British Journal of Rheumatology 1996;35:258-268

HEBERDEN ROUNDSEPTEMBER 1993

RHEUMATIC DISORDERS OF THE EYE AND THE VARIOUS STRUCTURES INVOLVED

B. L. HAZLEMAN
Rheumatology Research Unit, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ

As this Heberden Round was given in Cambridge, it is perhaps appropriate to give an insight into Cambridge in Heberden's time and his influence on medical training. William Heberden entered St John's College in 1724. He was a sizar, which meant he performed certain domestic tasks such as waiting in Hall and in return received free accommodation, free or cut-price tuition, plus a small allowance towards the cost of food. Also, the college had traditional methods of helping hard-pressed students who showed promise of academic success and in 1725 Heberden was admitted Foundress Scholar 'for the bell'a description denoting his duty to ring the chapel bell for the daily services [1]. Cambridge at that time was a market town with a population of under 10 000, of whom 800 were members of the university, and 120 were university or college servants. It cannot be claimed that the university made any serious attempt to encourage medical studies. The professorships of anatomy and chemistry gave status to existing independent teachers, the Jacksonian professorship was the benevolent endowment of a gouty clergyman; only the professorship of botany was initiated by the university. Senior members of the university were all too often ineffective and negligent, and the instruction of students was frequently neglected: lecturers might hold their appointments without delivering a single lecture; and it was possible for a professor to know nothing of the subject he was supposed to teach. William Heberden took his BA in 1728, one of a total of 27 students. He took his MA in 1732 after waiting the minimum 4 yr, and in 1731 was elected a St John's Fellowship and began to study medicine. In 1734, he was elected a medical fellowship at St John's and in the same year was appointed Linacre Lecturer in Physics. The lectureship was the oldest medical endowment in the university, but the founder's original intentions were no longer observed and the appointment provided the incumbent with a supplement to his income, without requiring him to undertake any duties. The total medical entry was an average 13 students a year and medical training depended largely on the student's own initiative. Heberden took his MD in 1738. There are records that state that he practised
Submitted 4 September 1995; accepted 7 September 1993.

