete blood count is required for the diagnosis of EGPA. Approximately 40% of patients with EGPA have positive ANCA, usually MPO-ANCA.
Approximately 10% of patients with pauciimune small vessel vasculitis with a presentation clinically indistinguishable from ANCA disease will be negative for ANCA. Patients with polyarteritis nodosa are negative for ANCA. Assessment of the urine sediment for dysmorphic red blood cell (acanthocytes), red blood cell casts, oval fat bodies, white blood cells and white blood cell casts is very helpful in evaluating the patient with renal involvement of small vessel vasculitis.
Chest X-ray should be performed on any patient with complaints of cough or hemoptysis when considering small vessel vasculitis. Diffuse alveolar hemorrhage can be seen as patchy infiltrates. Nodules and cavities can be noted by plain film of the chest in patients with GPA. Chest computed tomography (CT) and bronchoscopy may be necessary as well to further characterize pulmonary involvement of vasculits or even subglotic stenosis. Bronchoalveolar lavage is very useful in establishing the diagnosis of alveolar hemorrhage and differentiating this process from underlying infections.
CT scan of the head and sinuses may be useful for further evaluation of ear, nose, and throat (ENT) manifestations of disease. Often, however, laryngoscopic evaluation is required to fully asses ENT vasculitis.
Magnetic resonance imaging and angiography of the brain or cerebral angiography may be instructive when assessing for central nervous system vasculitis. Nerve conduction studies may also be helpful when assessing neuropathies. Often endoscopy is required for characterization of gastrointestinal vasculitis. Slit lamp evaluation by an ophthalmologist is often required for assessment of occular vasculitis manifestions. Renal ultrasound is also beneficial in work up of renal failure. Doppler ultrasound and ventilation perfusion scans may be required if deep vein thrombosis and pulmonary embolus is suspected.
For ANCA disease specifically, and all small vessel vasculitis in general, a biopsy is usually required to make or confirm diagnosis. Confirmatory renal biopsy for ANCA disease demonstrates focal segmental to global fibrinoid necrosis and crescent formation affecting variable proportions of glomeruli. Little or no endocapillary proliferation is present. Few or no immune deposits will be noted on immunoflorescence and electron microscopy.
Most commonly renal biopsy is performed but angiitis or leukocytoclasitic vasculitis on skin biopsy or vasculitis or granuloma on lung or sinus biopsy can be confirmative of the diagnosis. Peripheral nerve biopsy or temporal artery biopsy rarely can also be used for diagnosing ANCA disease. Often biopsy of the gastrointestinal tract will be required to establish the vasculitic etiology of gastrointestinal ulcers from those caused by other processes including glucocorticoid therapy.
In most circumstances, a biopsy confirmation of vasculitis is preferred prior to embarking on immunosuppressive therapy, due to risks of adverse events. A renal biopsy also provides valuable prognostic information based on the severity of disease and extent of irreverisible glomerular and intersitial sclerosis and fibrosis. In patients with contraindications to biopsy such as hemodynamic instabilty, inability to obtain adequate specimen, anticoagulation, or unilateral kidney, appropriate clinical scenario and serologies may leave a practitioner confident enough with the diagnosis to recommend therapy.
Immunosuppressive therapy should however not be delayed for a biopsy in patients with severe and rapidly progressive disease, such as rapidly progressive glomerulonephritis, or diffuse alveolar hemorrhage.With regards to kidney biopsy specifically, pauci-immune necrotizing and crescentic glomerulonephritis warrants therapy with corticosteroids and either cyclophosphamide or rituximab (and possibly even plasmapheresis) regardless of ANCA serologies.
In patients with a clinical scenario raising concern for small vessel vasculitis, positive ANCA serologies and biopsy confirmation of pauciimmune necrotizing vasculitis with or without granulomas confirm the diagnosis of ANCA disease. Significant staining for immune complexes should signify that another disease process is contributing if not entirely accountable for the vasculitis.
Patients presenting with frank pulmonary hemorrhage from diffuse alveolar capillaritis are at significant risk of repiratory failure and death. In this setting, awaiting pathologic confirmation of disease is not warrented. High clinical index of suspicion, prompt control of the airway and emergent treatment can be life saving.
