Microscopic Polyangiitis1

Microscopic polyangiitis1

Author: Professor J. Charles Jennette2 Creation Date: October 2002

Scientific Editor: Professor Loïc Guillevin

1This text was adapted from: Jennette JC, Thomas DB, Falk RJ. Microscopic polyangiitis (microscopic polyarteritis). Semin Diagn Pathol. 2001;18:3-13.

2Department of Pathology and Laboratory Medicine, University of North Carolina, 303 Brinkhous-Bullitt Building, NC 27599-7525 Chapel Hill, United States. [email protected]

Abstract Keywords Disease name Definition Differential diagnosis Frequency Clinical manifestation Diagnostic methods Treatment Unresolved questions References

Abstract Microscopic polyangiitis (MPA) refers to a necrotizing systemic vasculitis with few or no immune deposits that affects small vessels (ie, capillaries, venules and arterioles). Arteries, especially small arteries, are often but not always involved. Vessels of any type in any organ can be affected, resulting in a wide variety of signs and symptoms, and nonspecific clinical manifestations. Common signs and symptoms include nephritis, pulmonary hemorrhage, purpura, peripheral neuropathy, abdominal pain, myalgias and arthralgias. MPA is the most common antineutrophil cytoplasmic autoantibodies (ANCA)-associated small-vessel vasculitis. Most patients have positive myeloperoxidase MPOANCA (PANCA), although proteinase 3 PR3 ANCA (CANCA) may be also present. MPA has an incidence of approximately 1:100,000 with a slight predominance in men, and a mean age of onset of about 50 years. Treatment of patients with MPA consists of three phases: induction of remission, maintenance of remission, and treatment of relapse. Current induction therapy often consists of cyclophosphamide and corticosteroids.

Keywords Micoscopic polyangiitis, small-vessel vasculitis, antineutrophil cytoplasmic autoantibodies (ANCA), corticosteroid, cyclophosphamide.

Disease name few histological patterns of vascular Microscopic polyangiitis (MPA) inflammation. Small-vessel vasculitis is defined Microscopic polyarteritis as a vasculitis affecting vessels smaller than Microscopic polyangiitis is a more appropriate arteries, such as arterioles, venules and name than microscopic polyarteritis because capillaries. some patients show no evidence for arterial There is no widely accepted classification of involvement. primary vasculitis, although a working framework has been provided by a consensus reached by Definition the leading investigators at a meeting in Chapel Classification of systemic vasculitis Hill, North Carolina in 1995. Systemic Vasculitis is an inflammation of vessel walls. It vasculitides form a heterogeneous group of has many causes, although they result in only a

Jennette J.C.; Microscopic polyangiitis. Orphanet encyclopedia, October 2002 http://www.orpha.net/data/patho/GB/uk-MPA.pdf 1

vascular inflammatory diseases that can be sub- the presence of ANCA and few or no immune divided on the basis of the underlying deposits in the involved vessels. The kidneys are histopathology, the type of vessels involved, the the most commonly affected organs and are target organs involved, and the resulting clinical involved in 90% of patients who have this type of picture (table 1). vasculitis. Patients often present with variable combinations of renal manifestations, palpable Table 1: The Chapel Hill Consensus purpura, abdominal pain, cough, and Conference on the Nomenclature of Systemic hemoptysis. Most patients have positive Vasculitis myeloperoxidase MPOANCA (PANCA), although Large Vessel Vasculitis proteinase 3 PR3 ANCA (CANCA) may be also Giant-cell arteritis – granulomatous arteritis of the aorta present. and its major branches, especially the extracranial branches of the carotid artery; usually in patients over 50 years old and associated with polymyalgia rheumatica. Differential diagnosis Takayasu arteritis – granulomatous inflammation of the In recent years there has been substantial aorta and its major branches usually in patients <50 years progress in identifying attributes of specific types old. of vasculitis, thus enabling accurate diagnosis. Medium Vessel Vasculitis MPA must be differentiated not only from other Polyarteritis Nodosa – necrotizing inflammation of medium or small arteries without glomerulonephritis or vasculitis in forms of small-vessel vasculitis, but also from arterioles, capillaries, or venules. medium-sized vessel vasculitis, such as Kawasaki’s Disease – arteritis of large, medium, and small polyarteritis nodosa and Kawasaki disease. arteries associated with the mucocutaneous lymph node MPA may cause a necrotizing arteritis that is syndrome, often involves the coronaries, usually occurs in children histologically identical to that caused by Small Vessel Vasculitis polyarteritis nodosa (PAN). Clinical, Wegener’s granulomatosis epidemiological and pathological differences Churg-Strauss syndrome enable differentiation between MPA and PAN, as Microscopic polyangiitis capillaries and venules are affected in MPA but Henoch-Schonlein purpura Cryoglobulinemic vasculitis not in PAN. Cutaneous Leukocytoclastic Vasculitis The absence or paucity of immunoglobulin localization in vessel walls helps distinguish Microscopic Polyangiitis MPA from immune complex-mediated small MPA is a necrotizing systemic vasculitis with few vessel vasculitis, such as Henoch-Schönlein or no immune deposits that affects small vessels purpura and cryoglobulinemic vasculitis. (ie, capillaries, venules and arterioles), although The vasculitis in patients with MPA is it occasionally involves medium-sized arteries. pathologically indistinguishable from the MPA belongs to a category of vasculitis that also vasculitis of WG and CSS. Granulomatous includes Wegener’granulomatosis (WG), Churg- inflammation distinguishes WG from MPA. Strauss syndrome (CSS), Henoch-Schönlein Asthma and eosinophilia distinguish CSS from purpura, cryoglobulinemic vasculitis and others MP. necrotizing polyangiitides. MP, WG and CSS are all associated with MPA is the most common antineutrophil circulating ANCA (table 2). cytoplasmic autoantibodies(ANCA)-associated small-vessel vasculitis, and is characterized by

