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Wegener's granulomatosis presenting with sclerokeratitis diagnosed by antineutrophil cytoplasmic autoantibodies (ANCA)
SURVEY OF OPHTHALMOLOGY
VOLUME 37 - NUMBER 5. MARCH-APRIL 1993
AFTERIMAGES
, JONATHAN
WIRTSCHAFTER, EDITOR
Wegener’s Granulomatosis Presenting with Sclerokeratitis Diagnosed by Antineutrophil Cytoplasmic Autoantibodies (ANCA) CRAIG W. FLORINE,
M.D.,’ MARK DWYER, M.D.,2 AND EDWARD J. HOLLAND,
M.D.’
‘Cornea Service, Def,avtment of O/,&thalmology, University of Minnesota M?meapolis, Mimrsotn, ad -Bemidji Clinic, Bemidji, Mirmesota
Abstract. A U-year-old male presented with bilateral sclerokeratitis. He reported recent bronchitis, sinusitis, dyspnea on exertion, hemoptysis, arthralgias and myalgias. Wegener’s granulomatosis was diagnosed by a positive antineutrophil cytoplasmic autoantibody (ANCA) test and a nasal and subglotic biopsy showing granulomatous inflammation. Trcatment with cyclophosphamide, systemic corticosteroids and trimethoprimisulfamethoxazole resulted in resolution of the sclerokeratitis and remission of the disease. (SW-V Ophthalmol 37:373-376, 1993)
Key words. antineutrophil Wegcner’s granulomatosis
cytoplasmic
Case Kepol?. A 2%year-old white male presented with a s-month history of a red and increasingly painful right eye with an initial appearance of a conjunctivitis. He was treated with topical sulfacetamide TID OD. There was some improvement initially, but the patient had increasing injection with pain and developed conjunctival ulceration after one week of treatment. The inflammation progressed to a scleritis and peripheral keratitis in both eyes. Past ocular history was unremarkable. Past medical history was remarkable for recent treatment of bronchitis and sinusitis with Amoxicillin for two weeks with no improvement. Keview of systems revealed general malaise and anthralgias of both knees and right elbow, weight loss, dyspnea on exertion and hemoptysis that had gradually become worse over the past 3-4 months. Phvsical examination was remarkable for enlarged tonsils and transmitted
autoantibodies
l
scleritis
l
upper airway sounds, but no wheezes. rales or rhonchi. Eye examination on presentation at the University of Minnesota revealed visual acuities of 20120 in both eyes, with a correction of - 0.50 + 0.75 x 123 OD and - 0.50 + 0.50 x 88 OS. The pupils were equal in size and normally reactive without a relative afferent defect. Extraocular motility was full and the patient was orthophoric at distance. Slit-lamp examination revealed an area of injection of the medial palpebral conjunctiva of the right upper lid with overlying ulceration. There was a large ulcerated scleral nodule of the right eye at the limbus from 11 to 2 o’clock, along with diffuse conjunctival and scleral injection (Fig. 1). The cornea had a large peripheral superficial stromal infiltrate with thinning at 12 o’clpck and scattered peripheral epithelial lesions (Fig. 2). The left eye showed a sector of
374
Surv Ophthalmol
Fig. 1. eye.
Ulcerated
37 (5) March-April
1993
scleral nodule (arrow) of the right
FLORINE ET AL
Kg. 2. Nodular sclerokeratitis infiltrates of the right eye.
with superior
cornea1
conjunctival injection from 12 to 3 o’clock with early peripheral epithelial infiltrates. Both anterior chambers were deep and quiet. Intraocular pressures by applanation tonometry were 9 mm Hg OD and 15 mm Hg OS. Lens and vitreous were normal OU. Fundus exam showed normal optic nerve, macula, vessels and peripheral retina OU. Taking into account the patients three-month history of malaise, arthralgias, weight loss, dyspnea on exertion, bronchitis and sinusitis, a systemic vasculitic process, particularly Wegener’s granulomatosis, was suspected. Laboratory work-
up included normal complete blood count with differential, negative FANA, positive antineutrophi1 cytoplasmic autoantibodies with cytoplasmic staining pattern (C-ANCA), positive RF at a titre of 1: 168, creatinine 0.9, urinalysis with moderate blood and 30 mg/dl of protein. Sinus films were normal and a chest x-ray showed bilateral perihilar masses and narrowing of the trachea and bronchus at the level of the carina (Fig. 3). A diagnosis of Wegener’s granulomatosis was made and the patient was admitted to the hospital for treatment with IV cyclophosphamide 4 mg/kg/day, IV methylprednisolone 100 mg/day
Fig. 3. Chest x-ray showing bilateral perihilar masses and narrowing of the trachea at the level of the carina (arrow).