Patients with pauciimmune necrotizing crescentic glomerulonephritis with negative ANCA serologies have a disease process indistinguishable from patients with ANCA positive disease and therefore there is currently no difference in approach to treating these patients.
How should patients with glomerular and vascular diseases be managed?
In all patients with small vessel vasculitis, the most pressing concern for management is to determine which patients have life- or organ-threatening disease and to institute emergent therapy immediately. Subglottic stenosis and pulmonary hemorrhage can be life-threatening and establishment of a protected airway is paramount. Even patients who do not appear to be in emminent danger of respiratory failure should be monitored very closely as decompensation requiring intubation can occur.
Actively hemoptysizing patients will likely need packed red blood cell transfusion, fresh frozen plasma, and possibly platelet transfusion. If bleeding is life threatening and unrelenting, activated factor VII infusion should be considered.
For life- or organ-threatening presentations of small vessel vasculitis, our practice is to infuse 500 mg of intravenous methylprednisolone immediately on presentation. In the setting of hemoptysis and severe renal failure, including patients who present in need of dialysis, institution of plasmapheresis should be arranged urgently. Plasma is replaced with fresh frozen plasma in patients with active bleeding or recent biopsy and albumin in nonbleeding patients.
Institution of plasmapheresis and methylprednisolone infusion for patients with diffuse alveolar hemorrhage and glomerulonephritis (pulmonary-renal syndrome) should commence even prior to firmly establishing the diagnosis of small vessel vasculitis. Our practice for ANCA disease is to begin treatment with 3 daily infusions of 500 mg methylprednisolone followed by conversion to prednisone 60 mg by mouth daily. Plasmapheresis on a daily or every other day basis for a total of 7 to 10 treatments has been associated with improved mortality in ANCA disease for patients with diffuse alveolar hemorrhage.
If diagnosis of ANCA is confirmed, then infusion with cyclophosphamide 0.5 grams/meter2 body surface area (BSA) is appropriate induction therapy for patients with or without life- or organ-threatening disease. Alternatively, patients may receive daily oral cyclophosphamide starting at 2 mg/kg/day. The dose of cyclophosphamide should be adjusted to maintain a nadir leukocyte count above 3 x 109 cells/L. In a large randomized and controlled trial, induction therapy with the intravenous or daily oral cyclophosphamide regimen were associated with similar rate of remission.
The use of daily oral cyclophosphamide is associated with a greater rate of leukopenia, but possibly a lower long term rate of disease relapse. The intravenous regimen is also associated with a 2-3 fold lower cummulative dose of cyclophosphamide, and has thus become the currently preferred approach.
In ANCA disease, use of corticosteroids and rituximab (375 mg/m2 BSA weekly x 4) was shown to be non-inferior induction therapy compared to corticosteroids and intravenous cyclophosphamide in a large randomized controlled trial. Corticosteroid management in most circumstances should consist of intravenous methylprednisolone 500 mg daily x3 followed by prednisone 60 mg by mouth daily for 1 month.Prednisone is then taperd down over the subsequent 3-4 months. We usually follow an alternating day sequence resulting in a dose of 60 mg every other day by the end of 10 weeks (total) of prednisone and completely off glucocorticoids by the end of 16-20 weeks.
Regardless of the glucocorticoid taper used, in patients who reach remission, prednisone should be weaned off by 4-6 months after starting therapy. Weaning glucocorticoids completely off is not a universally accepted practice but evidence supports that this strategy is not associated with increased risk of relapse and reduces patient risk for infection and possibly steroid associated diabetes mellitus.
Cyclophosphamide should be given by infusion pulses on a monthly basis. Dosing starts at 0.5 grams/ meter squared and can be uptitrated to 1 gram/ meter squared depending on the 2 week Leukocyte nadir. Complete blood count with differential should be checked two weeks after cyclophosphamide infusion and goal is to not have leukocyte nadir dip below 3,000 x109. Cyclophosphamide therapy should continue for three months after remission has been obtained.
Following discontinuation of cyclophosphamide, azathioprine therapy at 1.5 to 2 mg/kg daily should be started and continued for 12-18 months for remission maintanence. Other options for remission maintanence have not proven to be more effective than azathioprine and potentially associated with greater side effect profiles. In patients who do not tolerate azathioprine the other options including mycophenolate mofetil, leflunomide, and, in patients without renal involvement of vasculitis, methotrexate could be used. In a large randomized controlled trial, maintenance therapy with mycophenolate mofetil was associated with a higher rate of relapse compared to azathioprine therapy.
