Lightman, SL

Pusey, CD

Shalchi, Z

Taylor, SRJ

English

100/50/13 meb. Publisher version ,Ok to add

Spiral - Imperial College Digital Repository

A sore red eye with systemic involvementZaid Shalchi ophthalmology specialty registrar year 2 andMSc student13, Susan L Lightman professorof clinical ophthalmology and consultant ophthalmologist 2 3, Charles D Pusey professor of medicineand head of renal medicine 2 4, Simon R J Taylor National Institute for Health Research clinicallecturer in ophthalmology 1 2 31Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK; 2Multidisciplinary Vasculitis Clinic, Imperial College Healthcare NHS Trust,Hammersmith Hospital, London, UK; 3UCL Institute of Ophthalmology, London, UK; 4Faculty of Medicine, Imperial College London, HammersmithHospitalA 20 year old man was referred to the eye clinic by his generalpractitioner with a four week history of a sore red left eye (fig1). Treatment for conjunctivitis had not resulted in improvement,and he reported that his eye was increasingly painful. He hadexperienced repeated nose bleeds over the past three months,together with constant left sided nasal stuffiness. He had recentlyfelt generally unwell and had lost 4 kg. On examination, hisvisual acuity was 6/9 in both eyes. His vital signs were stable,but urinalysis showed blood+++ and protein+.Fig 1 The patient’s eye at presentationQuestions1 What abnormalities are seen in the photograph?2 What is the most likely underlying diagnosis given hisextraocular symptoms?3 What further investigations are appropriate?4 What is the pathophysiology of this condition?5 What treatment would you recommend and what is theprognosis?Answers1 What abnormalities are seen in thephotograph?Short answerThe abnormality is in the sclera—the tough white outer coat ofthe globe. A large area of necrotic sclera can be seen extendingaround the superonasal side of the cornea.Long answerThe abnormality is in the sclera—the tough white outer coat ofthe globe. A large area of necrotic sclera can be seen extendingaround the superonasal side of the cornea. Non-necrotisingscleritis presents as a red sore eye, but the white avascular areaof sclera seen here is indicative of necrotising disease.2What is themost likely underlying diagnosisgiven his extraocular symptoms?Short answerNecrotising scleritis can be associated with several connectivetissue disorders, the most common being Wegener’sgranulomatosis. The combination of necrotising scleritis, upperairway symptoms, and constitutional symptoms strongly suggestthis as the diagnosis.Long answerNecrotising scleritis is associated with a medical disorder in39-50% of cases, particularly connective tissue disease orsystemic vasculitis.1 2 History taking, examination, andinvestigations should centre on a differential diagnosis ofsystemic lupus erythematosus; rheumatoid arthritis; Crohn’sdisease; or the antineutrophil cytoplasmic antibody (ANCA)associated vasculitides, including Wegener’s granulomatosis.Wegener’s granulomatosis is the most common cause, and theCorrespondence to: S R J Taylor s.r.taylor@ucl.ac.ukFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2012;344:e1121 doi: 10.1136/bmj.e1121 (Published 24 February 2012) Page 1 of 3EndgamesENDGAMEScombination of necrotising scleritis, upper airway symptoms,and constitutional symptoms strongly suggests this as thediagnosis.33What further investigations are appropriate?Short answerThe diagnosis of necrotising scleritis is clinical, but ifWegener’sgranulomatosis is suspected, serious renal involvement must beurgently excluded by urinalysis with a dipstick. Radiographicassessment of the respiratory system and formal evaluation forrenal disease are indicated. Antineutrophil cytoplasmicantibodies (ANCAs) are usually positive in systemicWegener’sgranulomatosis but can be negative, particularly if the diseaseis limited to the orbit.Long answerThe diagnosis of necrotising scleritis is clinical, but because itis often associated with systemic disease a thoroughinvestigation is essential. Patients should be investigated withurine dipstick for blood and protein, as well as serum rheumatoidfactor, antinuclear antibodies, and ANCAs. White cell count,C reactive protein concentration, and erythrocyte sedimentationrate are useful to look for evidence of systemic inflammation.If Wegener’s granulomatosis is suspected, it is important toexclude serious renal involvement urgently. Radiographicassessment of the respiratory system and evaluation for renaldisease are indicated. The ANCA test is usually positive insystemic Wegener’s disease but can be negative, particularly ifdisease is limited to the orbit.4 ANCAs may be present in otherconditions (such as ulcerative colitis, ankylosing spondylitis,and Churg-Strauss syndrome), and a negative ANCA test doesnot exclude a diagnosis of Wegener’s granulomatosis.4 Directimmunofluorescence can distinguish different patterns of ANCAstaining, and cytoplasmic ANCA (cANCA) staining is classic,whereas perinuclear ANCA (pANCA) staining is morecommonly a feature of microscopic polyangiitis. Thedemonstration of antiproteinase 3 antibodies on ELISA (enzymelinked