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Table 2: Features that allow differentiation of microscopic polyangiitis from several other forms of small-vessel vasculitis Henoch-Schonlein Cryoglobulinemic Microscopic Wegener’s Churg-Strauss Purpura Vasculitis Polyangiitis Granulomatosis Syndrome Small-vessel vasculitis Yes Yes Yes Yes Yes signs and symptoms

IgA-dominant immune Yes No No No No deposits

Cryoglobulins in blood No Yes No No No and vessels

ANCA in blood No No Yes Yes Yes

Necrotizing No No No Yes Yes granulomas

Asthma and No No No No Yes eosinophilia If a patient has systemic pauci-immune small-vessel vasculitis with no evidence for granulomatous inflammation, or asthma, the appropriate diagnosis is MPA The diagnosis of MPA is essentially made by exclusion of other diseases, which is always a difficult task.

pain as well as bloody stools, and possible Frequency intussusception, perforation, and pancreatitis. MPA has an incidence of approximately Respiratory tract: pulmonary manifestations 1:100,000, with a slight predominance in men, range from fleeting focal infiltrates to massive and a mean age at onset of about 50 years, pulmonary hemorrhage and hemoptysis although any age can be affected secondary to alveolar capillaritis. Histologic Findings Clinical manifestation The basic acute vascular lesion of MPA is Vessels of any type in any organ can be segmental vascular necrosis with infiltration of affected, resulting in a wide variety of signs and neutrophils and monocytes, often accompanied symptoms, and nonspecific clinical by leukocytoclasia and accumulation of fibrin. manifestations. Common signs and symptoms MPA may cause necrotizing arteritis that is include nephritis, pulmonary hemorrhage, histologically identical to that caused by PAN. purpura, peripheral neuropathy, abdominal pain, According to the Chapel Hill consensus myalgias and arthralgias. conference on the classification of vasculitis, Constitutional signs and symptoms such as PAN and MPA can be distinguished fever, arthralgias, myalgias, and "flu-like" pathologically by the absence of vasculitis in symptoms are often present early in the disease. vessels other than arteries in patients with PAN, Arthralgias tend to be migratory, affect large and and the presence of vasculitis in vessels smaller small joints with evidence of synovitis in 10-20%. than arteries, such as arterioles, venules, and Blood vessels in the skin, lungs, kidneys, gut, capillaries, in patients with MPA. nerves, and skeletal muscles are often involved The glomerulonephritis in MPA is characterized but vary between the different patients. MPA by focal necrosis, crescent formation, and the may cause pulmonary-renal syndrome. absence or paucity of immunoglobulin deposits. Skin: the most common cutaneous lesion is Pulmonary manifestations consist of pulmonary leukocytoclastic angiitis, which typically causes alveolar capillaritis. Biopsy of the muscle and purpura and ulcerations; other lesions include peripheral nerves may reveal necrotizing erythematous tender nodules, focal necrosis, vasculitis epineural arteries. and livedo reticularis. The most common cutaneous lesion is Peripheral neuropathy: mononeuritis multiplex leukocytocalstic angiitis affecting dermal is the most common neurological manifestation venules. Necrotizing dermal arteritis also occurs. of MPA; this is caused by inflammation of epineural arterioles leading to ischemia of both Diagnostic methods sensory and motor nerves. In patients with pauci-immune small vessel Gastrointestinal tract: inflammation of visceral vasculitis, (MPA, WG, CSS), the 2 major antigen blood vessels causes pain and elevated levels of specifities are for myeloperoxidase (MPO)- tissue enzymes; gut ischemia causes abdominal ANCA and proteinase 3 (PR3)-ANCA. These autoantibodies usually are detected by enzyme