When using rituximab for induction therapy, 375 mg rituximab per square meter of body-surface area is infused per week for 4 weeks.In addition to rituximab, one protocol for induction used cyclophosphamide 15 mg/kg IV x 2, 2 weeks apart. Either strategy is given in conjunction with corticosteroid therapy. Rituximab is also being evaluated as a potential adjunct therapy in treatment resistent disease and as a remission maintenance option.
In patients with severe renal dysfunction (creatinine > 5.7 mg/dl, or needing renal replacement therapy) the addition of plasmapheresis (seven treatments of 2 plasma volumes over 14 days) is superior to pulse methylprednisolone (up to 1000 mg daily x 3) in inducing recovery of renal function and dialysis-free survival at 3 months. Plasmapheresis was however not associated with improved long term patient survival at or beyond 12 months. Whether the addition of plasmapheresis to standard immunosuppression with glucocorticoids and cyclophosphamide or rituximab is beneficial in patients with less severe renal dysfunction is unknown, and is the focus of an ongoing large multicenter randomized and controlled trial (clinicaltrial.gov identifier:NCT00987389)
For patients who present in need of dialysis and remain on dialysis despite appropriate therapy, immunosuppression can be discontinued after 3 months if they exhibit no evidence of active extra-renal vasculitis. In the setting of end-stage renal disease, the risk of infectious complications from immunosuppression appears greater than the risk of relapse.
Relapses of ANCA disease are usually treated with repeat dosing of corticosteroids and cyclophosphamide or rituximab. The choice of therapy for relapsing disease should be guided by the severity of relapse, and prior exposure and tolerance of cyclophosphamide therapy. Patients with mild relpase may be treated with the reintroduction or increased dose of glucocorticoids or azathioprine. Patients with moderate or severe relapse (eg, with pulmonary, renal or neurologic symptoms, or severe ENT disease) may require treatment with cyclophosphamide or rituximab. Care should be given to limit the life time cumulative dose of cyclophosphamide. retrospective registry analysis detected an increased risk of malignancy among patients who have received a cummulative dose of cyclophosphamide greater than 36 gm.
Case report and case series evidence are available for using intravenous immunoglobulin (IVIg) and infliximab (tumor necrosis factor alpha blockade) in treatment of refractory disease.
In patients with anti-GBM disease, initiation of treatment prior to severe renal failure requiring of dialysis confers an improved prognosis. It is not as common in anti-GBM disease as it is in ANCA disease to reverse renal injury to the point of no longer requiring renal replacement therapy.
Anti-GBM disease in managed with corticosteroids, cyclophosphamide, and daily plasmapheresis. Plasmapheresis for anti-GBM disease is daily for at least 14 days or until circulating anti-GBM antibodies are undetectable. 50 mL/kg (maximum 4L) of plasma should be removed and replaced with a 5% albumin solution. For pulmonary hemorrhage fresh frozen plasma should be administered at the end of each treatment to replace clotting factors.
The use of IV methylprednisolone is unproven in anti-GBM disease but many nephrologists begin corticosteroid therapy with 3 pulses of methylprednisolone 500 mg IV due to the urgent nature of treatment initiation and inflammation reduction in anti-GBM disease. Oral corticosteroid management is similar to what is used for ANCA disease.
Prednisone is initiated at 60 mg by mouth daily for 1 month. Our practice is then to begin a taper of prednisone as follows: begin by alternating 50 mg of prednisone with 60 mg of prednisone every other day. After 1 week on this regimen move to 40 mg alternating with 60 mg for 1 week then drop to 30 mg alternating with 60 for a week. Drop the lower dose of prednisone by 10 mg alternating with 60 mg every week until alternating 0 mg with 60 mg. Then begin to drop the every other day of prednisone by 10 mg every week until the prednisone is weaned completely off. Regardless of the steroid taper used prednisone should be weaned off by 4-6 months after starting therapy
There is no data regarding the optimal modality or duration of cyclophosphamide in anti-GBM disease. It is our practice to use pulse IV cyclophosphamide every 4 weeks for 3 months in a fashion similar to that described above for ANCA disease.
