Rheumatic Disorders of Eye

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    HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE 259OCULAR FEATURESThe ophthalmologist has many roles in the m anage-ment of patients w ith rheumatological problems. M ostrheumatological diseases affect either the uvea, sclera,retina or optic nerve and produce symptoms andsigns that confirm their nature and aetiology. Mostrheumatological diseases have ocular complications,many of which are specific to the particular disease.Involvement of the uvea or sclera usually producespainful red eyes with preserved vision, whereas involve-ment of the retina or optic nerve causes profoundvisual loss without pain or redness. Occasionally,the clinical evidence of inflammation may not beimmediately app arent , as with the melting corneal ulcerof rheumatoid arthritis.The ocular features of systemic inflammatorydiseases vary according to the size and type of vesselpredominantly affected by the disease process.Generally, diseases tha t affect arterioles involve cornea,episclera, sclera and retinal arterioles, whereas those

    that affect venules produce uveitis, macular oedemaand retinal venous disease. The heterogeneousstructure of the three-layered eyeball with its tough,collagenous sclera, its highly vascular uvea andits exquisitely sensitive retina may account for thespecial qualifications of the eye as a target organ.Thus, rheum atic diseases directed against collagen findthe sclera and the peripheral cornea ideal as targettissues.The choroid, with its fine network of vessels, maytrap immune complexes in much the same way as therenal glomerulus. The retina, basically an outpocketingof the primitive brain, ap pears t o be subject to the samekinds of autoimmune results as the brain itself,manifesting perivascular inflammatory reactions in thecase of Behcet's disease.The ocular manifestations of rheumatoid arthritisare sicca syndrome, scleritis, scleromalacia perforans,corneal melt and Brown's syndrome.Patient 1: Mrs IR, date of birth 8.7.36This patient was born in Jamaica and in 1974developed seropositive erosive rheumatoid arthritis.Gold treatment led to proteinuria and had to bediscontinued. Penicillamine was ineffective. She hasbeen treated w ith prednisolone since 1980, azathioprinebetween 1985 and 1987, and methotrexate since 1987.She developed scleritis in June 198S which led tobilateral eye involvement and severe headaches. Shewas initially treate d with i.v. methylprednisolone whichled to a good effect, but was transient. It was repeated.She was subsequently treated with oral azathioprineand cyclophosphamide 150 mg/day with no benefit. InJune 1985, she was transferred to Addenbrooke'sHospital. Her visual acuity was 6/9 in the right eye and6/18 in the left.On examination, she had anterior and posteriorscleritis and macular oedema. She was treated initiallywith cyclosporin with good effect, but side-effects led toits discontinuation.

    She was then treated in July and September with i.v.pulses of methylprednisolone and cyclophosphamidewith good effect. The azathioprine was re-commencedin September 1985. Ultrasound scanning showedthickening posteriorly, and the angiogram wasabnormal and compatible with posterior scleritis. InSeptember 1989, she developed neck and head pain,she complained of linear floaters in the left eyefor 9 weeks, she had pain on eye movements andperiorbital pain and jaw claudication with concentricfield restriction. She had tenderness and loss ofpulsation over the left temporal artery, the righttemporal artery, the left brachial artery and leftfemoral artery, and a biopsy showed disrupted elasticlamina and scarring compatible with the changes ofgiant cell arteritis (GCA). An ESR was elevated at74mm/h. She was treated initially with i.v. methyl-prednisolone and 60 mg prednisolone orally, andwithin 24 h was pain free and her visual fieldsimproved.

    In 1990, she developed soreness of the eyes andcloudiness of vision. She had bilateral punctatekeratopathy. She was treated with hypromellose 0.3%initially hourly. In M ay 1992, gelatin rods were insertedinto the inferior puncta and in October 1992 she hadbilateral cautery of the inferior puncta with goodresults.She now has no scleritis, she has mild punctatekeratitis, her vision is 6/6 bilaterally and she useshypromellose drops intermittently.Episcleritis and scleritis are two distinct conditions,episcleritis being the milder condition often associatedwith allergic conditions and subsides spontaneously.The episclera has its own blood supply and isincompletely fixed to the underlying sclera. This is incontrast to the conjunctiva which is freely mobile overthe episclera. Episcleritis is a benign, self-limitingcondition that is usually nodular and unilateral. Inrheumatoid arthritis, most of the episcleritis is of thediffuse type. The affected episcleral vessels are dilatedwithin the affected area a nd the redn ess may be intense.Patients complain of irritation and redness rather thanpain. Non-steroidal anti-inflammatory drugs or topicalsteroids lead to resolution.Scleritis must be taken seriously because it can leadto blindness [4]. It occurs in 0.6% of rheumatoidpatients and is often associated with more severedisease. It is also a feature of other connectivetissue diseases, particularly those with a vasculiticcomponent; therefore, it is seen in systemic vasculitis,systemic lupus erythematosus (SLE) and Wegener'sgranulomatosis. In contrast to episcleritis, it is painfuland does not subside spontaneously. Pain is the mostprominent feature and may be very severe, andfrequently radiates to the orbit and face.Scleritis may be anterior or posterior. Anteriorscleritis occurs in three forms: diffuse, nodular andnecrotizing with or without inflammation. Althoughposterior scleritis is relatively underdiagnosed, anteriorscleritis is more common. Scleritis has an insidiousonset and is recurrent, and further attacks can be

