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ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIS PRESENTING AS SJOGREN'S SYNDROME ERWIN P. BOTTINGER, JOHN L. NILES, A. BERNARD COLLINS, ROBERT T. McCLUSKEY, and M. AMIN ARNAOUT A 63-year-old woman, in whom a diagnosis of Sjogren's syndrome was initially made, proved to have systemic vasculitis with salivary gland involvement and necrotizing and crescentic glomerulonephritis. Antineutrophil cytoplasmic autoantibodies (ANCA) against myeloperoxidase were positive. ANCA-associated vasculitis should be considered in the differential diagnosis of Sjogren's syndrome. A positive finding on immunoassay for ANCA against myeloperoxidase or proteinase 3 may help establish the diagnosis. The availability of tests for circulating antineutrophil cytoplasmic autoantibodies (ANCA) has altered the approach to the diagnosis and classification of a spectrum of diseases that includes Wegener's granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, primary necrotizing and crescentic glomerulonephritis, and related or overlapping forms of these vasculitides (1). Two types of ANCA have proven diagnostic value: anti-proteinase 3 (anti-PR3) and antimyeloperoxidase (anti-MPO) autoantibodies. By indirect immunofluorescence, these autoantibodies stain From the Leukocyte Biology and Inflammation Program, the Renal Unit, and the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Supported by NIH grant DK-42722. Dr. Bottinger is a fellow of the National Kidney Foundation. Erwin P. Bottinger, MD: Leukocyte Biology and Inflammation Program and Renal Unit; John L. Niles, MD: Department of Pathology; A. Bernard Collins: Department of Pathology; Robert T. McCluskey, MD: Department of Pathology; M. Amin Arnaout, MD: Leukocyte Biology and Inflammation Program and Renal Unit. Address reprint requests to Erwin P. Bottinger, MD, Leukocyte Biology and Inflammation Program, Eighth Floor, Massachusetts General Hospital East, 149 13th Street, Charlestown, MA 02129. Submitted for publication February 7, 1992; accepted in revised form June 6, 1992. Arthritis and Rheumatism, Vol. 35, No. 11 (November 1992)
with a cytoplasmic pattern (c-ANCA) or a perinuclear pattern (p-ANCA), respectively. One or the other of these autoantibodies, but not both, is found in a high percentage of patients with the conditions noted above, and rarely in patients with other diseases (2-4). Although the autoantibodies apparently identify a spectrum of related conditions, subclassification within the spectrum is imperfect, since the conditions often exhibit overlapping or atypical clinical and pathologic features, and since there is lack of agreement about terminology. Of practical importance, all of the conditions usually respond to cyclophosphamide and steroids. However, unless treatment is begun early, serious and irreversible damage may develop (5). Early diagnosis is especially difficult in patients who present with unusual features. We describe such a patient, whose initial manifestations were those of Sjogren's syndrome (SS); these manifestations resulted from lesions characteristic of Wegener's granulomatosis, involving the salivary glands.
CASE REPORT The patient, a 63-year-old woman, was transferred from an outside hospital with the diagnosis of SS and acute renal insufficiency. Seven months earlier, she had developed submandibular gland swelling with dry mouth and dry eyes. Four months thereafter she still had enlarged submandibular glands and severe xerostomia and had developed keratoconjunctivitis sicca with strongly positive Schirmer's test results bilaterally, as well as fever, night sweats, weight loss, and an erythrocyte sedimentation rate of 100 mml hour. Findings were negative on tests for antinuclear
BOTTINGER ET AL
1374
A
B
Figure 1. Biopsy sections of submandibular gland. A, Leukocyte infiltration of the wall and perivascular fibrosis in a small artery. B, Mononuclear and multinuclear histiocytes in the wall of a small artery. (Hematoxylin and eosin stained, original magnification x 313.)