Fig. 4. Nasal biopsy showing acute and chronic inflammation with a granuloma (arrow). (HE x 300)
WEGENER’S GRANULOMATOSIS
WITH SCLEROKERATITIS
F/g. 5.
Indirect immunoflrloresccrIce cytoplasmicst;lining ot the neutrophils arc dark in contrast.
DX BY ANCA
pattern
ofGANCA.
I‘he nuclei
I’rg. 6. Indirect immunofluoresccnce perinuclcar staining pattern of P-ANNA. This is an artifkt due to the redistribution ofsoluble cytoplasmic n~tcleophilic antigens to the perinuclear region drlring the staining process.
and trimethoprim/sulfatnethoxazole (Septra one tablet daily. A subglotic and nasal biopsy performed and showed acute and chronic
DS) was
inflammation with granuloma (Fig. 4). The patient’s course improved with resolution of all systemic symptoms and clearing of all inflammation of the left eye. The right eye had resolution of conjunctival and scleral inflamma-
clearing of‘the cornea1 infiltrates with residual thinning at 12 o’clock. The area of nodular scleritis had decreased in size and activity of inflammation. The patient was discharged on prednisone 50 mg PO I’ID, cyclophosphamide 3 mg/kg/day and Septra DS one tablet daily. The patient has continued to do well on slow tapering of the cyclophosphamide and prednisone and tion,
376
Surv Ophthalmol
the nodular
scleritis
37 (5) March-April
1993
of the right eye has resolved.
Discussion Scleritis represents inflammation of the deep vascular plexus adjacent to the sclera. Forty-six percent of patients with slceral inflammation have some other systemic disease; 35% have serologic evidence of connective tissue disorders and 17% manifest disease.” Wegener’s granulomatosis in its classic form is characterized by the triad of necrotizing granulomas of the respiratory tract, generalized focal necrotizing vasculitis and focal necrotizing glomerulonephritis. A limited form without the renal involvement is also well recognized.” Ocular involvement has been reported to occur in 28-58% of patients with Wegener’s granulomatosis.‘.“.6 Ocular manifestations reported inwith proptosis, clude orbital involvement scleritis, episcleritis, conjunctivitis, cornea1 ulceration, optic nerve vasculitis, retinal artery occlusion, retinitis, uveitis and nasolacrimal duct obstruction.‘,” Ocular signs have been reported as the presenting finding in 13-16% of patients with Wegener’s granulomatosis.‘,” Untreated Wegener’s granulomatosis carries a mean survival of five months, with 82% of patients dying within one year and more than 90% dying within two years.” Treatment with cyclocorticosteroids and trimethophosphamide, prim/sulfamethoxazole leads to a high remission rate of over 90%. Histopathological examination of biopsy specimens in patients with suspected Wegener’s seldom reveals the classic triad of vasculitis, necrosis and granulomatous inflammation,’ so the diagnosis is based on both clinical and pathological findings. Antineutrophil cytoplasmic autoantibodies (ANCA) offer a specific and sensitive laboratory test in the diagnosis of Wegener’s granulomatosis.x ANCA are specific for constituents of neutrophi1 primary granules and monocyte lysosomes. Multiple types ofANCA have been demonstrated with different specificities. The testing requires a 10 ~1 specimen that is collected in a standard chemistry tube and run by most major metropolitan laboratories. By indirect immunofluores-
FLORINE
ET AL
cence microscopy using alcohol-fixed neutrophils as substrate, two major categories ofANCA can be recognized, one with cytoplasmic staining (C-ANCA) (Fig. 5) and the other with artifactual perinuclear staining (P-ANCA) (Fig. 6). The basis for the artifactual nuclear binding of P-ANCA is the redistribution of soluble cytoplasmic nucleophilic antigens to the perinuclear region during the indirect immunostaining procedure.’ Some C-ANCA have specificity for proteinase 3 and some P-ANCA have specificity for myeloperoxidase, but there are additional C-ANCA and PANCA specificities. ANCA are found in the blood of patients with necrotizing systemic vasculitis, such as Wegener’s granulomatosis and polyarteritis nodosa, and patients with idiopathic crescentric glomerulonephritis.4.7 Patients with Wegener’s granulomatosis most often have C-ANCA and patients with renal-limited disease have PANCA. The addition of ANCA testing should be added to the laboratory workup in patients with scleritis.