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    260 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3minimized with pro mp t initial treatment. The course ofdiffuse and nodular scleritis is one of resolution withtreatment, perhaps leading to some scleral thinning.The course of necrotizing scleritis is progressive, isassociated with severe systemic disease and a highmortality if the underlying disease is not treatedaggressively. Involvement of the posterior sclera leadsto proptosis, serious retinal detachment and a swollenoptic disc.Clinically differentiating episcleritis from scleritismay be difficult, but examination of the deep scleralvessels will show their involvement in scleritis.Recently, low-dose anterior segment fluoresceinangiography has been demonstrated to be of value indetermining the vascular pattern and in estimating thedegree of vasculitis-related anterior scleral ischaemia.The pathogenesis of scleritis remains poorly under-stood. A review from Moorfield's indicates thatpatients usually remain with the same category of-disease; diffuse scleritis was the least prog ressive, whilevisual loss was 74% in necrotizing disease. Whenscleral and conjunctival biopsies were examined,immune complex deposition and neutrophil invasionwere seen in the vessels, suggesting an immune-complexdeposition.The treatment of scleritis involves relieving the painand halting the progression of the disease. Non-steroidal anti-inflammatory drugs are helpful innon-necrotizing scleritis. Many patients requiresystemic steroids. High-dose corticosteroids arerequired for initial control of necrotizing scleritis, butin the long-term immunosuppressive therapy isnecessary. Cyclosporin therapy can be very effective,and pulse therapy with methylprednisolone andcyclophosphamide may be necessary.Progressive destru ction may still occur in necrotizingscleritis and scleral rupture may occur, and grafting isnecessary. Corneo-scleral perforations are morecomm on in patients w ith severe rheumatoid arth ritis, inwhom peripheral comeal ulceration is associated withlabral and scleral inflammation. In these patients, acombined corneo-scleral graft may be required.If adjacent tissues are involved in the inflammatoryprocess, additional signs and symptoms develop:spread to the cornea produces keratitis.Sclerosing keratitis is the most common comealcomplication of scleritis. Pericorneal/limbus inflam-mation is associated with peripheral corneal vesselsspreading across the central cornea preceded bystromal opacities. In nodular scleritis, the cornealinvolvement may be restricted to one segment, but indiffuse scleritis the entire cornea may be involved,producing a dense corneal leukoma; perforation of thecornea may occur. Treatment of the condition is thesame as that for the underlying condition.A survey of the incidence of associated systemicdisease in 100 patients attending the scleritis clinic inMoorfield's Hospital was carried out by Lachmann,Hazleman and W atson [5]. The average age of thepatients was 46.6 yr. Nineteen patients withrheumatoid arthritis were seen, two with Sjogren's

    syndrome, one with pulmonary fibrosis, two withcutaneous vasculitis; there was also one patient withtemporal arteritis and three with gout.Scleromalacia perforans is seen particularly inwomen with long-standing rheumatoid disease. Theaffected sclera becomes white because the underlyinglesion is arteritic infarction. The underlying sclerabecomes atrophic and the blue underlying choroid isclearly seen. This is partly due to thinning, but mainlydue to reorientation of the collagen fibrils. Thiscondition is painless.Appearances of Wegener's granu lomatosis in the eyeare distinct, 50% of patients with this conditiondevelop eye problems, particularly those with limiteddisease. Marginal thinning with descemetocele andcorneal perforation may occur, as it can in relapsingpolychondritis and SLE. Breakdown of the cornealepithelium and corneal ulceration may occur, andthe treatment includes immunosuppression withcyclophosphamide. In many cases, surgical inter-vention is necessary [6].The aetiology of these melting disorders of thecornea is unclear. They usually occur predom inantly insevere rheumatoid arthritis, and a vasculitis element isprobably leading to collagenase secretion by infiltratinginflammatory cells and even by the corneal epithelium.Tissue damage is probably induced by activated cyto-lytic T cells or macrophages. This is the only systemicinflammatory disease that presents with orbital diseasedue to infiltration with granulomatous tissue.Patient 2: Mrs K H, date of birth 20.6.31In 1971, this patient's ulcerative colitis was treatedwith sulphasalazine. In 1985, the dorsum of her handwas swollen, morning stiffness was present and therewas tenderness of the metacarpophalangeal joints. In1987, recurrent uveitis of the left eye developed andproctocolectomy was carried out. In 1989, she haduveitis of both eyes with left marginal keratitis. In 1991,she developed recurrent inflammation of the ears,loosening of the skin of the bridge of the nose, andwas treated with prednisolone and azathioprine. Adiagnosis ofrelapsingpolychond ritis was m ade. Speechis still unaffected, but now she cannot sing, her hearingis impaired and she is still having recurrent anterioruveitis.The ocular findings in relapsing polychondritis weredescribed in Ophthalmology 1986 [7], 57 of 112 patientshad ocular involvement, 39% episcleritis, 14% scleritis,9-30% uveitis, 9% retinopathy.Uveitis can be classified into: anterioriritis oriridocyclitis; intermediatecyclitis, vitritis or parsplanitis; posteriorchoroiditis, chorido-retinitis orretinal vasculitis.The ophthalmological assessment of uveitis shouldbe to initially identify the type of u veitis, then to assessthe extent of disease within the eye and the presence ofcomplicating factors, such as cataract, glaucoma,neovascularization and retinal detachm ent. Visual lossin an acute anterior uveitis is due to a combination ofpathologies. There is an inflammatory infiltrate in the

