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PRACTITIONERS SECTION |
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| Year : 1997 | Volume
: 51
| Issue : 7 | Page : 236-239 |
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Anti-neutrophil cytoplasmic antibody (ANCA) - A review
DK Gupta, SS Kaushal, LS Pal
Department of Medicine, I. G. Medical College Shimla (H.P.) 171 001., India
Correspondence Address:
D K Gupta
Department of Medicine, I. G. Medical College Shimla (H.P.) 171 001.
India
PMID: 9401233
How to cite this article:
Gupta D K, Kaushal S S, Pal L S. Anti-neutrophil cytoplasmic antibody (ANCA) - A review. Indian J Med Sci 1997;51:236-9 |
The systemic vasculitis disorder, Wegener's granulomas and microscopic polyarteritis have a poor prognosis in the absence of immunosuppressive therapy. The morbidity and mortality are mainly related to the occurrence of severe lung haemorrhage and rapidly progressive glomerulonephritis. [1] Treatment with cyclophosphamide and predinisolone has greatly improved the outlook of these patients. Since then the recognition among the clinicians of Wegener's granulomatosis and its expanded spectrum has improved making early diagnosis and treatment possible. Patients with classic Wegener's triad have necrotizing granulomatous vasculitis of upper and lower respiratory tract associated with generalized angiitis and necrotizing glomerulonephritis. Patients with limited Wegener's granulomatosis may have vasculitis limited to the respiratory tract. Because of the potential clinical overlay with other diseases the diagnostic algorithm for patients with suspected Wegener's granulomatosis has traditionally included biopsy of upper airway, lung and kidney to confirm the diagnosis and to rule out other entities. [2] Because of the morbidity and the expense associated with biopsy, the anti-neurophil cytoplasmic antibody (ANCA) has attracted interest as a rapid and non-invasive way to diagnose Wegener's granulomatosis. [3]
ANCA was first described in 1982 ,in patients with systemic vasculitis and glomerulonephritis and thought to be a arboviral infection. [4] ANCA. was later identified as a seromarker for Wegener's granulomatosis. [5] Two types of ANCA pattern have been described on indirect immunofluorescence of thanol fixed neutrophils.
(a) Cytoplasmic (C-ANCA) pattern : Major antigen for C-ANCA is 29-Kd serine protease known as proteinase 3 which is found within azurophil granules of neutrophils.
(b) Perinuclear (P-ANCA) pattern : Major antigen for P-ANCA is myeloperoxidase, a lysosomal enzyme found in neutrophils. [6] However antibodies against elastase and lactoferrins can also give rise to perinuclear florescent pattern.
The C-ANCA pattern has been predominantly associated with wegener's granulomatosis and PANCA is associated with microscopic polyarteritis and other vasculitides, iodiopathic necrotizing and crescentic glomerulonephir.its (non-wegener group). Further studies have shown that the autoantigen recognized by ANCA may be associated with enzyme alkaline phosphatase. Antibodies of patients with wegener's granulomatosis and microscopic polyarteritis bind different epitopes on this enzyme which may account for different clinical manifestations of the two disorders. [7]
Three methods are currently availabble for measuring ANCA.
- Indirect immunofluorescence.
- Enzyme linked immunosorbent assay.
- Radio - immuno assay.
Indirect immunofluorescence is gold standard for measuring ANCA.
ANCA as diagnostic tool.: Most studies agree htat more than 91 % of patients with wegener's granulomatosis are positive for C-ANCA while perinuclear antibodies are present in only 10%,. Conversely, most patients with idiopathic crescenJc glomerulonephritis are positive for P-ANCA. C-ANCA and PANCA are present roughly in equal number of patients with polyarteritis nodosa. It has been proposed that these patients form a pathological continuum ranging from purely renal to widespread systemic vascular injury. [8] In a metanalysis four articles provided data on the disease activity. For active disease, the sensitivity of C-ANCA of C-ANCA for wegener's granulomatosis was 91% and specificity was 99%. For inactive disease the pooled sensitivity and specificity were 63% and 99.5% respectively. [9], Infact some investigators advocate immunosuppressive therapy for patients with positive C-ANCA test results and symptoms compatible with wegener's granulomatosis even in the absence of biopsy results. However several, recent reports document false positive results of C-ANCA in patients with tuberculosis, Hodgkins lymphomas, HIV, nasal sepal perforation, monoclonal gammopathies and drug induced wegener's like disease. [10],[11] Similarly, additional reports describe negative C-ANCA test results in patients with wegener's granulomatosis even in those with active disease. [12] So under recognition of false positive C-ANCA may lead to inappropriate immunosuppressive therapy and false negative may delay therapy for patients who have clinical features compatible with wegener's granulomatosis. Patients with extensive severe disease might be expected to have higher rate of positivity than those with limited disease. [9] If the prevalence or probability of s wegener's granulomatosis is low (probably 1% or less) a positive ANCA test. result is very likely to be a false positive result leading to much unnecessary, costly and even risky additional diagnostic testing. The C-ANCA may be most valuable in settings in which prevalence of wegener's granulomatosis is about 5-10%. In this prevalence range if clinician is considering the diagnosis of wegener's granulomatosis he may do an ANCA test to help identifying patients who might benefit from further evaluation such as biopsy. [9]
The time required to obtain a preliminary assessments is, two days with indirect immunofluorescence and 4-5 hours wish radioimmunoassay. A rapid service is helpful for patients with severe lung haemorrhage and for those patients whose renal functions are deteriorating allowing treatment to be staved early. [13]
ANCA for monitoring disease activity : This seems to be limited. Relapse usually occur when titers are high but increasing titers are not necessarily followed by relapses. [8] However an overall fall in antibody titers, when sustained, was corelated with disappearance of disease activity. In future this may be valuable in deciding when to withdraw treatment.
