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British Journal of Rheumatology 1997;36:273–275 CASE REPORT RELATIONSHIP BETWEEN THE DEVELOPMENT OF BLINDNESS IN CHURG–STRAUSS SYNDROME AND ANTI-MYELOPEROXIDASE ANTIBODIES N. SUTCLIFFE, V. MORRIS, B. GOMPERTS,* D. J. BRAZIER,† D. A. ISENBERG and G. CAMBRIDGE Bloomsbury Rheumatology Unit/Division of Rheumatology, Department of Medicine, *Department of Physiology and †Eye Department, University College London, London SUMMARY Occular involvement is infrequent and blindness rare in Churg–Strauss syndrome. We describe a patient with Churg–Strauss syndrome who presented with blindness. This was associated with the appearance of circulating autoantibodies to myeloperoxidase. K : Churg–Strauss syndrome, Anti-myeloperoxidase antibodies, Blindness. C–S syndrome is a triad of asthma, infraspinatus muscles with brisk reﬂexes in that arm. These eosinophilia (q1 × 109/l) and a systemic vasculitis ﬁndings had been long standing and were thought to be due involving two or more extrapulmonary organs. to his cervical nerve root compression. His investigations Whereas a number of diﬀerent organs may be aﬀected, showed normal renal function as well as normal full blood involvement of the eye is uncommon. We describe a count and ESR, except for an eosinophilia of 12%. No patient with Churg–Strauss syndrome who developed autoantibodies, including anticardiolipin antibodies, were blindness. detected on routine screening. Dilute Russell’s viper venom time was equivocal. His echocardiogram was normal. Carotid CASE REPORT Doppler studies showed bilateral 60–80% stenosis of the internal carotid arteries. Subsequently, a digital subtraction A 58-yr-old Caucasian male was admitted in December angiogram showed there was no operable lesion. He was 1993 with a history of transient blindness in the left eye. He treated with i.v. heparin for 3 days and his aspirin dose was had experienced frequent episodes of visual loss over the increased to 300 mg daily, and he was discharged. previous 10 weeks. These episodes occurred every 2–3 days He was readmitted 4 weeks later with blindness in the left and lasted 3–4 min, but always with complete recovery of eye which had developed over a 24 h period. He also gave a vision. There were no other associated neurological history of arthralgia of the shoulders, elbows and wrists. On symptoms. In the previous medical history, it was noted that examination, vasculitic lesions were noted overlying the he had had childhood asthma with allergic rhinitis which knees, elbows, wrists, the ﬁfth digit in the left hand and both resolved, only to recur at age 52 yr. On this occasion it ﬁfth toes. He also had a mildly swollen right ankle. became severe, requiring oral steroid treatment as well as Ophthalmic examination showed that his visual acuities were inhaled steroids and bronchodilators. He developed severe right 6/6, left 6/12 corrected. (His visual acuity had been 6/6 side-eﬀects, including osteoporotic fractures of several ribs, corrected on both sides following his cataract operations.) compression of thoracic vertebrae, and cataracts which were There was oedema of the left macular retina and two cotton treated with lens implants. He had also had papilloma of the wool spots. There was no obvious retinal vascular disease bladder, haemorrhoids and cervical spondylosis with cervical and no emboli were seen in the retinal circulation (Fig. 1). nerve root compression. In the family history, his father had Clinically, the picture was consistent with macular had a cerebrovascular accident aged 70 and his mother had retinal artery occlusion. The rest of his examination was had urticaria. unremarkable. His blood pressure was 125/70 mmHg. The patient had never smoked and his medications on On this admission, investigations showed a normal Hb and admission were prednisolone 6 mg o.d., aspirin 150 mg o.d. platelet count, but a raised white cell count (17.4 × 109/l) with and Ventolin inhalers. Owing to the side-eﬀects of oral eosinophilia (53%). His ESR (Westergen) was raised steroids, he was started on inhaled ﬂuticasone propionate (35 mm/h), but renal and liver function, serum triglycerides which enabled the reduction of his daily oral steroid dose and cholesterol, serum protein electrophoresis, immuno- from 30 to 6 mg. During this period, nodules on his elbows globulins and CRP were normal. The autoantibody screen were noted which were thought to be cholesterol deposits. was negative, except