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    HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE 261anterior chamber, and an inflammatory infiltrate cancoat the lens. There is disturbance of accommodationdue to ciliary spasm and anterior synechiae (adhesionsbetween the iris and posterior cornea) lead to anincrease of intraocular pressure, causing cornealclouding. Posterior synechiae (adhesions between theiris and lens also form) an d cata racts develop especiallyin children.Anterior uveitis is most frequently an acute, recur-rent condition involving the iris and ciliary body. It isthe most common form of uveitis; chronic forms alsooccur, as with juvenile arth ritis, but ar e much less com-mon. Typically, the patient presents with a moderatelyinjected eye, variable pain and discomfort dependingon the degree of ciliary muscle spasm and/or rise inintraocular pressure, and some degree of reducedvision.Inflammation of the ciliary body (cyclitis) causesdifficulty in accommodation, affecting reading ability,in the presence of persistent inflammation; aqueousprod uction by the ciliary body is affected which maylead to ocular hypotension.The appearance of uveitis in ankylosing spondylitisis well described, 25% of patients develop acuteanterior uveitis. Uveitis is seen in 10-15% of patientswith other seronegative arthropathies. Signs areidentical regardless of the underlying disease. Theattacks are usually unilateral and the posterior segmentof the eye is uncommonly affected. Rothova [8]reported on 865 patients who presented with uveitis;17% had a B27-associated uveitis, 7% sarcoidosis and6% a B27 seronegative spondarthropathy. It appearsthat HLA-B27 positive patients with uveitis can bedistinguished from HLA-B27-negative uveitis.Findings in the B27-positive patients include: malepredominance, unilaterality with alternating recur-rences, absence of 'mutton fat' keratitic precipitates, ahigh ocular complication rate and frequent associationwith spondylarthropathies. Rosenbaum in 1992 [9]described the appearances of uveitis associated withspondarthropathies. Onset was acute and unilateral,the recurrence in the contralateral eye was frequent,55% of patients were B27 positive and there wasassociated joint disease in 84% of the B27-related iritispatients.Sarcoidosis leads to eye involvement in 30-40% ofpatients. It has common appearances of acute orchronic uveitis; 25% develop posterior uveitis andretinal vasculitis, and 5% of patients develop granulo-matous optic neuropathy with profound visual losswhich is steroid sensitive. It has been suggested that70 % of patients with sarcoidosis have cellularinfiltrates and/or granulomatous lesions in theconjunctiva and the infiltrate is probably of a CD4-positive T cell and that a conjunctival biopsy might behelpful in diagno sis, althoug h this findin g has not beenwidely reported.Patient 3: Master AD, date of birth 20.8.87In September 1988, this patient developed a painfulleft eye. His haemoglobin was 10.7 g, ESR 51 mm/h

    and the ANA was 1/100 positive, rheumatoid factornegative. Treatment was with Naproxen.In 1990,flexiondeformity of the knee occurred withswelling of the proximal interphalangeal joints of theright hand. He developed swelling of both knees withinjections required in 1991 and because of neck painwas given a soft collar. He developed a vaigusdeformity of 10 in the left knee, flexion deformity of5 and had overgrowth of 1 cm. He developed uveitisin 1991 and was treated with a topical steroid. Hisarthritis became polyarticular and he developed activesynovitis of both wrists, metacarpal phalangeal andproximal interphalangeal joints. Treatment withmethotrexate was successful. He developed recurrentuveitis which was treated with prednisolone 0.5% andcyclopentolate 0.5%.Affected children are mostly girls and are usuallyyoung at onset of arthritis (mean age 3 yr). Jointinvolvement is usually pauciarticular, although it mayspread to become polyarticular; 90% of patients withchronic uveitis are ANA positive. In ANA-positivepatients with pauciarticular onset before the age of5 yr, there is a 60-70% risk of uveitis; 50% of uveitispatients present within 1 yr of onset. However, uveitishas been recorded before the onset of arthritis in 10%of patients. Whilst uveitis is usually detected within 7 yrof onset, it h as developed 34 yr after th e onset o fjoint symptoms. The eyes and joint disease evolveindependently and the overall severity of each is likelyto differ.Owing to the insidious nature of this inflammatorydisorder, the visual consequence can be severe. Theinflammation occurs predominantly as a low-gradecellular infiltrate. Extensive posterior synechiae, withcataract formation and secondary cystoid macularoedema, account for the visual loss, although only10-20% of affected eyes become blind. Early onset ofuveitis, either symptomatic or when picked up inroutine screening within the first year of arth ritis, andparticularly if associated with posterior synechiae atthe first examination, is associated with a worseprognosis for vision.A report published by a joint working party of theRoyal College of Ophthalmologists and the BritishPaediatric Association has suggested that patientsshould be regarded as at risk of developing uveitisaccording to the following categories: high riskearlyonset (under 6yr), pauciarticular onset, positive forANA; medium riskpolyarticular onset, and positivefor ANA or pauciarticular disease and negative forANA; low risksystemic juvenile chronic arthritis,juvenile chronic arthritis associated with HLA -B27, ordisease starting over the age of 11 yr .Patients in the high- and medium-risk categoriesshould be screened every 3-6 months for 5 yr from theonset of juvenile chronic arthritis, with subsequentscreening annually for lOyr after the onset or until theage of 12, whichever is shorter.Posterior uveitis presents with a wide variety ofclinical syndromes of markedly different severity andvisual consequences. It occurs in association with many

