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Sjögren's syndrome with ANCA-associated crescentic extramembranous glomerulonephritis
Available online at
www.sciencedirect.com Joint Bone Spine 76 (2009) 188e189
Case report
Sjo¨gren’s syndrome with ANCA-associated crescentic extramembranous glomerulonephritis Xavier Guillot a,*, Elisabeth Solau-Gervais a, Alix Coulon b, Franc¸oise Debiais a b
a Service de rhumatologie, CHU de POITIERS, Hoˆpital Jean Bernard, Avenue Jacques Cœur, 86000 Poitiers, France Laboratoire d’anatomopathologie, CHU de POITIERS, Hoˆpital Jean Bernard, Avenue Jacques Cœur, 86000 Poitiers, France
Accepted 7 May 2008 Available online 3 February 2009
Abstract A 49-year-old woman with a 1-year history of Sjo¨gren’s syndrome was diagnosed with cutaneous leukocytoclastic vasculitis and necrotizing crescentic membranous glomerulonephritis. Antineutrophil cytoplasmic antibodies targeting myeloperoxidase were found. She reported a transient episode of nephritis 4 years earlier. This pattern of kidney disease is not typical of Sjo¨gren’s syndrome. Methylprednisolone boluses followed by oral glucocorticoid therapy were given in combination with mycophenolate mofetil. Renal function stabilized after 2 months, and tests for anti-myeloperoxidase reverted to negative. Ó 2008 Socie´te´ Franc¸aise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved. Keywords: Sjo¨gren’s syndrome; Leukocytoclastic vasculitis; Antineutrophil cytoplasmic antibodies; Anti-myeloperoxidase antibodies; Necrotizing glomerulonephritis; Mycophenolate mofetil
1. Case-report A 49-year-old woman was admitted to our rheumatology department in November 2006 for evaluation of polyarthralgia with xerophthalmia and xerostomia. In 2001, she had been diagnosed with hypertension and nephritis (proteinuria, 0.54 g/ 24 h; microscopic hematuria; and normal renal function), for which she had received follow-up at the nephrology department. A renal biopsy done in 2002 had shown a single focus of segmental hyalinosis. Treatment with the angiotensin-converting enzyme inhibitor ramipril had been effective in reversing the renal manifestations. She also reported a history of meningeal hemorrhage due to a carotid artery aneurysm. She had been on fluoxetine since 2002 and was also using a tixocortolechlorhexidine oral spray, and acetaminophen. She reported a 1-year history of incapacitating dryness of the mouth and eyes and of mixed-pattern polyarthralgia affecting the proximal interphalangeal joints, shoulders, knees, and ankles. She woke up two or three times each night and had morning * Corresponding author. Tel.: þ33 676 362 167; fax: þ33 549 444 945. E-mail address: [email protected] (X. Guillot).
stiffness for 1 h. Pain in the left flank and constipation had been present for the last few months. She also reported dysesthesia of the dorsal aspect of both feet. Sjo¨gren’s syndrome had been considered by a rheumatologist 1 month earlier. She then experienced three episodes of purpura, which resolved spontaneously. The third episode started on the day of her admission. At admission, she had a fever of 38.5 C. Her blood pressure was 130/70 mm Hg. Urine dipstick analysis showed 200 erythrocytes, 15 leukocytes, and traces of protein. Palpation showed tenderness of the finger and hand joints, wrists, shoulders, ankles, and metatarsophalangeal joints. A known mitral regurgitation murmur was heard upon auscultation of the chest. Telengiectasias were noted over the hands, forearms, ankles, and abdomen. These findings were consistent with Sjo¨gren’s syndrome. An ophthalmological evaluation with a Schirmer test and lissamine green staining confirmed the presence of xerophthalmia. Salivary flow, however, was normal (3 ml in 15 min). A minor salivary gland biopsy showed Chisholm grade 3 sialadenitis (Fig. S1; see the supplementary material associated with this article online). Laboratory tests showed inflammation (erythrocyte sedimentation rate, 99 mm/h; and C-reactive protein, 59 mg/L).