ANCA in pathogenesis : Antineutrophil antibody could theoretically play a direct role in patohgenesis by causing granulocyte lysis and subsequent tissue necrosis. Since cytoplasmic antineutrophil antibodies may bind to both a 29-kd serine protease within neutrophils and to a much larger antigen present in neutrophil supernatant and sputum it is attractive to speculate that the target antigen may be both the protein and the complex formed by proteinase and its inhibitor. [8] Proteinase antibody complex may be protective against the inactivation by inhibitors and transported through the body to organs such as kidneys. If the proteinase in these complexes retain their enzymatic activity they might cause local damage. It has been shown that T-lymphocytes from several patients with wegener's granulomatosis are stimulated to proliferate by this antigen in contrast to lymphocytes from healthy controls. In the light of these findings, it His attractive to speculate that T-cells directed against this antigen might invade lesions which contain proteinase antibody complexes. The presence of tissue necrosis and proteinase antibndy complexes might than induce granuloma formation. [8]
Thus, for investigators the discovery of C-ANCA and its antigen provide exciting new insights into pathogenesis of wegener's granulomatosis. C-ANCA serves as useful clinical marker of wegener's granulomatosis in some patients and active disease in others.
| ¤ References | |  |
| 1. | Haworth SJ, Sawage COS, Cari D, Hughes M, Roes AJ. Lung haemorrhage in patient with wegener's granulomatosis and microscopic polyarteritis. Br Med J 1985:290: 1775-78.  |
| 2. | Haynes BF', Allen NB, Fauci AS, Diagnostic and therapeutic approach to patients with vasculitis. Med Clin North Am. 1986;70:355-68. |
| 3. | Jennette JC, Falk RJ. Diagnostic classification of antineutrophil cytoplasmic antibody-associated vasculitides. Am J Kidney Dis. 1991;18: 184-7. |
| 4. | Davies DJ, Moran JE, Niall JF, Ryan JB. Segmental necrotizing glomerulonephritis with antineurophil antibody;; possible arbovirus aetiology? Br Med J. 1982;285:606. |
| 5. | Vander Woude FJ. Anticytoplasmic antibodies in wegener's granulomatosis Lancet. 1985;2:48. |
| 6. | Falk RJ, Jennette JC. Antineurophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patient swith systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engi J Med. 1988;318:1651-57. |
| 7. | Lockwood CM, Bakes D, Jones S. Whitakes KB, et al, Association of alkaline phosphatase with an autoantigen recognised by circulating antineutrophil antibodies in systemic vasculitis. Lancet. 1987;i:716-20. |
| 8. | Vander Woude FJ and Vanes LA. Pathogenesis of angitis. In : Oxford Textbook of Clinical Nephrology. Eds; Camerson S, Davidson AM, Grunfedd JP et al, Oxford University Press 1992;592-93. |
| 9. | Rao JK, Weinberger M, Oddone EZ, Allen NB et al. The role of antineutrophil cytoplasmic antibody testing in the diagnosis of wegener's granulornatosis. Ann Intern Med. 1995;123:925-32. |
| 10. | Davenport A. False positive perinuclear and cytoplasmic antineutrophil cytoplasmic antibody results leading to disdiagnosis of wegener's granulomatosis and/or microscopic cpolyarteritis. Clin Nephrol. 1992; 37:124-30. |
| 11. | Koderisc J, Anhdrassy K, Rasmussen N, Hartmann M, Tilgen W. False positive antineutrophil cytoplasmic antibodies in HIV infection. Lancet 1990;35:1227-28. |
| 12. | Mustonen J, Soppi E, Pasternack A, Hallstrom 0. Clinical significance of autoantibodies against neutrophils cytoplasmic components in patients with renal disease Ain J Nephrol. 1990;10:482-8. |
| 13. | Savage COBS, Winearls CG, Jones S et al. Prospective study of radioimmmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. 1987:1:1389-93. |
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