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    262 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3systemic diseases; however, in a large prospective studyof systemic disease linkage with uveitis, only 26% werefound to have an association, of which the mostcommon was sarcoidosis.It is important to differentiate uveitis associated withsystemic disease from those forms of uveitiswhich havea clear infectious aetiology, such as herpes simplex-induced acute retinal necrosis, cytomegalovirus retinitisand toxoplasmosis retinochoroiditis.Behcet's disease leads to eye involvement in 70% ofpatients and up to 25% will lose sight. The anterioruveitis is typically recurrent, but can resolvespontaneously. The high incidence of blindness is dueto the severity of the retinal changes, the characteristicfeatures are sequential occlusions of branch retinalveins and retinal infiltrates resulting in progressiveretinal ischaemia and optic disc atrophy. Pathologicalstudies h ave show n little difference in the mechanism oftissue destruction that occurs with retinal vasculitis ofBehcet's and retinal vasculitis in isolation. Involvementof the choroid in posterior uveitis is commonly a parsplanitis with vitreous exudation [10].The pathology of posterior uveitis consists ofactivated T cells present in the vitreous fluid, granulo-matous lesions containing abundant macrophages andCD4 and CDS T cells. The CD4 T cells express theinterleukin 2 receptor and dendritic cells are detected.There are good experimental models of posterioruveitis which resemble human disease and have assistedin defining the clinical heterogeneity of posterioruveitis.Several retinal antigens have been described,including retinal S antigen, interphotoreceptor retinalbinding protein and rhodopsin. The best characterizedof these antigens is S antigen which is also understudy by other groups as a regulatory protein forphototransduction. These antigens can all induce aspectrum of uveitis severity which can be modified bythe dose of antigen, the species of experimental animaland the state of immunosuppression of the animal.Inflammation induced in the model is assumed tobe autoimmune in nature since the inflammationis inducible with heterologous, homologous andautologous antigen. The target cell has been identifiedas the photoreceptor cell, partly on the basis that thecells appear to hom e in on this layer of cells, and partlybecause most of the antigens derive from thephotoreceptor/retinal pigment epithelium (RPE)interface.A major advantage of these models for humanstudies is that the earliest stage of the disease can beinvestigated. Thus, it has been shown that at the onsetCD 4 + T cells and macrophage s predom inate, whileC D 8 + T cells appear later in the disease. B cellsincrease in number during the healing phase, whileMHC Class II expression occurs on several cells fromthe earliest stages of the disease.Recent studies on peptides from retinal S antigenhave suggested that there is a 'core sequence' within theprotein which is essential for disease induction, andthat this sequence has considerable homology for

    certain sequences from viral and fungal proteins.Treatment of experimental uveitis has included T-cellvaccination which protects against induction; feedingrats with retinal S antigen also prevents induction as dospecific monoclonal antibodies [11].Management of uveitisAnterior uveitis usually responds to topically appliedsteroids and mydriatics which prevent complicationssuch as synechiae. It is important to give adequatetreatment since the inflammation can escape controland lead to hypopyon and secondary glaucoma.Chronic anterior uveitis is more difficult to treat and,while it is usually responsive to systemic steroids,immunosuppressive drugs may be required.Posterior uveitis may not require therapy whensymptoms are restricted to floaters, as occurs in mildpars planitis. Visual loss occurs with macular oedema,then macular and premacular fibrosis. Subretinalneovascular membranes cause permanent visual loss.Vitreous contraction may lead to retinal holeformation and detachment. Vitreous opacities can beremoved, but usually reveal the true cause of visuallossmaculopathy. If vision is threatened in posterioruveitis and all infective causes have been exclude d, thentreatment with high-dose steroids and immuno-suppressive drugs is usually indicated.Patient 4: Mrs EB, date of birth 10.7.27In 1948, this patient developed seropositiverheumatoid arthritis. In 1958, she was treated withchloroquine sulpha te 200 mg daily. In 1988, this waschanged to hydroxychloroquine 400 mg daily. In 1990,there was good visual acuity, but blue haloes aroundpoint sources. She was not able to drive at night andhad slight reduction of colour vision. A diagnosis ofkeratopathy was made. Electrodiagnostic testing in1991 showed no h ard evidence of retinal abnorm ality.EOG (pigment epithelium) was at the lower range ofnormal, the ERG (peripheral retina) was subnormal.The pattern ERG was also subnormal, but there werecorneal opacities.The use of antimalarials raises the questions shouldophthalmological screening be done? Who shouldscreen? How often should the patient be screened andwith what methods? Corneal toxicity leads to blurredvision and haloes around lights due to corneal dep osits.There is transient loss of accommodation, poliosis,reduced corneal sensitivity and ocular muscle palsies.The major concern with antimalarials is thedevelopment of retinal toxicity. Chloroquine has a highaffinity for melanin, including the retinal pigmentepithelium. The retinal damage is related to mal-function of the phagolysosomes, resulting in faultyclearance of ageing photoreceptor membranes. Thebuild-up of lamellar myelin bodies disturbs the meta-bolism of the retinal pigment epithelium.The consequences are as follows.1. The corneal deposits disappear when the drug isstopped and are not related to retinal toxicity. These

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    HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE 263are the most frequent lesion and are dose related.The major problem is a maculopathy or retinopathywhich can lead to visual field defects and areduction in visual acuity.2. A premaculopathy leads to development of visualfield loss to a red target between 4 and 9 fromfixation. The macular changes at this stage may beminimal and visual fields revert to normal if thedrug is withdrawn. Identification at this stage is thegoal of screening programmes, as cessation oftreatment will usually prevent progression.3. A maculopathy leads to a central scotoma andimpaired visual acuity. The central part of themacula is hyperpigmented and the surroundingregion hypopigmented (bull's-eye maculopathy).The maculopathy is irreversible and vision mayworsen, which may occur months or years after thedrug is withdrawn.

    Ocular changes are less likely to occur in patientsreceiving hydroxychloroquine than chloroquine.Toxicity is unlikely if the cumulative dose of hydroxy-chloroq uine sulphate does not exceed 200 g.Chloroquine is said to cause a higher incidence ofmaculopathy, but this may have been due to the veryhigh doses of this drug used in the 1960s. Very fewcases of toxicity have been reported when the total dosehas been less than 300 g of the pho sphate.The retinal lesions described with hydroxy-chloroquine are not unique to hydroxychloroquine use.Cases of retinopathy including the classical bull's eyeappearance occur in the absence of any predisposingcause. For instance, Scherbel et al. [12] found theincidence of pigmentary retinopathy in chloroquine-and hydroxychloroquine-treated patients to be lessthan in untreated rheumatoid patients. The maculo-pathy in both groups was reported as beingindistinguishable. The electro-octogram is consideredto be a sensitive test of retinal function, but 20% ofuntreated rheumatoid arthritis patients have anabnormal result.One can conclude that cases of retinopathy havebeen described following hydroxychloroquine useand drug cessation seems to have prevented furtherdeterioration. There is no single identifiable retinalpathology resulting from hydroxychloroquine use.The incidence of sight-threatening retinopathy onhydroxychloroquine at the recommended dose isextremely small and the incidence of retinopathy maynot be higher than background population rates. In thelight of these conclusions, the College of Ophthal-mologists has recommended that patients have theireyes examined before treatment is started and anyabnormality at this stage may require further ophthal-mological supervision. Otherwise, patients can be givenan Amsler chart with instructions on its use. Thisshould be used monthly and the patient advised that ifthey note any abnormality they should stop the drugand seek advice.