antibody, rheumatoid factor, anti-So-A, anti-SS-B, human immunodeficiency virus, and purified protein derivative. The results of indirect immunofluorescence tests for ANCA, performed at a reference laboratory, were negative. Radiographs of the chest showed bilateral hyperinflation and a possible infiltrate in the medial segment of the right middle lobe. Bone marrow biopsy showed no abnormalities. Results of urinalysis and renal function testing were normal. Findings on submandibular gland biopsy were interpreted as indicative of acute and chronic sialadenitis. A diagnosis of SS was made and the patient was treated with oral prednisone, without improvement. One month later her serum creatinine level was 2.0 mg/dl. One week before transfer to our hospital, she presented with pulmonary edema, hypertension, and a serum creatinine level of 2.3 mg/dl. Results of physical examination on admission to our hospital were remarkable for enlarged submandibular glands bilaterally. Findings on chest radiogra-
phy were normal. Urinary sediment showed red blood cell casts. Twenty-four-hour urinary protein excretion was 2,075 mg. Findings on tests for anti-SS-A, antiSS-B, anti-double-stranded DNA, and rheumatoid factor were again negative. Testing for ANCA was performed on the second day of the admission. By indirect immunofluorescence, perinuclear staining of ethanol-fixed neutrophils was seen. Radioimmunoassays (4) revealed autoantibodies to MPO. A renal biopsy was performed on the same day, after which treatment was started with intravenous pulse methylprednisolone (l gm/day for 3 days) and cyclophosphamide (2 mg/kg/day). Renal biopsy showed necrotizing and crescentic glomerulonephritis, periglomerular granulomatous inflammation, and focal arteritis; findings on direct immunofluorescence were negative. Subsequent review of the earlier submandibular gland biopsy sections (Figures IA and B) revealed irregular infiltration by lymphocytes, with scattered eosinophils and neutro-
1375
ANCA-POSITIVE VASCULITIS PRESENTING AS SS
phils. There was lymphocytic invasion of ducts and acini, but no epithelial islands were seen. Several small arteries showed necrosis and neutrophil infiltration of their walls. Multinuclear giant cells were seen in 2 vessels. Based on these histologic findings, we classified this patient as having Wegener's granulomatosis (6). Four weeks later the submandibular gland swelling had disappeared. Xerostomia and keratoconjunctivitis sicca had resolved. Renal function remained stable without red blood cell casts. Findings on a repeat test for ANCA were negative.
with isolated lesions in the sclera (7,8), lacrimal glands (9), salivary glands (10,11), and respiratory tract (6,12,13), some of whom subsequently developed disseminated disease with renal involvement. Most patients with documented lesions of Wegener's granulomatosis have anti-PR3 autoantibodies (2); nevertheless, some have anti-MPO autoantibodies (7,8,14). The present case illustrates the importance of considering the diagnosis of ANCA-associated vasculitis in patients who present with apparent SS. Assays for autoantibodies against MPO and PR3 may help establish the diagnosis before serious pulmonary and renal disease develops.
DISCUSSION The patient described herein was first considered to have Sjogren's syndrome, but was later recognized to have an ANCA-associated form of vasculitis that initially involved the salivary glands. The diagnosis became clear only after she had developed renal insufficiency from necrotizing and crescentic glomerulonephritis and was found to have anti-MPO autoantibodies. Although the results of a test for ANCA performed shortly after her initial presentation were reported as negative, the only method used was immunofluorescence, which is unreliable for the documentation of anti-MPO autoantibodies (3,4). Whether a more sensitive antigen-specific radioimmunoassay or enzyme-linked immunosorbent assay would have detected autoantibodies at that apparently limited stage of her disease is not known. However, it is possible that the initial result was truly negative, because some patients with limited Wegener's granulomatosis develop detectable autoantibodies only after the disease becomes systemic (2). The present case of ANCA-associated vasculitis can be classified as Wegener's granulomatosis, which deserves comment. Based on the pathologic finding of necrotizing and crescentic glomerulonephritis with scant immune deposits, together with arteritis in the kidney and salivary gland, the only other diagnosis that can be considered is polyarteritis nodosa. Because of the presence of granulomatous features in the salivary glands, we concluded that Wegener's granulomatosis was the most appropriate diagnosis. The patient did not have all the classic features of the disease, especially when she was first seen, but it is clear that not all patients with this disease have the triad of upper and lower respiratory tract and kidney involvement. There are numerous reports of patients with Wegener's granulomatosis who have presented
ACKNOWLEDGMENT We thank Dr. R. Fienberg (Department of Pathology, Massachusetts General Hospital) for expert analysis of the salivary gland tissue specimen.