immunosorbent assay) has a sensitivity of 91% andspecificity of 99% for active Wegener’s granulomatosis.3A biopsy showing granulomatous inflammation and necroticvasculitis is the gold standard in disease diagnosis. This maybe obtained from an affected organ, such as the skin (in patientswith cutaneous vasculitis), kidney, lung, or orbit (in those withgranulomatous orbital inflammation). Although biopsy findingsare notoriously non-specific, renal biopsies may have a higherdiagnostic yield when performed by a skilled clinician andreviewed by an experienced histopathologist.The modified American College of Rheumatology criteria forthe diagnosis ofWegener’s granulomatosis (1990) stipulate thatat least two of the following be present: nasal or oralinflammation, abnormal chest radiograph, active urine sediment(microhaematuria or red cell casts), and positive biopsy. Somehave argued that a positive ANCA titre be included as a fifthcriterion.54 What is the pathophysiology of thiscondition?Short answerWegener’s granulomatosis is an autoimmune systemic vasculitis,which commonly affects small and medium sized vessels. Theprecise causes are not known, and it belongs to a larger groupof vasculitides in which disease is strongly associated withANCAs, including Churg-Strauss syndrome and microscopicpolyangiitis.Long answerWegener’s granulomatosis is a rare disease. Its prevalence is5-16 per 100 000 in northern Europe6 and three per 100 000 inthe United States.7 The average age of onset is 40-55 years, butit may present at any age. There is no sex bias. The conditionis more common in white people than in Afro-Caribbeans.Wegener’s granulomatosis is an autoimmune diseasecharacterised by systemic vasculitis, which commonly affectssmall and medium sized vessels, as well as by granulomaformation. The precise causes are not known,8 and it belongs toa larger group of vasculitides in which disease is stronglyassociated with ANCAs, including Churg-Strauss syndromeand microscopic polyangiitis.ANCAs are present in 90-95% of patients with systemicWegener’s disease.9 ANCAs directed against serum proteinase3 lead to neutrophil activation, with resultant release of reactiveoxygen species and proteolytic enzymes, which cause damageto the vascular endothelium and result in vasculitis.10Activationof the immune system leads to disease in small and mediumsized vessels and causes multiorgan disease. The conditioncommonly affects the upper respiratory tract and lungs, as wellas the kidneys, where rapidly progressive glomerulonephritiscommonly leads to chronic renal failure if not treated quicklyand aggressively. Wegener’s granulomatosis can also causepainful swollen joints and skin nodules on the elbows; lesscommonly, it also affects the brain and peripheral nervoussystem, heart, and gastrointestinal tract. The varied andnon-specific nature of the symptoms often leads to delayeddiagnosis.5 What treatment would you recommend andwhat is the prognosis?Short answerWegener’s granulomatosis is life threatening and requiresaggressive immunosuppression; cyclophosphamide hasrevolutionised themanagement of this previously fatal condition.Once the diagnosis is confirmed, start patients on intravenousinfusions of cyclophosphamide and high dose oral prednisolone(1-2 mg/kg/day). Treatment of the underlying condition leadsto rapid resolution of necrotising scleritis without the need forlocal treatment, unless the globe has already perforated, in whichcase emergency surgery may be needed. Most patients respondwell to treatment, and survival is about 95% at five years and80% at 10 years.Long answerWegener’s granulomatosis is life threatening and requiresaggressive immunosuppression; cyclophosphamide hasrevolutionised the management of this previously fatalcondition.11 Once the diagnosis is confirmed, patients shouldbe started on intravenous infusions of cyclophosphamide andhigh dose oral prednisolone (1-2 mg/kg/day). Treatment of theunderlying condition leads to rapid resolution of necrotisingscleritis without the need for local treatment, unless the globehas already perforated, in which case emergency surgery maybe needed.Patients treated with cyclophosphamide must be monitored forserious treatment related toxicity, including bone marrowsuppression and haemorrhagic cystitis.12 Once remission isinduced, introduce less toxic drugs such as azathioprine orFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2012;344:e1121 doi: 10.1136/bmj.e1121 (Published 24 February 2012) Page 2 of 3ENDGAMESmethotrexate instead.13 14 Taper steroids to 7.5 mg/day or lessand continue treatment for at least one year. Plasmapheresis iseffective in pulmonary haemorrhage secondary to Wegener’sdisease.15Newer biological agents have also been evaluated, and theRAVE (Rituximab in ANCA associated Vasculitis) studycompared the ability of rituximab plus corticosteroids versuscyclophosphamide plus corticosteroids to induce remission inpatients with severe systemic Wegener’s disease.16 Rituximabwas as effective as cyclophosphamide in inducing remissionbut more effective in treating relapsing disease. Rituximab isalso effective in the treatment of