    Special attention should be paid to higher riskpatients: (1) those with hepatic/renal impairment; (2)

    those exceeding chloroquine base dose of 4 mg/kg leanbody weight a day and hydroxychloroquine dose of6.5 mg/kg lean b ody weight a day; (3) patients receivingtreatment for more than 2yr, although this risk issmall.The problems are that many patients at pre-treatment may have macular abnormalities and thereare no clinical features or tests, including electro-diagnostic tests, that can reliably detect the retinopathyat a reversible stage.Patient 5: Mrs JB, date of birth January 1947This patient developed a tonic clonic seizure at theage of 20during her first delivery. Eight y ears later, shedeveloped arthralgia, an urticarial rash and absenceseizures. Her rheumatoid factor was negative. HerANA was weakly positive. She presented again aged40 yr with a pho tosensitive rash an d synovitis of theknees. Investigations then revealed a positive ANAwith a homogeneous pattern and an elevated DNA of100 units (normal

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    264 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3peripheral nerve involvement, MRI appearance and theassociated scrological abnormalities. In addition,cutaneous vasculitis had been previously presentCorticosteroids did not arrest the development of newneurological lesions and the brainstem syndromedeveloped after the first i.v. pulse of cyclophosphamide.Disease progression was apparently only halted whenFVlg was used, suggesting that this treatment may beadded to existing therapeutic strategies for vasculiticneurological manifestations of SLE. FVIg has beenused with benefit in other systemic vasculitides, andfor non-neurological complications of SLE. Themechanism of action is uncertain, but it is consideredthat it alters idiotypic networks.

    Manifestations of neurolupus include non-focalcerebral dysfunction (35-60%), organic brainsyndrome, psychosis, affective disorder and neurosis.Seizures are seen in 15-35%, focal deficits in 10-35%,cranial neuropathies in 10-35%. Peripheral neuro-pathies are seen in 10-15%. Aseptic meningitis,Eaton-Lambert syndrome, myasthenia gravis andinfectious complications have been described.Ocular sym ptoms are comm on in patients with SLE.Scleritis can been seen a t some stage in 10% of patients.Its presence indicates active systemic disease and mayrequire an increase in systemic therapy. U veitis is onlyseen in association with severe scleritis. Patients maysuffer from dry eye, as well as peripheral cornealthinning Do uble vision may result from involvementof the extraocular muscles.The hallmark of retinal involvement is the cytoidbody, which is the descriptive term used in systemiclupus for cotton-wool s po t Retinal haemorrhages andocclusions of central and branch retinal arteries mayoccur, and are due to the deposition of immunecomplexes rathe r tha n vasculitis. The patients may alsoshow signs of hypertensive retinopathy , with occlusionsof branch retinal veins [13].

    GIANT CELL ARTERITISGiant cell arteritis was initially described byJon ath an Hu tchins on in 1890 [14]. The patientRumbold was described as developing red streaks onhis head which were painful and prevented him fromwearing his hat The term 'arteritis of the aged' wasused. The Archives of Internal Medicine 1993 [15]suggests that Adolf Hitler suffered from GCA; he isdescribed as suffering from temporal headaches,tenderness of the temporal and supra orbital regions,enlarged temporal arteries, visual loss in the right eye,low-grade fever, weight loss, a nonnochromic anaemiaand an elevated ESR. Whereas the symptoms and signsof polymyalgia,, rheum atica and GCA are usuallyreadily identifiable, general sym ptoms of night sweats,depression, anorexia, malaise, fever and weight losscan lead to delay in diagnosis, as can laboratoryabnormalities, particularly the raised alkaline phospha-tase and anaemia. In a survey at Addenbrooke'sHospital [8] of 108 patients admitted as medicalin-patients, initial diagnoses included neoplasticpolymyositis; four were investigated for space-

    occupying lesions, 10 for liver disease, 11 for neoplasia,12 for anaemia and nine for a pyrexia of unknownorigin [16].Healey and Wilske [17] documented the presentingcomplaints of 50 consecutive patients with biopsy-proven GCA; 16 presented with polymyalgia rheu-matica, 13 with symptoms of temporal arteritis, eightwith weight loss and malaise and a flu-like illness, fivewith fever of undermined origin, two with loss ofvision, two with anaemia, two w ith headach es and onewith leg claudication. Clinical manifestations at latestages included 31 with symptoms of polymyalgiarheumatica, 31 having symptoms of temporal arteritis,15 having a fever greater than 100T, 14 developedvisual manifestations, 10 jaw pain , six developed aperipheral neuropathy, four developed leg claudicationand one patient died with a ruptured aortic aneurysm.It has been suggested that if cranial arteritis is tobecome clinically apparent it will do so within 1 yr ofthe onset of general symptoms; however, examples ofcranial arteritis developing 2 yr or longer after systemicsymptoms have been described.