1297-319X/$ - see front matter Ó 2008 Socie´te´ Franc¸aise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2008.05.010
X. Guillot et al. / Joint Bone Spine 76 (2009) 188e189
Serum albumin was low (35 g/L), with no monoclonal component or hypergammaglobulinemia by serum protein electrophoresis. Serum urea was 8.9 nmol/L, serum creatinine 111 mmol/L, and creatinine clearance 57 ml/min compared to 80 ml/min 6 months earlier. Urine tests showed glomerular proteinuria (0.48 g/24 h), 20 leukocytes/mm3 and 9 erythrocytes/mm3, 5556 leukocytes/min and 8333 erythrocytes/min, and negative cultures. Blood cell counts were normal. Results were negative from blood cultures and from serological tests for HIV and hepatitis B and C viruses. Antinuclear antibodies were found in a titer of 1/800, with a uniform speckled pattern. Antibodies to dsDNA were positive by Crithidia luciliae assay (1/50) and negative by immunoenzymetric assay. Tests were negative for antibodies to soluble nuclear antigens including Ro/SSA and La/SSB, cryoglobulinaemia, rheumatoid factors (by latex and Waaler-Rose tests), and anti-CCP antibodies. Levels of complement (C3, C4, and CH50) were normal. Antineutrophil cytoplasmic antibodies (ANCA) were found in a perinuclear pattern. The ANCAs were IgGs to myeloperoxidase (MPO), in a titer of 21 IU. There were no antiproteinase-3 antibodies. A skin biopsy showed severe diffuse leukocytoclastic capillaritis (Fig. S2). Electrophysiological test results were consistent with mild sensory axonal polyneuropathy of the lower limbs. Findings were normal from radiographs of the chest, anteroposterior radiographs of the hands, transthoracic echocardiography, and thin-slice computed tomography of the chest. Worsening renal failure and proteinuria prompted a renal biopsy, in December 2006. Necrotizing and crescentic glomerulonephritis affecting about one glomerule in six was found (Fig. S3). Three glomerules showed long-standing sclerosis and one exhibited segmental fibrinoid necrosis with scarring and adhesion of the capillary tuft to the capsule (Fig. S4). The other glomerules were patent. Long-standing fibrosis in the interstitium was seen as scleroatrophic parenchymatous bands. The walls of the interlobular arterioles exhibited fibroelastic subintimal proliferation, with no visible fibrinoid necrosis. By direct immunofluorescence, none of the antibodies to heavy or light immunoglobulin chains or to complement components bound specifically to the glomerules. Anti-fibrinogen antibody bound strongly to two recent foci of segmental fibrinoid necrosis of the capillary tufts with crescent formation. The interlobular arterioles showed no evidence of necrotizing vasculitis. The fever resolved as the purpuric lesions developed over the first 24 h of the hospital stay. The purpura then cleared spontaneously within 48 h. The sicca syndrome was treated with artificial tears and the cholinergic agonist pilocarpine (10 mg/day orally). The limited number of damaged glomerules indicated a fairly good prognosis of the renal disease. Intravenous methylprednisolone pulse therapy was administered for 3 days, after which the patient was switched to oral prednisolone therapy combined with mycophenolate mofetil in a dosage of 1 g bid during 12e18 months. An evaluation was performed 2 months into mycophenolate mofetil therapy, at a time when the prednisolone dosage was 40 mg/day. Renal function and proteinuria were unchanged. Tests were negative for anti-MPO ANCAs. The joint pain was considerably
189
alleviated, whereas the manifestations of sicca syndrome persisted unchanged. Two further episodes of purpura had occurred. In November 2007 an evaluation at the nephrology department showed no further deterioration in renal function. The patient reported occasional joint pain and persistence of the ocular and oral symptoms. 2. Discussion Sjo¨gren’s syndrome is an autoimmune disease that chiefly targets the exocrine glands but occasionally extends to multiple organs such as the skin, kidney, and nervous system, as illustrated by our case-report. The symptoms and laboratory findings led us to consider a number of diagnoses. The final diagnosis was Sjo¨gren’s syndrome with renal and cutaneous vasculitis. The typical pattern of renal disease associated with Sjo¨gren’s syndrome is tubulointerstitial nephritis with distal acidosis. However, a review published in 2005 suggested that glomerulonephritis may account for up to 44% of cases of renal disease in patients with primary Sjo¨gren’s syndrome and may be associated with cryoglobulinaemia in about half the cases [1]. Anti-MPO ANCA has been found in 26% of patients with Sjo¨gren’s syndrome [2]. The original feature of our case-report is the presence of vasculitis associated with Sjo¨gren’s syndrome, with crescentic membranous glomerulonephritis and anti-MPO ANCAs consistent with microscopic polyangiitis [3]. Our case-report illustrates the ill-defined nature of the boundaries that separate the various patterns of small-vessel vasculitis [4]. Mycophenolate mofetil, as used in our patient, was associated with a 50% complete-remission rate in a study of 51 patients who had relapsing ANCA-associated vasculitis [5]. This drug is being increasingly used as the first-line treatment, based on its better safety profile compared to cyclophosphamide.