Dialysis dependent patients without pulmonary hemorrhage should have treatment discontinued after 8-12 weeks if there is no recovery of renal function.
What happens to patients with glomerular and vascular disease?
Remission in ANCA disease is on the order of 70% to 85% in patients given corticosteroids and cyclophosphamide with 1 and 5 year survival rates of 85% and 75% respectively. Mortality is greater for older patients. Prior to the routine use of plasmapheresis, diffuse alveolar hemorrhage carried an 8-fold risk of death. Creatinine at presentation is the major predictor of renal outcome. For patients who present on dialysis about 50% remain in need of renal replacement therapy.
Relapse in ANCA disease occurs in about 45% of patients over a median of 44 months. Patients with PR3-ANCA, upper respiratory disease or pulmonary vasculitis are at highest risk of relapse. In fact, patients with all three of these risk factors have a 3.7 times increased risk of relapse over patients with none of these three risk factors. ANCA titers are not followed routinely as predictors for relapse.
Recurrent glomerulonephritis can occur with hematuria, increase in creatinine and. in some patients, chronic progressive scarring manifested by increasing proteinuria and creatinine. Eventual renal replacement therapy with dialysis or kidney transplant may be required. Approximately 20% of patients that survive initial disease presentation go on to eventually develop end stage renal disease.
Kidney transplant is recommended in patients in remission from vasculitis even in the presence of positive ANCA titers. Recurrent vasculitis occurs in approximately 17% of patients with ANCA disease following kidney transplant with a mean time to recurrence of 31 months. Vasculitis relapse rate was 0.02 per patient-years. Sixty percent of recurrences of vasculitis include glomerulonephritis.
Scarring from recurrent pulmonary capillaritis may lead to pulmonary fibrosis.
Recurrent episodes of sinusitis are common and patients often are encouraged to continuously perform nasal lavage and are given rounds of antibiotics to limit infectious triggers to ear, nose and throat vasculitis.
Saddle nose deformity and peripheral neuropathy usually have lasting effects after the treament of vasculitis. Saddle nose deformity may require plastic surgery intervention.
Life long immunosuppression is not mandatory in ANCA disease but patients off therapy must be followed closely for signs of relapse with urine analysis, history and physical exam, and laboratory work.
Long term, the major causes of death in ANCA disease are infection and cardiovascular disease.
Anti-GBM disease is not expected to relapse and patients on renal replacement therapy can undergo kidney transplant after the disappearence of anti-GBM antibodies.
ANCA disease incidence is 10-20 cases per million. It is a disease much more commonly found in caucasians. The peak age is 65-74.
Patients with ANCA disease may have long standing profound fatigue, renal failure or recurrent episodes of glomerulonephritis, progressive proteinuria, recurrent sinusitis, progressive subglottic stenosis, hearing loss or tinnitus, pulmonary fibrosis, chronic parasthesias or weakness; this is in contradistinction to anti-GBM disease where relapse is uncommon.
Patients treated for small vessel vasculitis are placed on immune modulating therapy. Most patients in remission from ANCA disease will be maintained on immunosuppressive therapy for many months and even years. The risk to this therapy in general includes infectious complications and increased risk for malignancy.
Cyclophosphomide leads to leukopenia, anemia, hemorrhagic cystitis and can adversely impact fertility. Cyclophosphamide treated patients are at increased risk for non-melanoma skin cancer, bladder cancer and acute myelogenous leukemia.
Corticosteroids impact mood, cause psychosis, sleeplessness, weight gain and Cushing's syndrome, hyperglycemia, gastritis/espohagitis, gastrointestinal ulcers, osteopenia/osteoporosis, avascular necrosis, and bruising. It is advisable to use calcium and vitamin D therapy along with proton pump inhibitors while patients are on corticosteroids for bone and GI protection.
Azathioprine can lead to a life threatening hypersensitivity reaction, anemia, leukopenia, pancreatitis, and nausea/ vomiting. Prior to initiating azathioprine it is important to check that patients have two alleles for the enzyme thiopurine methyltransferase (TPMT). About 9% of people are heterozygous for the TPMT allele and can tolerate azathioprine but should be given reduced doses starting at 50 mg daily. About 1% of people are homozygous TPMT-negative patients and should not be given azathioprine as they could have life-threatening bone marrow toxicity.