    GCA has a peak age of onset between the ages of 60an d 75 yr. The annual incidence of biopsy-positivepatients is 6.7:100 000. The an nual incidence rate overpatients of 50yr of age is 18.3:100000. It is a diseasethat affects mainly northern Europeans and northernstates of the USA. Biopsy studies from OlmsteadCounty [18] have shown an increase in incidence ofbiopsy-positive patients in females, but not in menbetween 1965 and 1985. Ostberg [19] examined thetemporal arteries and aorta of all adults who died inMahno throughout 1 yr, and found evidence ofprevious arteritis in 1.7% of the 889 cases.Patient 6: Mrs MW , date of birth 21.6.22In January 1989, she developed pain of the neck andshoulder girdles and both buttocks and thighs. Therewere no headaches, her general health was good.Haemoglobin was 11.6g/dl, ESR 45mm/h, C-reactiveprotein 29 mg/1. A diagnosis of polymyalgia rheum-atica was made. She was treated with 15mg pred-nisolone a day and her symptoms resolved. In January1990, she was receiving prednisolone 5mg alternatingwith 7.5 mg. She developed three episode s lasting10 min of loss of vision of the left eye with pain in thejaw on chewing and pain arou nd the left eye. Her ESRwas 18mm/h, her C-reactive protein 7.8 mg/1. Herprednisolone was increased to 40 mg a d ay and atemporal artery biopsy was carried out. This showedcharacteristic changes of GCA with narrowing of thelumen, intimal proliferation and medial infiltration oflymphocytes and plasma cells, and disruption ofinternal elastic lamina.

    She is now well and req uires 3-5 mg prednisolo nedaily. She has had some recurrence of limb girdlestiffness an d jaw pain, and pain a rou nd the left eye andleft temple. These symptoms have responded to atemporary small increase of corticosteroid dosage.In 1991 Wise et at. [20] described the characteristicsof patients with temporal arteritis and a low ESR. The

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    HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE 265low-ESR group were more likely to have previouspolymyalgia rheumatica or to have received steroidtherapy. It is thought that the reason for failure of theESR and CRP to increase may be due to down-regulation of the acute-phase response in chronicinflammation. In patients with uveitis, Yorston et al.[21] have described smaller response in the ESR if therehave been several previous attacks of uveitis despite asimilar level of inflammation. Kyle et al. [22] havefollowed ESR and C-reactive protein in patientsprospectively, and ~ 50% of patients flare without arise in C-reactive p rotein o r ES R. Th ere seems to be noadvantage of measuring C-reactive protein in additionto ESR. Pountain and colleagues [23] have not beenable to demonstrate a prolonged fall in CD8-positive Tcells in patients with active polymyalgia rheumaticaand GCA, and cannot confirm that measurement ofCD8 T cells helps in monitoring disease activity. Atransient fall is seen which we have attributed toinitiation of steroid therapy. However, a measurementof a-1 antichymotrypsin levels may help in manage-ment [24]. These levels are raised in active disease andfall with remission, and then patients can be success-fully weaned offcorticosteroid therapy . There is a widedistribution of ESR in patients with polymyalgiarheumatica and GCA. However, the ESR is usuallygreatly elevated and provides a useful means ofmonitoring treatmen t, although it must be appreciatedthat some elevation of the ESR may occur in other-wise healthy elderly people. Establishing a raised ESRis the key investigation, although a normal ESRis occasionally found in patients with activebiopsy-proven disease.

    Patient 7: Mr TP, age 74 yrThis patient presented with 2 months' depression,anorexia, weight loss and headaches, eased bydiazepam and analgesics. Bilateral carotid and femoralbruits were present. ESR was 20mm/h, the gammaglutamyl transferase was elevated at 110 /x/1. Th epatient was advised to stop smoking and drinking, withimprovement. Two months later, he presented withpain and loss of central vision in the right eye. Twoweeks previously he had developed a tender scalpwhich was thought to be due to herpes zoster. He thendeveloped three episodes of obscured vision lasting 15 swhich were thought to be atheromatous anteriorischaemic optic atrophy. Five days later, he lost visionin both eyes. At t hat time, a temporal artery biopsy wascarried out and was positive. Unfortunately, despite ahuge volume of literature on visual loss and otherocular man ifestations of GC A, such cases are still seen.My experience over the last 25 yr, like that of manyothers, has shown that if the disease is detected early,and managed adequately, blindness is almost totallypreventable. This makes early diagnosis and manage-ment of the disease all important.Ocular temporal arteritis was described by Simmonsand Cogan in 1962 [25]. Patients developed suddenpainless visual loss in one eye; 30% went blind in theother eye without treatment, in most cases within 7

    days, but it could occur as early as 24 h. Many ocularlesions can be seen in GC A, these are essentially due toocclusion of the various orbital or ocular arteries. Theincidence of various ocular manifestations given in theliterature varies widely because the incidence dependson a number of factors, the most important of whichis how early the diagnosis of GCA is established andthe treatment started. It also depends upon the rigourwith which cases are diagnosed; for example, it is notuncommon to find that the diagnosis has been madesolely on clinical grounds. The most common lesion isoptic nerve ischaemia, these can be anterior which isthe most common lesion, they can be partial butusually leads to complete visual loss. They canoccasionally be posterior which can lead to partial orcomplete loss. Extraocular motility disorders areusually transient and not associated with visual loss.Pupillary abnormalities can be seen secondary to visualloss. Cerebral ischaemic lesions producing visual lossare rare, as are anterior segment ischaemic lesions andchoroidal infarcts. Retinal ischaemic lesions can affectthe central retinal artery, this is associated with severevisual loss. The cilioretinal artery can be occluded, butis invariably associated with anterior ischaemic opticneuropathy (AION) [26].