Appendix. Supplementary material Supplementary material (Fig. S1eS4) associated with this article can be found at http://www.sciencedirect.com, at doi: 10.1016/j.jbspin.2008.05.010. References [1] Ramos-Casals M, Tzioufas AG, Font J. Primary Sjogren’s syndrome: new clinical and therapeutic concepts. Ann Rheum Dis 2005;64:347e54. [2] Gross WL, Schmitt WH, Csernok E. Antineutrophil cytoplasmic antibody associated diseases: a rheumatologist’s perspective. Am J Kidney Dis 1991;18:175e9. [3] Radaelli F, Meucci G, Spinzi G, et al. Acute self-limiting jejunitis as the first manifestation of microscopic polyangiitis associated with Sjogren’s disease: report of one case and review of the literature. Eur J Gastroenterol Hepatol 1999;11:931e4. [4] Kahn MF, Peltier A, Meyer O, et al. Classification des vascularites syste´miques. Maladies et syndromes syste´miques. 4e e´d. Paris: Flammarion Me´decine-Sciences; 2000. p. 28e29. [5] Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clin Pract 2006;102:c100e7.
www.sciencedirect.com Joint Bone Spine 76 (2009) 188e189
Case report
Sjo¨gren’s syndrome with ANCA-associated crescentic extramembranous glomerulonephritis Xavier Guillot a,*, Elisabeth Solau-Gervais a, Alix Coulon b, Franc¸oise Debiais a b
a Service de rhumatologie, CHU de POITIERS, Hoˆpital Jean Bernard, Avenue Jacques Cœur, 86000 Poitiers, France Laboratoire d’anatomopathologie, CHU de POITIERS, Hoˆpital Jean Bernard, Avenue Jacques Cœur, 86000 Poitiers, France
Accepted 7 May 2008 Available online 3 February 2009
Abstract A 49-year-old woman with a 1-year history of Sjo¨gren’s syndrome was diagnosed with cutaneous leukocytoclastic vasculitis and necrotizing crescentic membranous glomerulonephritis. Antineutrophil cytoplasmic antibodies targeting myeloperoxidase were found. She reported a transient episode of nephritis 4 years earlier. This pattern of kidney disease is not typical of Sjo¨gren’s syndrome. Methylprednisolone boluses followed by oral glucocorticoid therapy were given in combination with mycophenolate mofetil. Renal function stabilized after 2 months, and tests for anti-myeloperoxidase reverted to negative. Ó 2008 Socie´te´ Franc¸aise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved. Keywords: Sjo¨gren’s syndrome; Leukocytoclastic vasculitis; Antineutrophil cytoplasmic antibodies; Anti-myeloperoxidase antibodies; Necrotizing glomerulonephritis; Mycophenolate mofetil
1. Case-report A 49-year-old woman was admitted to our rheumatology department in November 2006 for evaluation of polyarthralgia with xerophthalmia and xerostomia. In 2001, she had been diagnosed with hypertension and nephritis (proteinuria, 0.54 g/ 24 h; microscopic hematuria; and normal renal function), for which she had received follow-up at the nephrology department. A renal biopsy done in 2002 had shown a single focus of segmental hyalinosis. Treatment with the angiotensin-converting enzyme inhibitor ramipril had been effective in reversing the renal manifestations. She also reported a history of meningeal hemorrhage due to a carotid artery aneurysm. She had been on fluoxetine since 2002 and was also using a tixocortolechlorhexidine oral spray, and acetaminophen. She reported a 1-year history of incapacitating dryness of the mouth and eyes and of mixed-pattern polyarthralgia affecting the proximal interphalangeal joints, shoulders, knees, and ankles. She woke up two or three times each night and had morning * Corresponding author. Tel.: þ33 676 362 167; fax: þ33 549 444 945. E-mail address: [email protected] (X. Guillot).