REFERENCES 1. Jennette JC, Falk RJ: Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides. Am J Kidney Dis 18:184-187, 1991 2. Nolle B, Specks U, Ludemann J, Rohrbach MS, DeRemee RA, Gross WL: Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med 111:28-40, 1989 3. Cohen Tervaert JW, Goldschmeding R, Elema JD, Limburg PC, van der Giessen M, Huitema MG, Koolen MI, Hene RJ, The TH, van der Hem GK, von dem Borne AEGKr, Kallenberg CGM: Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 33:1264-1272, 1990 4. Niles JL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R, Arnaout MA, McCluskey RT: Value of antigen-specific radioimmunoassays for measuring antineutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 2:27-36, 1991 5. Pinching AJ, Lockwood CM, Pussell BA, Rees AJ, Sweny P, Evans DJ, Bowley N, Peters DK: Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q J Med 208:435-460, 1983 6. Fienberg R: Necrotizing granulomatosis and angiitis of the lungs and its relationship to chronic pneumonitis of the cholesterol type. Am J Pathol 29:913-931, 1953 7. Pulido JS, Goeken JA, Nerat JA, Sobol WM, Folberg R: Ocular manifestations of patients with circulating antineutrophil cytoplasmic antibodies. Arch Ophthalmol 108:845-850, 1990 8. Soukiasion SH, Foster CS, Niles JL, Raizman MB:
1376
Diagnostic value of anti-neutrophil cytoplasmic antibodies (ANCA) in scleritis associated with Wegener's granulomatosis. Ophthalmology 99: 125-132, 1992 9. Schmidt R, Koederisch J, Krastel H, Zeier M, Andrassy K: Sicca syndrome in patients with Wegener's granulomatosis (letter). Lancet 1:904-905, 1989 10. Specks UM, Colby TV, Olsen KD, DeRemee RA: Salivary gland involvement in Wegener's granulomatosis. Arch Otolaryngol Head Neck Surg 117:218-223, 1991 11. Murty GE, Mains BT, Bennett MK: Salivary gland
BOTTINGER ET AL
involvement in Wegener's granulomatosis. J Laryngol Otol 104:259-261, 1990 12. Fienberg R: The protracted superficial phenomenon in pathergic (Wegener's) granulomatosis. Hum Pathol 12: 458-467, 1981 13. Carrington CB, Liebow AA: Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med 41:497-527, 1966 14. Ulmer M, Rautmann A, Gross WL: Immunodiagnostic aspects of autoantibodies against myeloperoxidase. Clin Nephrol 37:161-168, 1992
ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIS PRESENTING AS SJOGREN'S SYNDROME ERWIN P. BOTTINGER, JOHN L. NILES, A. BERNARD COLLINS, ROBERT T. McCLUSKEY, and M. AMIN ARNAOUT A 63-year-old woman, in whom a diagnosis of Sjogren's syndrome was initially made, proved to have systemic vasculitis with salivary gland involvement and necrotizing and crescentic glomerulonephritis. Antineutrophil cytoplasmic autoantibodies (ANCA) against myeloperoxidase were positive. ANCA-associated vasculitis should be considered in the differential diagnosis of Sjogren's syndrome. A positive finding on immunoassay for ANCA against myeloperoxidase or proteinase 3 may help establish the diagnosis. The availability of tests for circulating antineutrophil cytoplasmic autoantibodies (ANCA) has altered the approach to the diagnosis and classification of a spectrum of diseases that includes Wegener's granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, primary necrotizing and crescentic glomerulonephritis, and related or overlapping forms of these vasculitides (1). Two types of ANCA have proven diagnostic value: anti-proteinase 3 (anti-PR3) and antimyeloperoxidase (anti-MPO) autoantibodies. By indirect immunofluorescence, these autoantibodies stain From the Leukocyte Biology and Inflammation Program, the Renal Unit, and the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Supported by NIH grant DK-42722. Dr. Bottinger is a fellow of the National Kidney Foundation. Erwin P. Bottinger, MD: Leukocyte Biology and Inflammation Program and Renal Unit; John L. Niles, MD: Department of Pathology; A. Bernard Collins: Department of Pathology; Robert T. McCluskey, MD: Department of Pathology; M. Amin Arnaout, MD: Leukocyte Biology and Inflammation Program and Renal Unit. Address reprint requests to Erwin P. Bottinger, MD, Leukocyte Biology and Inflammation Program, Eighth Floor, Massachusetts General Hospital East, 149 13th Street, Charlestown, MA 02129. Submitted for publication February 7, 1992; accepted in revised form June 6, 1992. Arthritis and Rheumatism, Vol. 35, No. 11 (November 1992)
with a cytoplasmic pattern (c-ANCA) or a perinuclear pattern (p-ANCA), respectively. One or the other of these autoantibodies, but not both, is found in a high percentage of patients with the conditions noted above, and rarely in patients with other diseases (2-4). Although the autoantibodies apparently identify a spectrum of related conditions, subclassification within the spectrum is imperfect, since the conditions often exhibit overlapping or atypical clinical and pathologic features, and since there is lack of agreement about terminology. Of practical importance, all of the conditions usually respond to cyclophosphamide and steroids. However, unless treatment is begun early, serious and irreversible damage may develop (5). Early diagnosis is especially difficult in patients who present with unusual features. We describe such a patient, whose initial manifestations were those of Sjogren's syndrome (SS); these manifestations resulted from lesions characteristic of Wegener's granulomatosis, involving the salivary glands.