    Hayreh in 1990 [27] described his experience of ~800patients with AION , 12% had arteritic AION and 88%non-arteritic. He suggested that the features suggestingarteritic AION and helping to differentiate it fromnon-arteritic AION were systemic symptoms and anelevated ESR. Amaurosis fugax was rarely seen innon-arteritic AION. Arteritic AION was usuallyassociated with early visual loss. A chalky white diskwas highly suggestive of arteritic AION. Optic discoedema was associated with cilioretinal occlusion andwas due to arteritis. Early non-filling of the choroid onangiography was also associated with arteritis.Does the temporal artery biopsy influence treatment?It can be useful in patients with symptoms of GCA andis particularly reassuring if patients respond poorly tocorticosteroid therapy. It is not usually of value inpatients with polymyalgia rheumatica alone, but iscrucial in making the diagnosis of GCA in patients withnon-specific constitutional symptoms alone. Positivebiopsy indicates the need for steroid therapy in higherdoses than those used for polymyalgia rheumatica,more intense follow-up and commits a physician totreatment despite steroid complications.

    Clinicians vary greatly in their approach to temporalartery b iopsy. Some consider it emphasizes the value ofa positive histological diagnosis, especially months oryears later, when side-effects of the steroid treatmenthave developed. Others feel that a high false-negativerate diminishes the value of the procedure. In mostinstances, the high false-negative rate can be attributedto the focal nature and involvement of the superficialtemporal artery by the inflammatory process. In 1976Klein el al. [28] demo nstrated 'skip ' lesions in 17 of 60temporal artery biopsies; some segments showingactive disease were as short as 350 //m. The rate offalse-negative biopsies depends on many variables,

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    266 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3including the size of the biopsy, the number of levelsexamined, whether biopsies were taken from one orboth sides of the scalp, and the duration of steroidtherapy before the procedure.Three papers examine the value of temporalartery biopsy. In 1981 AJlsop and Gallagher [29]described 58% of patients with clinical arteritis havinghistological confirmation. This figure rose to 66% inthe late 1980s. In up to 6% of all biopsies, the originalreporting patho logist ha d m istaken the usual feature ofageing (arteriosclerosis) as evidence of active or healedcranial arteritis. In a single case, the histologicalevidence of arteritis had been overlooked. Hall et al.,in the Lancet of 1983 [30], subsequently in 1984concluded that a normal biopsy predicted the absenceof need for corticosteroid therapy in 91 % of patients,but a 4-6 cm artery specimen was needed to say thatthe artery was not clearly abnormal; 86% of patientswere diagnosed by unilateral biopsy, but 14% ofpatients required examination of the other side.Wilkinson and Russell [31] have also shown a clearcorrelation between the amount of elastic tissue in thehead and neck vessels and the susceptibility to arteritis,and some transient visual disturbance may be due tomicroemb oli arising from arteritis of vertebral arteries.

    There have been anecdotal reports of the use ofchloroquine, dapsone and cyclosporin and cyclophos-phamide in the treatment of GCA. Widespread studieslooking at the use of prednisolone in combination withmethotrexate or azathioprine have demonstrated themto have weak steroid-sparing properties. Clearly, theuse of steroids leads to better symptom control andreduced incidence of blindness, but it is uncertainwhether their use shortens the disease duration. Thereare few clinical trials to help decide on the correctinitial dose and the rate of corticosteroid reductiononce initial symptoms are controlled.Kyle and Hazleman [32] have carried out a pro-spective study looking at dosage and length of treat-men t, a nd suggested that 15-20 mg prednisoloneinitially is usually sufficient for the treatment ofpolymyalgia rheumatica, aiming to reduce the dosageafter a month to about 10 mg by 2 months. An initialdose of 40 mg pre dniso lone for G CA is usually suffi-cient, reducing the dose after a month to ~20mg by2 months, a maintenance dose of ~ 10 mg by 6 monthsand 7.5 mg by a year. M ost p atients will need 3-4 yr oftreatm ent, but w ithdrawal after 2 yr is worth attem pt-ing. The risk of relapse, particularly with arteriticcomplications, has to be balanced against the risks ofcorticosteroid-associated side-effects. Between one-fifthand a half of patients may experience serious side-effects. There is an increased risk if there is a high initialdose ( > 30mg of prednisolone), a maintenance dose of> 10 mg prednisolone and high cumulative dosagesand increased duration of therapy. Maintenance dosesof < 5 mg seem relatively safe.Patient 8: Mr RB, date of birth 12.6.42In December 1989, this patient presented with painin the head, face, neck and difficulty eating. He had

    periorbital oedema and tenderness of the righttemporal artery with bilateral carotid and right sub-clavian bruits. An ESR was elevated at 91mm/h. Archaortogram was normal. He was treated initially withprednisolone 60 mg then increased to 100 mg a day tocontrol his symptoms. In November 1990, he lostvision on two occasions following exercise, at that timean ESR was 40 mm/h and a carotid angiogram w asnormal. In March 1990, he was treated with hydro-chloride and also in March 1990 he presented withthree episodes of loss of vision in the right eye, his ESRwas elevated at 85 mm/h. He was treated with pulsemethylprednisolone and the dosage of prednisolonewas 60mg/day and of azathioprine 300 mg/d ay.

    It is probable that he has Uhth off's symptom . Thiswas described by Raymond et al. in 1980 [33]. Thesymptoms are a reduction of visual acuity with exerciseor heat The syndrome is associated with multiplesclerosis and neurological disease. Raymond describedtwo patients with vascular disease, one wh o had GC A,another patient had total carotid occlusion.Patient 9: Mrs EB , age 72This 72-yr-old retired cleaner had a hysterectomyand repair in May 1984. Her histology showed GCA ofthe myometrial arteries [34]. She was referred to therheumatology clinic in July 1985 with coldness of theright hand, her right arm was aching after use, she hadstiffness of the buttocks and groins, she was tired, therewas weight loss of 18 lbs and she had describedoccasional visual blurring for a year.An arteriogram showed almost total occlusion of theaxillary artery and her symptoms gradually improvedwith corticosteroid therapy; it is characteristic thatthese symptoms are slow to improve. Clinical evidenceof large artery involvement is present in 10-15% ofcases, and in some instances aortic dissection andrupture occur. Bruits are often present over largearteries and there may be tenderness, particularly overthe subclavian artery. An early sign of arteritis isincreased sensitivity of the carotid sinus. Ligh t pressurewill often lead to transient asystole for two or morebeats, so it is advisable for the patient to be lying downwhen examined.Patient 10: Mrs JT, age 85The last patient presented in 1978 at the age of 70 yrwith 2 weeks temporal headaches and scalp tenderness.There was no visual disturbance, no joint pa ins and nonight sweats or symptoms of polymyalgia rheumatica,but a 4 month history of lethargy and ill-health.Investigations showed a haemoglobin of 11 g/dl, anelevated ESR of 94 mm/h and an elevated alkalinephosphatase of 120 n( \ (normal range 30-92/i/1).Immune complexes were elevated at 6 1 % (normalrange 0-24) and acute-phase proteins were elevated.Chest X-ray showed a slight left ventricularenlargement with the aorta unfolding. T em poral arterybiopsy was normal.In December 1979, she was asymptomatic onprednisolone 5 mg/day, atenolol and a diuretic; blood