for a positive ANCA with a p-ANCA On examination, his blood pressure was 134/86 mmHg and staining pattern. Antigen-speciﬁc ELISAs showed that the the general examination was normal. There were no p-ANCA were speciﬁc for myeloperoxidase (MPO) and were ophthalmic signs, including retinal changes on dilated fundus of the IgG class (53% of positive control serum; upper limit examination. Neurological examination revealed mild wast- of normal range 20%). In addition, using subclass-speciﬁc ing of the medial aspect of the right forearm, right supra- and mouse monoclonal antibodies, it was found that the anti-MPO antibodies were predominantly of the IgG4 Submitted 8 February 1996; revised version accepted 19 July 1996. subclass (data not shown). Retrospective serum samples were Correspondence to: N. Sutcliﬀe, Rheumatology Unit, 4th Floor, also available and tested for anti-MPO antibodies (Fig. 2). As Arthur Stanley House, 40–50 Tottenham Street, London W1P 9PG. is shown, although anti-MPO antibodies were slightly above = 1997 British Society for Rheumatology 273 274 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 2 the normal range (q20% of the positive control), signiﬁcant levels of anti-MPO antibodies were found only at diagnosis at the same time as the maximal eosinophil count. Midstream urine showed a trace of protein, 24 h urinary protein was normal. A skin biopsy of the left little ﬁnger showed changes of a wedge-shaped dermal infarct with overlying, probably secondary, bulla formation. A moderate number of eosinophils were present in the associated inﬂammatory cell inﬁltrate. Thromboses were present within several small vessels of the superﬁcial dermis. The appearances were of a dermal/epidermal infarct. Histological appearances were consistent with an obstructed vessel in the deeper dermis and vasculitis. In view of late-onset asthma, eosinophilia, skin vasculitis with extravascular eosinophils on the skin biopsy and presumed retinal vasculitis, a diagnosis of Churg–Strauss syndrome was made. In addition, elevated levels of F. 2.—Serial measurements of eosinophil count and circulating circulating anti-MPO antibodies were found. Subsequently, anti-myeloperoxidase antibodies of patient BG over the time of the patient was treated with i.v. and oral steroids followed by study. The upper limit of the normal range for anti-MPO antibodies azathioprine. His skin lesions resolved and he has had no is indicated by the vertical line. further symptoms of asthma. However, 2 yr later, there has been little improvement in vision in the left eye. He has managed to reduce his prednisolone to 5 mg o.d. and continued to take azathioprine 150 mg o.d. Another patient who had visual loss also had a temporal artery biopsy which showed vasculitis with DISCUSSION eosinophils, but no giant cells. This patient had an Ocular involvement in Churg–Strauss syndrome is improvement of visual acuity with high-dose steroid infrequent, but includes scleritis, uveitis, corneal treatment . Another patient with severe visual loss ulcerations, conjunctival inﬂammation, cranial nerve due to an acute bilateral sequential optic neuropathy palsies, retinal infarctions, amaurosis fugax and had treatment with i.v. cyclophosphamide and had no ischaemic optic neuropathy . Blindness is a rare visual recovery . Churg–Strauss syndrome is in the ﬁnding and has been described previously in only ﬁve diﬀerential diagnosis of amaurosis fugax and, if patients [1–5]. Three of these patients had monocular considered, an early diagnosis may prevent blindness. blindness which was irreversible despite treatment with Circulating ANCA with speciﬁcity for MPO have steroids [3–5]. Two underwent temporal artery been described in some reports as being present in from biopsies; one was normal , the other showed 56 to 75% of patients with Churg–Strauss syndrome histology consistent with Churg–Strauss syndrome . [6, 7]. Anti-MPO antibodies of the IgG4 subclass have been associated with other forms of ANCA-associated vasculitis , but no extensive studies of the subclass distribution of anti-MPO antibodies in Churg–Strauss syndrome in particular have been reported. The IgG4 subclass is associated with prolonged antigen exposure, eosinophilia and hypersensitivity. It is the predominant and pathogenic immunoglobulin subclass of autoanti- bodies in patients with epidemic pemphigus bullosum  and is also over-represented in anti-colon antibodies in ulcerative colitis . It has been proposed that in vasculitis, IgG1 and IgG3 subclass anti-MPO anti- bodies may be pathogenic due to their ability to cross-link FcgRIIa receptors and surface-bound MPO on neutrophils, resulting in neutrophil activation and endothelial cell damage . The signalling mechanism for neutrophil activation would therefore be through the intracellular domain of the FcgRIIa receptor. Neutrophils do not, however, possess Fc receptors for IgG4, neither does this immunoglobulin subclass signiﬁcantly ﬁx complement. In this case report, the patient developed predominantly IgG4 subclass anti- MPO antibodies within a relatively short period of F. 1.