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immunoassays (EIA), using purified MPO and Treatment PR3 as substrate. ANCA also can be detected Tremendous therapeutic advances have been by indirect immunofluorescence microscopy made in recent years in the treatment of (IFA). However, IFA without confirmatory EIA is systemic necrotizing vasculitides, which are not recommended because of the increased usually fatal if untreated. The primary aim of the numbers of false-positive results with IFA. When treatment is to induce rapid remission with high alcohol-fixed neutrophils are used as substrate drug doses at the expense of short-term toxicity. for IFA, PR3-ANCA usually causes cytoplasmic The next step is to taper the drug doses or staining (C-ANCA), whereas perinuclear staining switch to safer drugs, and maintain a low-dose (P-ANCA) is usually associated with MPO- therapy for a prolonged period to prevent ANCA. disease relapse. Current outcome studies show Laboratory Studies a relatively high mortality despite treatment, Hematology lab studies especially in the elderly and in those with renal Leukocytosis involvement. Anemia (normocytic anemia) Survivors may suffer relapsing disease and Elevated erythrocyte sedimentation rate (ESR) chronic morbidity due to vasculitic damage and Renal tests the long-term consequences of Elevated serum BUN (blood urea nitrogen) and immunosuppression. creatinine (70%) The treatment should not be delayed until the Abnormal urine sediment diagnosis of MPA versusWG or CSS is made Proteinuria (80%) because all of these diseases warrant Hematuria (67%) aggressive immunosuppressive therapy when Leukocyturia (44%) there is active damage of major organ such as Erythrocyte casts glomerulonephritis or pulmonary hemorrhage. Antineutrophil cytoplasmic antibodies Treatment of patients with MPA includes three ANCA positive (80%) phases: (1) induction of remission, (2) Perinuclear ANCA related to myeloperoxidase maintenance of remission, and (3) treatment of ANCA (60%) relapse. Current induction therapy often consists Cytoplasmic ANCA related to proteinase-3 of cyclophosphamide and corticosteroids. For ANCA (40%) aggressive disease, use of high-dose Blood cultures to rule out bacterial endocarditis intravenous methylprednisolone for three days is recommended, combined with intravenous or Imaging Studies oral cyclophosphamide. Tapering doses of Chest radiographs show diffuse parenchymal prednisone should follow, along with infiltrates secondary to pulmonary alveolar cyclophosphamide maintenance for 12 to 18 capillaritis and hemorrhage; other imaging months. The lowest dosage of steroids sufficient studies are indicated for the complications of the to control the disease should be used, and disease and specific organ system involvement, infection should be considered if the symptoms such as abdominal CT scan for pancreatitis or appear to exacerbate. For patients in sustained mesenteric angiography to differentiate from remission at 12 months, the use of all MPA from PAN. medications may be gradually discontinued. Patients whose symptoms are under good Other Tests control must, nevertheless, be closely followed Ordered according to the specific organ system at six-month intervals for signs and symptoms of involved. relapse. During treatment with these agents, Electrocardiography is indicated for myocardial complete blood counts and liver function tests infarction, pericarditis, and congestive heart should be performed periodically. failure. Other treatment regimens that may be of benefit Gastrointestinal endoscopy in case of include methotrexate, azathioprine, gastrointestinal bleeding. trimethoprim-sulfamethoxazole, plasma Electromyography (EMG) in case of clinical exchange, cyclosporine, intravenous evidence of neuropathy. immunoglobulin, and monoclonal antibodies. During the use of potentially ulcerogenic Biopsies immunosuppressive therapy, patients may be Skin biopsy if skin is involved given H2-blockers or proton-pump inhibitors. Open lung biopsy Prophylactic treatment with fluconazole orally for Renal biopsy to help diagnose crescentic fungal infection may be considered, as well as glomerulonephritis trimethoprim-sulfamethoxazole (480 mg), three Sural nerve biopsy if EMG results are consistent times weekly, for prophylactic treatment of with sural nerve involvement patients with Pneumocystis carinii prophylaxis.