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    HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE 267

    pressure was 150-80. H er ESR was 21 mm/h. InJanuary 1980, she presented with interscapular andright shoulder pain. Her right arm was cold withabsent pulses. There were no bruits or radial femoraldelay. Her apex beat was displaced. An angio-gram demonstrated a dissecting aortic aneurysm.Her aortic aneurysm was treated with an arterialgraft and the biopsy of the aorta showed activeGCA [35].GCA as a cause of aortic dissection has beenrecorded rarely at autopsy, and most exceptionallyduring life. This elderly patient with a dear symptomcomplex of polymyalgia rheumatica subsequentlypresented as an emergency with chest pain. Thediagnosis of GCA causing dissection of the aorta withsurvival of the patient is most unusual. Most of thepatients reported had a history of hypertension orfeatures of hypertensive disease at autopsy . In ad dition,there is a higher proportion of females than is found inGCA. This case serves to illustrate that the clinicianshould be aware of potential life-threatening large-vessel disease in GCA, particularly in female patientswith hypertension.In both clinical and histological terms, cranialarteritis is one of the most distinctive of all vasculardisorders. Although ultrastructural and immunohisto-chemical studies have provided some insight into theunderlying pathological changes, they have notcontributed directly to the diagnosis of cranial arteritis.Immunological studies have suggested that a cell-mediated immune reaction, possibly against anautologous antigen, occurs locally in the arteriticlesions. The observed HLA-DR expression can beaccounted for by the sum of macrophages andactivated T cells, the macrophages being the mostprobable antigen-presenting cells. The interdigitatingreticulum cells may also be involved in an tigen presen-tation. What the antigen(s) may be is, however, stillunknown, as are the factors initiating the inflammatoryprocess.

    In this presentation, the association between eyedisease and connective disorders has been described.Failure to be aware of the ocular problems is notuncommon, but these are of particular importancebecause slight disturbances of function causesymptoms, because progressive lesions may result inblindness with its devastating consequences, becausethey are often thefirst issues to be involved and becauseany pathological changes in the eye can readily bevisualized and monitored with slitlamp or ophthalmo-scope. This is uniquely fascinating for the clinician whocan only get a superficia] view of skin, synovia orepithelia and has to depend on histological sections foran entirely static view of events occurring in the tissues.REFERENCES

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    orders with particular reference to retinopathy. N Engl JM ed 1963^73:360-6.13. Coppeto J, Lessel S. Retinopathy in systemic lupuserythematosus. Arch Ophthalmol 1977^)5:794-7.14. Hutchinson J. On a peculiar form of thrombotic arteritisof the aged which is sometimes productive of gangrene.Arch Surg 1890;l:323-7.15. Redlich F . A new medical diagnosis of Adolf Hitler. ArchIntern Med 1993;153:693-7.16. Jones JG, Hazleman BL. Prognoses and management ofpolymyalgia rheumatica. Ann Rheum Dis 1981;4(hl-5.17. Healey LA, Wilske KR. Manifestations of giant cellarteritis. Med Clin North Am 1977;61:261-70.18. Bengtsson BA. Epidemiology of giant cell arteritis. In:Hazleman BL, Bengtsson BA, eds. Giant cell arteritis.London: Bailliere Tindall, 1991.19. Ostberg G. On arteritis with special reference topolymyalgia arteritica. Ada Pathol Microbiol Scand1973;237(suppl.):l-59.20. Wise CM , Agudelo CA , Chmelewski W, M cKnight K .Temporal arteritis with low erythrocyte sedimentationrate. A review of five cases. Arthritis Rheum 1991;34:1571-4.21. Yorston D, Whicher J, Chambers R et al. The acutephase response in acute anterior uveitis. Trans Ophthal-mol Soc UK 1985;104:166-70.22. Kyle MV, Cawston TE, Hazleman BL. ESR and C-reactive protein in the assessment of polymyalgiarheumatica/giant cell arteritis on presentation and duringfollow-up. Ann Rheum Dis 1989;48:667-71.23. Pountain GD, Keogan MT, Brown DL, Hazleman BL.Circulating T cell subtypes in polymyalgia rheumaticaand giant cell arteritis: variation in the percentage ofCD8+ cells with prednisolone treatment. Ann RheumDis 1993;52:730-3.24. Pountain GD, Calvin J, Hazleman BL. al-antichy-motrypsin, C-rcactive protein and erythrocyte sedimen-tation rate in PMR/GCA. Br J Rheumatol 1994;33:550-4.25. Simmons RJ, Cogan DG . Occult temporal arteritis. ArchOphthalmol 1962;68:8-18.26. Hayreh SS. Ophthalmic features. In: Hazleman BL,Bengtsson BA. Giant cell arteritis. London: BailliereTindall, 1991.27. Hayreh SS. Anterior ischaemia optic neuropathy.

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