stiffness for 1 h. Pain in the left flank and constipation had been present for the last few months. She also reported dysesthesia of the dorsal aspect of both feet. Sjo¨gren’s syndrome had been considered by a rheumatologist 1 month earlier. She then experienced three episodes of purpura, which resolved spontaneously. The third episode started on the day of her admission. At admission, she had a fever of 38.5 C. Her blood pressure was 130/70 mm Hg. Urine dipstick analysis showed 200 erythrocytes, 15 leukocytes, and traces of protein. Palpation showed tenderness of the finger and hand joints, wrists, shoulders, ankles, and metatarsophalangeal joints. A known mitral regurgitation murmur was heard upon auscultation of the chest. Telengiectasias were noted over the hands, forearms, ankles, and abdomen. These findings were consistent with Sjo¨gren’s syndrome. An ophthalmological evaluation with a Schirmer test and lissamine green staining confirmed the presence of xerophthalmia. Salivary flow, however, was normal (3 ml in 15 min). A minor salivary gland biopsy showed Chisholm grade 3 sialadenitis (Fig. S1; see the supplementary material associated with this article online). Laboratory tests showed inflammation (erythrocyte sedimentation rate, 99 mm/h; and C-reactive protein, 59 mg/L).
1297-319X/$ - see front matter Ó 2008 Socie´te´ Franc¸aise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2008.05.010
X. Guillot et al. / Joint Bone Spine 76 (2009) 188e189
Serum albumin was low (35 g/L), with no monoclonal component or hypergammaglobulinemia by serum protein electrophoresis. Serum urea was 8.9 nmol/L, serum creatinine 111 mmol/L, and creatinine clearance 57 ml/min compared to 80 ml/min 6 months earlier. Urine tests showed glomerular proteinuria (0.48 g/24 h), 20 leukocytes/mm3 and 9 erythrocytes/mm3, 5556 leukocytes/min and 8333 erythrocytes/min, and negative cultures. Blood cell counts were normal. Results were negative from blood cultures and from serological tests for HIV and hepatitis B and C viruses. Antinuclear antibodies were found in a titer of 1/800, with a uniform speckled pattern. Antibodies to dsDNA were positive by Crithidia luciliae assay (1/50) and negative by immunoenzymetric assay. Tests were negative for antibodies to soluble nuclear antigens including Ro/SSA and La/SSB, cryoglobulinaemia, rheumatoid factors (by latex and Waaler-Rose tests), and anti-CCP antibodies. Levels of complement (C3, C4, and CH50) were normal. Antineutrophil cytoplasmic antibodies (ANCA) were found in a perinuclear pattern. The ANCAs were IgGs to myeloperoxidase (MPO), in a titer of 21 IU. There were no antiproteinase-3 antibodies. A skin biopsy showed severe diffuse leukocytoclastic capillaritis (Fig. S2). Electrophysiological test results were consistent with mild sensory axonal polyneuropathy of the lower limbs. Findings were normal from radiographs of the chest, anteroposterior radiographs of the hands, transthoracic echocardiography, and thin-slice computed tomography of the chest. Worsening renal failure and proteinuria prompted a renal biopsy, in December 2006. Necrotizing and crescentic glomerulonephritis affecting about one glomerule in six was found (Fig. S3). Three glomerules showed long-standing sclerosis and one exhibited segmental fibrinoid necrosis with scarring and adhesion of the capillary tuft to the capsule (Fig. S4). The other glomerules were patent. Long-standing fibrosis in the interstitium was seen as scleroatrophic parenchymatous bands. The walls of the interlobular arterioles exhibited fibroelastic subintimal proliferation, with no visible fibrinoid necrosis. By direct immunofluorescence, none of the antibodies to heavy or light immunoglobulin chains or to complement components bound specifically to the glomerules. Anti-fibrinogen antibody bound