CASE REPORT The patient, a 63-year-old woman, was transferred from an outside hospital with the diagnosis of SS and acute renal insufficiency. Seven months earlier, she had developed submandibular gland swelling with dry mouth and dry eyes. Four months thereafter she still had enlarged submandibular glands and severe xerostomia and had developed keratoconjunctivitis sicca with strongly positive Schirmer's test results bilaterally, as well as fever, night sweats, weight loss, and an erythrocyte sedimentation rate of 100 mml hour. Findings were negative on tests for antinuclear
BOTTINGER ET AL
1374
A
B
Figure 1. Biopsy sections of submandibular gland. A, Leukocyte infiltration of the wall and perivascular fibrosis in a small artery. B, Mononuclear and multinuclear histiocytes in the wall of a small artery. (Hematoxylin and eosin stained, original magnification x 313.)
antibody, rheumatoid factor, anti-So-A, anti-SS-B, human immunodeficiency virus, and purified protein derivative. The results of indirect immunofluorescence tests for ANCA, performed at a reference laboratory, were negative. Radiographs of the chest showed bilateral hyperinflation and a possible infiltrate in the medial segment of the right middle lobe. Bone marrow biopsy showed no abnormalities. Results of urinalysis and renal function testing were normal. Findings on submandibular gland biopsy were interpreted as indicative of acute and chronic sialadenitis. A diagnosis of SS was made and the patient was treated with oral prednisone, without improvement. One month later her serum creatinine level was 2.0 mg/dl. One week before transfer to our hospital, she presented with pulmonary edema, hypertension, and a serum creatinine level of 2.3 mg/dl. Results of physical examination on admission to our hospital were remarkable for enlarged submandibular glands bilaterally. Findings on chest radiogra-
phy were normal. Urinary sediment showed red blood cell casts. Twenty-four-hour urinary protein excretion was 2,075 mg. Findings on tests for anti-SS-A, antiSS-B, anti-double-stranded DNA, and rheumatoid factor were again negative. Testing for ANCA was performed on the second day of the admission. By indirect immunofluorescence, perinuclear staining of ethanol-fixed neutrophils was seen. Radioimmunoassays (4) revealed autoantibodies to MPO. A renal biopsy was performed on the same day, after which treatment was started with intravenous pulse methylprednisolone (l gm/day for 3 days) and cyclophosphamide (2 mg/kg/day). Renal biopsy showed necrotizing and crescentic glomerulonephritis, periglomerular granulomatous inflammation, and focal arteritis; findings on direct immunofluorescence were negative. Subsequent review of the earlier submandibular gland biopsy sections (Figures IA and B) revealed irregular infiltration by lymphocytes, with scattered eosinophils and neutro-
1375
ANCA-POSITIVE VASCULITIS PRESENTING AS SS
phils. There was lymphocytic invasion of ducts and acini, but no epithelial islands were seen. Several small arteries showed necrosis and neutrophil infiltration of their walls. Multinuclear giant cells were seen in 2 vessels. Based on these histologic findings, we classified this patient as having Wegener's granulomatosis (6). Four weeks later the submandibular gland swelling had disappeared. Xerostomia and keratoconjunctivitis sicca had resolved. Renal function remained stable without red blood cell casts. Findings on a repeat test for ANCA were negative.
with isolated lesions in the sclera (7,8), lacrimal glands (9), salivary glands (10,11), and respiratory tract (6,12,13), some of whom subsequently developed disseminated disease with renal involvement. Most patients with documented lesions of Wegener's granulomatosis have anti-PR3 autoantibodies (2); nevertheless, some have anti-MPO autoantibodies (7,8,14). The present case illustrates the importance of considering the diagnosis of ANCA-associated vasculitis in patients who present with apparent SS. Assays for autoantibodies against MPO and PR3 may help establish the diagnosis before serious pulmonary and renal disease develops.