refractory ophthalmic disease.17Untreated,Wegener’s granulomatosis is rapidly fatal as a resultof renal failure and pulmonary haemorrhage, with a mediansurvival of five months. The use of steroids helped increaseaverage survival to eight months, but it was the use ofcyclophosphamide in the 1970s that led to dramaticimprovements in prognosis. These days, most patients respondwell to treatment, and survival is about 95% at five years and80% at 10 years.11 18Relapses are common and should be treatedaggressively. Long term complications include chronic renalfailure and hearing loss.Patient outcomeOur patient was diagnosed with Wegener’s granulomatosis.Pulmonary nodules were seen on chest radiography and he waspositive for ANCAs on direct immunofluorescence and forantiproteinase 3 antibodies on ELISA.He was started on 80 mg oral prednisolone daily; concurrentinfusions of cyclophosphamide were arranged in conjunctionwith the renal physicians through our multidisciplinary vasculitisclinic, which includes renal doctors; ophthalmologists; and ear,nose, and throat surgeons.His symptoms improved rapidly with treatment. His nose bleedsand nasal congestion improved, and he rapidly regained someweight and felt better systemically. The necrotising scleritisresolved without compromise to his vision (fig 2).Fig 2 The patient’s eye six months laterCompeting interests: All authors have completed the ICMJE uniformdisclosure form at www.icmje.org/coi_disclosure.pdf (available onrequest from the corresponding author) and declare: no support fromany organisation for the submitted work; no financial relationships withany organisations that might have an interest in the submitted work inthe previous three years no other relationships or activities that couldappear to have influenced the submitted work.Provenance and peer review: Not commissioned; externally peerreviewed.Patient consent obtained.1 Akpek EK, Thorne JE, Qazi FA, Do DV, Jabs DA. Evaluation of patients with scleritis forsystemic disease. Ophthalmology 2004;111:501-6.2 Raiji VR, Palestine AG, Parver DL. Scleritis and systemic disease association in acommunity-based referral practice. Am J Ophthalmol 2009;148:946-50.3 Taylor SR, Salama AD, Pusey CD, Lightman SL. Ocular manifestations of Wegener’sgranulomatosis. Expert Rev Ophthalmol 2007;2:91-103.4 Gómez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis insmall-vessel vasculitis: an update. Am J Pathol 2009;175:1790-8.5 Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The AmericanCollege of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis.Arthritis Rheum 1990;33:1101-7.6 Mohammad AJ, Jacobsson LT, Mahr AD, Sturfelt G, Segelmark M. Prevalence ofWegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa andChurg-Strauss syndrome within a defined population in southern Sweden.Rheumatology(Oxford) 2007;46:1329-37.7 Langford CA, Hoffman GS. Rare diseases. 3: Wegener’s granulomatosis. Thorax1999;54:629-37.8 Kallenberg CG, Tadema H. Vasculitis and infections: contribution to the issue ofautoimmunity reviews devoted to “autoimmunity and infection.” Autoimmun Rev2008;8:29-32.9 Hu N, Westra J, Kallenberg CG. Membrane-bound proteinase 3 and its receptors:relevance for the pathogenesis of Wegener’s granulomatosis. Autoimmun Rev2009;8:510-4.10 Schilder AM. Wegener’s granulomatosis vasculitis and granuloma. Autoimmun Rev2010;9:483-7.11 Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, TravisWD, et al. Wegenergranulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98.12 Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nölle B, et al. Aninterdisciplinary approach to the care of patients withWegener’s granulomatosis: long-termoutcome in 155 patients. Arthritis Rheum 2000;43:1021-32.13 De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission inearly systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum2005;52:2461-9.14 Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, et al; EuropeanVasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associatedwith antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-44.15 Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al; EuropeanVasculitis Study Group. Randomized trial of plasma exchange or high-dosagemethylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol2007;18:2180-8.16 Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al; RAVE-ITNResearch Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med 2010;363:221-32.17 Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL. Rituximab is effective in thetreatment of refractory ophthalmic Wegener’s granulomatosis. Arthritis Rheum2009;60:1540-7.18 Villa-Forte A, Clark TM, Gomes M, Carey J, Mascha E, Karafa MT, et al. Substitution ofmethotrexate for cyclophosphamide inWegener granulomatosis: a 12-year single-practiceexperience. Medicine (Baltimore) 2007;86:269-77.Cite this as: BMJ 2012;344:e1121© BMJ Publishing Group Ltd 2012For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2012;344:e1121 doi: 10.1136/bmj.e1121 (Published 24 February 2012) Page 3 of 3ENDGAMES

A sore red eye with systemic involvement

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