References ‘IJ, McDonald TJ, DeRemee RA: I. Hullen CL, Liesegang Ocular complications of Wegener’s granulomatosis. Uphlhnl?tlologp 90:279-290, 1983 2. Devaney KO, Travis WD, Hoffman G, et al: Interpretation of head and neck biopsies in Wegener’s granulomatosis. Art1 J Surg P&ho1 14:555-564, 1990 G, Coners H, Nolle B: Ocular involvement in 3. Duncker Wegener’s granulomatosis. APMIS Su#d. 19, 98:22, 1990 systemic 4. Falk RJ, Jennette JC: Wegener’s granulomatosis, vasculitis, and antineutrophil cytoplasmic autoantibodies. Atmu Krr, Md 42;459-469, 1991 5. Fauci AS, Haynes SF, Katz P, Wolff SM: Wegener’s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. A?ln In1 Mrd 98:76-85, 1989 6. Haynes RF, Fishman ML, Fauci AS, WolffSM: .I‘he ocular manifestations of Wegener’s granulomatosis. ,4m J Md h3:151-141, 1977 Jennette JC, Falk RJ: Antineutrophil cytoplasmic autoantibodies and associated diseases: A review. Am J Kidney Dk 15:517-529, 1990 Soukiasian SW, Foster CS, Niles JL, Raizman MB: Diagnostic value of antineutrophil cytoplasmic antibodies in scleritis associated with Wegener’s granulomatosis. Ophihnlmolom 99: 125-l 32, 1992 Watson PC;: The diagnosis and management of scleritis. O,f~lrlh/rlrt~oln~ R7:7 I G-720, 1980 II.
Reprint address: Edward J, Holland, M.D., Department of Ophthalmology, University of Minnesota, Box 493 UMHC, 516 Delaware St. SE, Minneapolis, MN 55455.
VOLUME 37 - NUMBER 5. MARCH-APRIL 1993
AFTERIMAGES
, JONATHAN
WIRTSCHAFTER, EDITOR
Wegener’s Granulomatosis Presenting with Sclerokeratitis Diagnosed by Antineutrophil Cytoplasmic Autoantibodies (ANCA) CRAIG W. FLORINE,
M.D.,’ MARK DWYER, M.D.,2 AND EDWARD J. HOLLAND,
M.D.’
‘Cornea Service, Def,avtment of O/,&thalmology, University of Minnesota M?meapolis, Mimrsotn, ad -Bemidji Clinic, Bemidji, Mirmesota
Abstract. A U-year-old male presented with bilateral sclerokeratitis. He reported recent bronchitis, sinusitis, dyspnea on exertion, hemoptysis, arthralgias and myalgias. Wegener’s granulomatosis was diagnosed by a positive antineutrophil cytoplasmic autoantibody (ANCA) test and a nasal and subglotic biopsy showing granulomatous inflammation. Trcatment with cyclophosphamide, systemic corticosteroids and trimethoprimisulfamethoxazole resulted in resolution of the sclerokeratitis and remission of the disease. (SW-V Ophthalmol 37:373-376, 1993)
Key words. antineutrophil Wegcner’s granulomatosis
cytoplasmic
Case Kepol?. A 2%year-old white male presented with a s-month history of a red and increasingly painful right eye with an initial appearance of a conjunctivitis. He was treated with topical sulfacetamide TID OD. There was some improvement initially, but the patient had increasing injection with pain and developed conjunctival ulceration after one week of treatment. The inflammation progressed to a scleritis and peripheral keratitis in both eyes. Past ocular history was unremarkable. Past medical history was remarkable for recent treatment of bronchitis and sinusitis with Amoxicillin for two weeks with no improvement. Keview of systems revealed general malaise and anthralgias of both knees and right elbow, weight loss, dyspnea on exertion and hemoptysis that had gradually become worse over the past 3-4 months. Phvsical examination was remarkable for enlarged tonsils and transmitted
autoantibodies
l
scleritis
l
upper airway sounds, but no wheezes. rales or rhonchi. Eye examination on presentation at the University of Minnesota revealed visual acuities of 20120 in both eyes, with a correction of - 0.50 + 0.75 x 123 OD and - 0.50 + 0.50 x 88 OS. The pupils were equal in size and normally reactive without a relative afferent defect. Extraocular motility was full and the patient was orthophoric at distance. Slit-lamp examination revealed an area of injection of the medial palpebral conjunctiva of the right upper lid with overlying ulceration. There was a large ulcerated scleral nodule of the right eye at the limbus from 11 to 2 o’clock, along with diffuse conjunctival and scleral injection (Fig. 1). The cornea had a large peripheral superficial stromal infiltrate with thinning at 12 o’clpck and scattered peripheral epithelial lesions (Fig. 2). The left eye showed a sector of
374
Surv Ophthalmol
Fig. 1. eye.