DISCUSSION The patient described herein was first considered to have Sjogren's syndrome, but was later recognized to have an ANCA-associated form of vasculitis that initially involved the salivary glands. The diagnosis became clear only after she had developed renal insufficiency from necrotizing and crescentic glomerulonephritis and was found to have anti-MPO autoantibodies. Although the results of a test for ANCA performed shortly after her initial presentation were reported as negative, the only method used was immunofluorescence, which is unreliable for the documentation of anti-MPO autoantibodies (3,4). Whether a more sensitive antigen-specific radioimmunoassay or enzyme-linked immunosorbent assay would have detected autoantibodies at that apparently limited stage of her disease is not known. However, it is possible that the initial result was truly negative, because some patients with limited Wegener's granulomatosis develop detectable autoantibodies only after the disease becomes systemic (2). The present case of ANCA-associated vasculitis can be classified as Wegener's granulomatosis, which deserves comment. Based on the pathologic finding of necrotizing and crescentic glomerulonephritis with scant immune deposits, together with arteritis in the kidney and salivary gland, the only other diagnosis that can be considered is polyarteritis nodosa. Because of the presence of granulomatous features in the salivary glands, we concluded that Wegener's granulomatosis was the most appropriate diagnosis. The patient did not have all the classic features of the disease, especially when she was first seen, but it is clear that not all patients with this disease have the triad of upper and lower respiratory tract and kidney involvement. There are numerous reports of patients with Wegener's granulomatosis who have presented
ACKNOWLEDGMENT We thank Dr. R. Fienberg (Department of Pathology, Massachusetts General Hospital) for expert analysis of the salivary gland tissue specimen.
REFERENCES 1. Jennette JC, Falk RJ: Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides. Am J Kidney Dis 18:184-187, 1991 2. Nolle B, Specks U, Ludemann J, Rohrbach MS, DeRemee RA, Gross WL: Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med 111:28-40, 1989 3. Cohen Tervaert JW, Goldschmeding R, Elema JD, Limburg PC, van der Giessen M, Huitema MG, Koolen MI, Hene RJ, The TH, van der Hem GK, von dem Borne AEGKr, Kallenberg CGM: Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 33:1264-1272, 1990 4. Niles JL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R, Arnaout MA, McCluskey RT: Value of antigen-specific radioimmunoassays for measuring antineutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 2:27-36, 1991 5. Pinching AJ, Lockwood CM, Pussell BA, Rees AJ, Sweny P, Evans DJ, Bowley N, Peters DK: Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q J Med 208:435-460, 1983 6. Fienberg R: Necrotizing granulomatosis and angiitis of the lungs and its relationship to chronic pneumonitis of the cholesterol type. Am J Pathol 29:913-931, 1953 7. Pulido JS, Goeken JA, Nerat JA, Sobol WM, Folberg R: Ocular manifestations of patients with circulating antineutrophil cytoplasmic antibodies. Arch Ophthalmol 108:845-850, 1990 8. Soukiasion SH, Foster CS, Niles JL, Raizman MB:
1376
Diagnostic value of anti-neutrophil cytoplasmic antibodies (ANCA) in scleritis associated with Wegener's granulomatosis. Ophthalmology 99: 125-132, 1992 9. Schmidt R, Koederisch J, Krastel H, Zeier M, Andrassy K: Sicca syndrome in patients with Wegener's granulomatosis (letter). Lancet 1:904-905, 1989 10. Specks UM, Colby TV, Olsen KD, DeRemee RA: Salivary gland involvement in Wegener's granulomatosis. Arch Otolaryngol Head Neck Surg 117:218-223, 1991 11. Murty GE, Mains BT, Bennett MK: Salivary gland
BOTTINGER ET AL
involvement in Wegener's granulomatosis. J Laryngol Otol 104:259-261, 1990 12. Fienberg R: The protracted superficial phenomenon in pathergic (Wegener's) granulomatosis. Hum Pathol 12: 458-467, 1981 13. Carrington CB, Liebow AA: Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med 41:497-527, 1966 14. Ulmer M, Rautmann A, Gross WL: Immunodiagnostic aspects of autoantibodies against myeloperoxidase. Clin Nephrol 37:161-168, 1992