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Unresolved questions antineutrophil cytoplasm autoantibody- There are no agreement upon diagnostic criteria associated systemic vasculitis: initiatives of the for small vessel vasculitis. The American College European Community Systemic Vasculitis of Rheumatology published a classification Clinical Trials Study Group. Mayo Clin Proc approach in 1990 for use in clinical trials, but not 1997;72:737-747. for diagnosis; in 1994 the Chapel Hill Jayne DR, Chapel H, Adu D, et al. Intravenous International Consensus Conference proposed immunoglobulin for ANCA-associated systemic names and definitions for various vasculitides vasculitis with persistent disease activity. QJM but no diagnostic criteria were suggested. 2000;93:433-439. There are no clear therapeutic guidelines in the Jennette JC, Falk RJ, Andrassy K, Bacon PA, treatment of systemic necrotizing vasculitides. Churg J, Gross WL, Hagen EC, Hoffman GS, There is incomplete knowledge of Hunder GG, Kallenberg CG, et al. Nomenclature immunoregulatory defects and poor of systemic vasculitides. Proposal of an understanding of genetic / epidemiologic / international consensus conference. Arthritis environmental risk factors. Rheum. 1994;37:187-92. Jennette JC, Falk RJ. Small-vessel vasculitis. N References Engl J Med. 1997;337:1512-23. Falk RJ, Hogan S, Carey TS: Clinical course of Jennette JC, Thomas DB, Falk RJ. Microscopic anti-neutrophil cytoplasmic autoantibody- polyangiitis (microscopic polyarteritis). Semin associated glomerulonephritis and systemic Diagn Pathol. 2001;18:3-13. vasculitis. The Glomerular Disease Collaborative Langford CA. Treatment of polyarteritis nodosa, Network. Ann Intern Med 1990; 113: 656-63 microscopic polyangiitis, and Churg-Strauss Fries JF, Hunder GG, Bloch DA: The American syndrome: where do we stand? Arthritis Rheum. College of Rheumatology 1990 criteria for the 2001;44:508-12 classification of vasculitis. Summary.Arthritis Lhote F, Cohen P, Genereau T: Microscopic Rheum 1990; 33: 1135-6. polyangiitis: clinical aspects and treatment. Ann Guillevin L, Durand-Gasselin B, Cevallos R, Med Interne (Paris) 1996; 147:165-77. Gayraud M, Lhote F, Callard P, Amouroux J, Lightfoot RW Jr, Michel BA, Bloch DA: The Casassus P, Jarrousse B. Microscopic American College of Rheumatology 1990 criteria polyangiitis: clinical and laboratory findings in for the classification of polyarteritis nodosa. eighty- five patients. Arthritis Rheum 1999; 42: Arthritis Rheum 1990; 33: 1088-93 421-30 Luqmani RA, Robinson H. Introduction to, and Guillevin L, Lhote F. Treatment of systemic classification of, the systemic vasculitides. Best vasculitides. Adv Nephrol Necker Hosp. Pract Res Clin Rheumatol. 2001;15:187-202 1999;29:35-52 Savage CO, Harper L, Adu D: Primary systemic Haubitz M, Schellong S, Gobel U, et al. vasculitis. Lancet 1997; 349: 553-8 Intravenous pulse administration of Sneller MC, Fauci AS: Pathogenesis of cyclophosphamide versus daily oral treatment in vasculitis syndromes. Med Clin North Am 1997 patients with antineutrophil cytoplasmic Jan; 81(1): 221-42 antibody-associated vasculitis and renal Savige J. Testing for antineutrophil cytoplasmic involvement: a prospective, randomized study. antibodies. Expert Rev Mol Diagn. 2001;1:281-9 Arthritis Rheum 1998;41:1835-1844. Sorensen SF, Slot O, Tvede N, Petersen J.A Hoffman GS, Stone JH. Proceedings of the 10th prospective study of vasculitis patients collected International Vasculitis and ANCA Workshop. in a five year period: evaluation of the Chapel Cleveland Clinic J Med 2002; 69(Suppl. 2):1-196 Hill nomenclature.Ann Rheum Dis. 2000 Hughes LB, Bridges SL Jr. Polyarteritis nodosa Jun;59(6):478-82. and microscopic polyangiitis: etiologic and Watts RA, Jolliffe VA, Carruthers DM: Effect of diagnostic considerations. Curr Rheumatol Rep. classification on the incidence of polyarteritis 2002 ;4:75-82. nodosa and microscopic polyangiitis. Arthritis Jayne DR, Rasmussen N. Treatment of Rheum 1996 Jul; 39: 1208-12.

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