Ulcerated
37 (5) March-April
1993
scleral nodule (arrow) of the right
FLORINE ET AL
Kg. 2. Nodular sclerokeratitis infiltrates of the right eye.
with superior
cornea1
conjunctival injection from 12 to 3 o’clock with early peripheral epithelial infiltrates. Both anterior chambers were deep and quiet. Intraocular pressures by applanation tonometry were 9 mm Hg OD and 15 mm Hg OS. Lens and vitreous were normal OU. Fundus exam showed normal optic nerve, macula, vessels and peripheral retina OU. Taking into account the patients three-month history of malaise, arthralgias, weight loss, dyspnea on exertion, bronchitis and sinusitis, a systemic vasculitic process, particularly Wegener’s granulomatosis, was suspected. Laboratory work-
up included normal complete blood count with differential, negative FANA, positive antineutrophi1 cytoplasmic autoantibodies with cytoplasmic staining pattern (C-ANCA), positive RF at a titre of 1: 168, creatinine 0.9, urinalysis with moderate blood and 30 mg/dl of protein. Sinus films were normal and a chest x-ray showed bilateral perihilar masses and narrowing of the trachea and bronchus at the level of the carina (Fig. 3). A diagnosis of Wegener’s granulomatosis was made and the patient was admitted to the hospital for treatment with IV cyclophosphamide 4 mg/kg/day, IV methylprednisolone 100 mg/day
Fig. 3. Chest x-ray showing bilateral perihilar masses and narrowing of the trachea at the level of the carina (arrow).
Fig. 4. Nasal biopsy showing acute and chronic inflammation with a granuloma (arrow). (HE x 300)
WEGENER’S GRANULOMATOSIS
WITH SCLEROKERATITIS
F/g. 5.
Indirect immunoflrloresccrIce cytoplasmicst;lining ot the neutrophils arc dark in contrast.
DX BY ANCA
pattern
ofGANCA.
I‘he nuclei
I’rg. 6. Indirect immunofluoresccnce perinuclcar staining pattern of P-ANNA. This is an artifkt due to the redistribution ofsoluble cytoplasmic n~tcleophilic antigens to the perinuclear region drlring the staining process.
and trimethoprim/sulfatnethoxazole (Septra one tablet daily. A subglotic and nasal biopsy performed and showed acute and chronic
DS) was
inflammation with granuloma (Fig. 4). The patient’s course improved with resolution of all systemic symptoms and clearing of all inflammation of the left eye. The right eye had resolution of conjunctival and scleral inflamma-
clearing of‘the cornea1 infiltrates with residual thinning at 12 o’clock. The area of nodular scleritis had decreased in size and activity of inflammation. The patient was discharged on prednisone 50 mg PO I’ID, cyclophosphamide 3 mg/kg/day and Septra DS one tablet daily. The patient has continued to do well on slow tapering of the cyclophosphamide and prednisone and tion,
376
Surv Ophthalmol
the nodular
scleritis
37 (5) March-April
1993
of the right eye has resolved.