—Photograph of left fundus from a 40° colour photograph. time, and their appearance also correlated with an Two cotton wool spots are located temporal to the optic disc. Retinal acute vasculitic episode. Patients with ANCA-related vascular calibres were considered within normal limits with no vasculitis have also been described in whom the only evidence of retinal emboli. subclass of immunoglobulin present is IgM . Fc SUTCLIFFE ET AL.: CHURG–STRAUSS VASCULITIS 275 receptors for IgG4 are, however, present on basophils 6. Guillevin L, Visser H, Noel LH, Pourrat J, Vernier I, and mast cells. In vasculitis, the preferential production Gayraud M et al. Antineutrophil cytoplasmic antibodies of IgG4 subclass anti-MPO antibodies may allow in systemic polyarteritis nodosa with and without binding of antibody/antigen complexes to basophils or Hepatitis B virus infection and Churg–Strauss syndrome. J Rheumatol 1993;20:1345–9. mast cells, rather than clearance of complexes through 7. Cohen-Tervaert JW, Limburg PC, Elema JD, Huitema conventional Fc receptor and complement-mediated MG, Horst G, The TH et al. Detection of autoantibodies pathways. Basophils and mast cells are also known to against myeloid lysosomal enzymes: a useful adjunct to release mediators such as histamine, transforming classiﬁcation of patients with biopsy proven necrotising growth factor-b and interleukin 4 which can aﬀect arteritis. Am J Med 1991;91:59–66. B-cell and neutrophil function following cross-linking 8. Brouwer E, Cohen Tervaert JW, Horst G et al. of IgG4 Fc receptors . This case study suggests that Predominance of IgG1 and IgG4 sub-class of antineu- the functional properties of IgG4 anti-MPO antibodies trophil cytoplasmic antibodies (ANCA) in patients with should also be investigated. Wegener’s granulomatosis and clinically related dis- orders. Clin Exp Immunol 1991;83:379–86. 9. Emery DJ, Diaz LA, Fairley JA, Lopez A, Taylor R AF, Giudice GJ. Pemphigus foliaceus and pemphigus 1. Alan RA, Richard L, Kenneth RA, Elliot KC, Myron S, vulgaris autoantibodies react with the extracellular Richard AF. Reversible monocular blindness complicat- domain of desmoglein 1. J Invest Dermatol 1995;104: ing Churg–Strauss syndrome. J Rheumatol 1994;21:363– 323–8. 5. 10. Ohara M, Hibi T, Watanabe N, Kobayashi K, Takaishi 2. Acheson JF, Cockerell OC, Bentley CR, Sanders MD. H, Hayashi A et al. Immunoglobulin G (IgG) sub-class Churg–Strauss vasculitis presenting with severe visual distribution of anticolon antibodies in ulcerative colitis. loss due to bilateral sequential optic neuropathy. Br J J Gastroenterol Hepatol 1995;10:158–64. Ophthalmol 1993;77:118–9. 11. Mulder AHL, Heeringa P, Brouwer E, Limburg PC, 3. Weinstein JM, Chui H, Lane S, Corbett J, Towﬁghi J. Kallenberg CGM. Activation of granulocytes by Churg–Strauss syndrome (allergic granulomatous angi- anti-neutrophil cytoplasmic antibodies (ANCA): a itis): Neuro-ophthalmologic manifestations. Arch Oph- FcgRII-dependent process. Clin Exp Immunol thalmol 1983;101:1217–20. 1994;98:270–8. 4. Conn DL, Dickson ER, Carpenter HA. The association 12. Cambridge G, Williams M, Leaker B, Corbett M, Smith of Churg–Strauss vasculitis with temporal artery CR. Anti-myeloperoxidase antibodies in patients with involvement, primary biliary cirrhosis, and polychondri- rheumatoid arthritis: prevalence, clinical correlates, and tis in a single patient. J Rheumatol 1982;9:744–8. IgG subclass. Ann Rheum Dis 1994;53:24–9. 5. Finan MC, Winkelmann RK. The cutaneous extravascu- 13. Fagan DL, Slaughter CA, Capra JD, Sullivan TJ. lar necrotising granuloma (Churg–Strauss granuloma) Monoclonal antibodies to immunoglobulin G4 induce and systemic disease. A review of 27 cases. Medicine histamine release from human basophils in vitro. J 1983;62:142–58. Allergy Clin Immunol 1982;70:399–404.
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