strongly to two recent foci of segmental fibrinoid necrosis of the capillary tufts with crescent formation. The interlobular arterioles showed no evidence of necrotizing vasculitis. The fever resolved as the purpuric lesions developed over the first 24 h of the hospital stay. The purpura then cleared spontaneously within 48 h. The sicca syndrome was treated with artificial tears and the cholinergic agonist pilocarpine (10 mg/day orally). The limited number of damaged glomerules indicated a fairly good prognosis of the renal disease. Intravenous methylprednisolone pulse therapy was administered for 3 days, after which the patient was switched to oral prednisolone therapy combined with mycophenolate mofetil in a dosage of 1 g bid during 12e18 months. An evaluation was performed 2 months into mycophenolate mofetil therapy, at a time when the prednisolone dosage was 40 mg/day. Renal function and proteinuria were unchanged. Tests were negative for anti-MPO ANCAs. The joint pain was considerably
189
alleviated, whereas the manifestations of sicca syndrome persisted unchanged. Two further episodes of purpura had occurred. In November 2007 an evaluation at the nephrology department showed no further deterioration in renal function. The patient reported occasional joint pain and persistence of the ocular and oral symptoms. 2. Discussion Sjo¨gren’s syndrome is an autoimmune disease that chiefly targets the exocrine glands but occasionally extends to multiple organs such as the skin, kidney, and nervous system, as illustrated by our case-report. The symptoms and laboratory findings led us to consider a number of diagnoses. The final diagnosis was Sjo¨gren’s syndrome with renal and cutaneous vasculitis. The typical pattern of renal disease associated with Sjo¨gren’s syndrome is tubulointerstitial nephritis with distal acidosis. However, a review published in 2005 suggested that glomerulonephritis may account for up to 44% of cases of renal disease in patients with primary Sjo¨gren’s syndrome and may be associated with cryoglobulinaemia in about half the cases [1]. Anti-MPO ANCA has been found in 26% of patients with Sjo¨gren’s syndrome [2]. The original feature of our case-report is the presence of vasculitis associated with Sjo¨gren’s syndrome, with crescentic membranous glomerulonephritis and anti-MPO ANCAs consistent with microscopic polyangiitis [3]. Our case-report illustrates the ill-defined nature of the boundaries that separate the various patterns of small-vessel vasculitis [4]. Mycophenolate mofetil, as used in our patient, was associated with a 50% complete-remission rate in a study of 51 patients who had relapsing ANCA-associated vasculitis [5]. This drug is being increasingly used as the first-line treatment, based on its better safety profile compared to cyclophosphamide.
Appendix. Supplementary material Supplementary material (Fig. S1eS4) associated with this article can be found at http://www.sciencedirect.com, at doi: 10.1016/j.jbspin.2008.05.010. References [1] Ramos-Casals M, Tzioufas AG, Font J. Primary Sjogren’s syndrome: new clinical and therapeutic concepts. Ann Rheum Dis 2005;64:347e54. [2] Gross WL, Schmitt WH, Csernok E. Antineutrophil cytoplasmic antibody associated diseases: a rheumatologist’s perspective. Am J Kidney Dis 1991;18:175e9. [3] Radaelli F, Meucci G, Spinzi G, et al. Acute self-limiting jejunitis as the first manifestation of microscopic polyangiitis associated with Sjogren’s disease: report of one case and review of the literature. Eur J Gastroenterol Hepatol 1999;11:931e4. [4] Kahn MF, Peltier A, Meyer O, et al. Classification des vascularites syste´miques. Maladies et syndromes syste´miques. 4e e´d. Paris: Flammarion Me´decine-Sciences; 2000. p. 28e29. [5] Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clin Pract 2006;102:c100e7.