Discussion Scleritis represents inflammation of the deep vascular plexus adjacent to the sclera. Forty-six percent of patients with slceral inflammation have some other systemic disease; 35% have serologic evidence of connective tissue disorders and 17% manifest disease.” Wegener’s granulomatosis in its classic form is characterized by the triad of necrotizing granulomas of the respiratory tract, generalized focal necrotizing vasculitis and focal necrotizing glomerulonephritis. A limited form without the renal involvement is also well recognized.” Ocular involvement has been reported to occur in 28-58% of patients with Wegener’s granulomatosis.‘.“.6 Ocular manifestations reported inwith proptosis, clude orbital involvement scleritis, episcleritis, conjunctivitis, cornea1 ulceration, optic nerve vasculitis, retinal artery occlusion, retinitis, uveitis and nasolacrimal duct obstruction.‘,” Ocular signs have been reported as the presenting finding in 13-16% of patients with Wegener’s granulomatosis.‘,” Untreated Wegener’s granulomatosis carries a mean survival of five months, with 82% of patients dying within one year and more than 90% dying within two years.” Treatment with cyclocorticosteroids and trimethophosphamide, prim/sulfamethoxazole leads to a high remission rate of over 90%. Histopathological examination of biopsy specimens in patients with suspected Wegener’s seldom reveals the classic triad of vasculitis, necrosis and granulomatous inflammation,’ so the diagnosis is based on both clinical and pathological findings. Antineutrophil cytoplasmic autoantibodies (ANCA) offer a specific and sensitive laboratory test in the diagnosis of Wegener’s granulomatosis.x ANCA are specific for constituents of neutrophi1 primary granules and monocyte lysosomes. Multiple types ofANCA have been demonstrated with different specificities. The testing requires a 10 ~1 specimen that is collected in a standard chemistry tube and run by most major metropolitan laboratories. By indirect immunofluores-
FLORINE
ET AL
cence microscopy using alcohol-fixed neutrophils as substrate, two major categories ofANCA can be recognized, one with cytoplasmic staining (C-ANCA) (Fig. 5) and the other with artifactual perinuclear staining (P-ANCA) (Fig. 6). The basis for the artifactual nuclear binding of P-ANCA is the redistribution of soluble cytoplasmic nucleophilic antigens to the perinuclear region during the indirect immunostaining procedure.’ Some C-ANCA have specificity for proteinase 3 and some P-ANCA have specificity for myeloperoxidase, but there are additional C-ANCA and PANCA specificities. ANCA are found in the blood of patients with necrotizing systemic vasculitis, such as Wegener’s granulomatosis and polyarteritis nodosa, and patients with idiopathic crescentric glomerulonephritis.4.7 Patients with Wegener’s granulomatosis most often have C-ANCA and patients with renal-limited disease have PANCA. The addition of ANCA testing should be added to the laboratory workup in patients with scleritis.
References ‘IJ, McDonald TJ, DeRemee RA: I. Hullen CL, Liesegang Ocular complications of Wegener’s granulomatosis. Uphlhnl?tlologp 90:279-290, 1983 2. Devaney KO, Travis WD, Hoffman G, et al: Interpretation of head and neck biopsies in Wegener’s granulomatosis. Art1 J Surg P&ho1 14:555-564, 1990 G, Coners H, Nolle B: Ocular involvement in 3. Duncker Wegener’s granulomatosis. APMIS Su#d. 19, 98:22, 1990 systemic 4. Falk RJ, Jennette JC: Wegener’s granulomatosis, vasculitis, and antineutrophil cytoplasmic autoantibodies. Atmu Krr, Md 42;459-469, 1991 5. Fauci AS, Haynes SF, Katz P, Wolff SM: Wegener’s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. A?ln In1 Mrd 98:76-85, 1989 6. Haynes RF, Fishman ML, Fauci AS, WolffSM: .I‘he ocular manifestations of Wegener’s granulomatosis. ,4m J Md h3:151-141, 1977 Jennette JC, Falk RJ: Antineutrophil cytoplasmic autoantibodies and associated diseases: A review. Am J Kidney Dk 15:517-529, 1990 Soukiasian SW, Foster CS, Niles JL, Raizman MB: Diagnostic value of antineutrophil cytoplasmic antibodies in scleritis associated with Wegener’s granulomatosis. Ophihnlmolom 99: 125-l 32, 1992 Watson PC;: The diagnosis and management of scleritis. O,f~lrlh/rlrt~oln~ R7:7 I G-720, 1980 II.
Reprint address: Edward J, Holland, M.D., Department of Ophthalmology, University of Minnesota, Box 493 UMHC, 516 Delaware St. SE, Minneapolis, MN 55455.