Mycophenolate mofetil is associated with nausea, vomiting and loose stools as well as abdominal cramps, anemia and leukopenia. The risks to using rituximab are still being investigated but include progressive multifocal leukoencepholopathy. Use of PCP prophylaxis is usually recommended for patients with small vessel vasculitis on immunomodulatory therapy.
• With plasmapheresis, cyclophosphamide and corticosteroids, 85% of patients with anti-GBM disease survive and 40% go on to end stage renal disease.
• The earlier anti-GBM disease is recognized and treatment is initiated, the better the patient and renal survival.
• Anti-GBM disease is not expected to relapse and therefore remission maintence therapy is not required.
• Patients should undergo kidney transplant after the disappearence of anti-GBM in circulation; recurrence of disease post transplant is exceedingly rare.
How to utilize team care?
When dealing with small vessel vasculitis in general and ANCA disease and anti-GBM disease specifically. it is important to have a multidisciplinary approach. In patients with life- or organ-threatening disease, the intensive care/pulmonary team must work closely with ENT, nephrology, rheumatology, infectious disease, neurology, GI, and/or dermatology. Vasculitis presents with myriad complications from disease, and as such, a variety of specilaists are often essential to optimal care and saving organs as well as lives.
In patients with life-threatening complications, specifically subglottic stenosis and pulmonary hemorrhage, nursing surveillance is of paramount importance in assessing for patient decompensation.Emergent actions including alerting physicians, airway protection, and adequate hemostasis may make the difference between life and death for many patients with pulmonary-renal syndrome.
Close supervision by pharmacists of the medications provided for ANCA disease and other small vessel vasculitis is critical. The adverse event profiles of immunomodulatory drugs are daunting. For example, interactions between medications like trimethoprime sulfamethoxasole and azathioprine can lead to potentially serious adverse events. In many small vessel vasculitis patients, medications must be dosed appropriately for decreased kidney function. Pharmacist evaluation of medicine lists and assistance with monitoring drug toxicities are essential for optimal patient outcomes.
Dietitians have an important impact in management of hospitalized and outpatients alike. In the profoundly ill, monitoring and assuring sufficient nutritional intake can promote recovery and reduce adverse events. Patients with renal dysfunction from vasculitis will require reduced sodium diets and possibly other modifications such as phosphate restriction. Dietary counseling plays an important role in minimizing the risk of weight gain and hyperglycemia in patients receiving glucocorticoids. Ensuring appropriate nutrition can have a key impact on over-all patient outcome and can reduce inpatient hospital stay.
Physical, speech, and occupational therapists may play an important role in patients with ANCA disease. Mobility and prevention of deconditioning is vital for recovery in any patient with multi-system disease. Arthritis, mylagias, arthrlagias and neuropathies can make ambulation, activities of daily living and mobilization challenging for many patients with vasculitis. Upper respiratory vasculitis can have impact on speech, swallowing and balance that may require intervention by the therapy team to significantly improve patient function.
Are there clinical practice guidelines to inform decision making?
In the near future, KDIGO guidelines will be published for management of renal ANCA disease and Anti-GBM disease. Limitations to these guidelines are that patients without renal manifestations of ANCA disease are not expressly adressed in these guidelines.
DRG code: 446.4
Typical lengths of stay varies depending on severity of manifestations of disease. Patients who do not have life- or organ-threatening illness may remain in the hospital only long enough for the infusion of induction therapy, 3 days at least. Patients who require intensive care unit management, initiation of renal replacement therapy, plasmapheresis or open lung biopsy may be in the hospital for weeks.
What is the evidence?
Jennette, JC, Falk, RJ, Andrassy, K, Bacon, PA, Churg, J, Gross, WL, Hagen, EC, Hoffman, GS, Hunder, GG, Kallenberg, CG. " Nomenclature of systemic vasculitides. Proposal of an international consensus conference". Arthritis Rheum. vol. 37. 1994. pp. 187-192.
Falk, RJ, Jennette, JC. " ANCA disease: where is this field heading?". J Am Soc Nephrol. vol. 21. 2010. pp. 745-752.
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