from his college rooms at St Johns, sometimes accompanied by students. In 1740, he delivered the first course of lectures on materia medica; in 1745, he left Cambridge for London. The specimens used by Heberden to illustrate his lectures are housed in a large cabinet in St Johns, as are annotated printed hand bills setting out the subjects to be covered in each lecture. There were a total of 26 lectures; the length was usually one and a half hours, but the final lecture lasted two and a quarter hours. On his 1747 programme, he states 'left off a week for Newmarket races'. An important section of Heberden's lectures on materia medica was concerned with the properties of vegetables and Heberden played a prominent part in establishing a botanic garden in Cambridge. His efforts did not have immediate effects, but it was opened in 1762. Heberden also in 1741 completed 'An Introduction to the Study of Physic', which gave guidance to students as to what books they should read and advice about gaining sufficient information generally. It is clear that Heberden was well aware of the deficient Cambridge medical education and was effective in trying to offer something better to bis students. Sir Lionel Whitby, Regius Professor of Physic at Cambridge from 1945 to 1956, gave the first Heberden Round in 1948 at Addenbrooke's Hospital. It was a true round, moving from bed to bed with Whitby holding Heberden's 'Commentaries on the History and Care of Diseases', and was attended by some 18 members of the Heberden Society. Whitby was in charge of the Army Blood Transfusion Service in the Second World War and during his time in Cambridge did much towards planning a new Addenbrooke's teaching hospital; he also built up a haematology unit at Cambridge with an international reputation [2]. I would like to turn to a previous Cambridge Regius Professor of Physic for the theme of my Heberden round. Sir Clifford Allbutt was Regius Professor from 1892 to 1925. Before becoming Regius, he had for 30 yr been in private practice in Leeds and a consulting physician to the infirmary there for 20 yr. He had a particular interest in preventive medicine and mental illness. The ophthalmoscope to which he was introduced by Ogle of St George's fascinated Allbutt and stimulated him to publish a monograph 'On The use of the Ophthalmoscope in Diseases of the Nervous System and of the Kidneys' in 1871. He introduced the term 'choked disc' and is regarded as the father of medical ophthalmology [3].
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HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE OCULAR FEATURES The ophthalmologist has many roles in the management of patients with rheumatological problems. Most rheumatological diseases affect either the uvea, sclera, retina or optic nerve and produce symptoms and signs that confirm their nature and aetiology. Most rheumatological diseases have ocular complications, many of which are specific to the particular disease. Involvement of the uvea or sclera usually produces painful red eyes with preserved vision, whereas involvement of the retina or optic nerve causes profound visual loss without pain or redness. Occasionally, the clinical evidence of inflammation may not be immediately apparent, as with the melting corneal ulcer of rheumatoid arthritis. The ocular features of systemic inflammatory diseases vary according to the size and type of vessel predominantly affected by the disease process. Generally, diseases that affect arterioles involve cornea, episclera, sclera and retinal arterioles, whereas those that affect venules produce uveitis, macular oedema and retinal venous disease. The heterogeneous structure of the three-layered eyeball with its tough, collagenous sclera, its highly vascular uvea and its exquisitely sensitive retina may account for the special qualifications of the eye as a target organ. Thus, rheumatic diseases directed against collagen find the sclera and the peripheral cornea ideal as target tissues. The choroid, with its fine network of vessels, may trap immune complexes in much the same way as the renal glomerulus. The retina, basically an outpocketing of the primitive brain, appears to be subject to the same kinds of autoimmune results as the brain itself, manifesting perivascular inflammatory reactions in the case of Behcet's disease. The ocular manifestations of rheumatoid arthritis are sicca syndrome, scleritis, scleromalacia perforans, corneal melt and Brown's syndrome. Patient 1: Mrs IR, date of birth 8.7.36 This patient was born in Jamaica and in 1974 developed seropositive erosive rheumatoid arthritis. Gold treatment led to proteinuria and had to be discontinued. Penicillamine was ineffective. She has been treated with prednisolone since 1980, azathioprine between 1985 and 1987, and methotrexate since 1987. She developed scleritis in June 198S which led to bilateral eye involvement and severe headaches. She was initially treated with i.v. methylprednisolone which led to a good effect, but was transient. It was repeated. She was subsequently treated with oral azathioprine and cyclophosphamide 150 mg/day with no benefit. In June 1985, she was transferred to Addenbrooke's Hospital. Her visual acuity was 6/9 in the right eye and 6/18 in the left. On examination, she had anterior and posterior scleritis and macular oedema. She was treated initially with cyclosporin with good effect, but side-effects led to its discontinuation.

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She was then treated in July and September with i.v. pulses of methylprednisolone and cyclophosphamide with good effect. The azathioprine was re-commenced in September 1985. Ultrasound scanning showed thickening posteriorly, and the angiogram was abnormal and compatible with posterior scleritis. In September 1989, she developed neck and head pain, she complained of linear floaters in the left eye for 9 weeks, she had pain on eye movements and periorbital pain and jaw claudication with concentric field restriction. She had tenderness and loss of pulsation over the left temporal artery, the right temporal artery, the left brachial artery and left femoral artery, and a biopsy showed disrupted elastic lamina and scarring compatible with the changes of giant cell arteritis (GCA). An ESR was elevated at 74mm/h. She was treated initially with i.v. methylprednisolone and 60 mg prednisolone orally, and within 24 h was pain free and her visual fields improved. In 1990, she developed soreness of the eyes and cloudiness of vision. She had bilateral punctate keratopathy. She was treated with hypromellose 0.3% initially hourly. In May 1992, gelatin rods were inserted into the inferior puncta and in October 1992 she had bilateral cautery of the inferior puncta with good results. She now has no scleritis, she has mild punctate keratitis, her vision is 6/6 bilaterally and she uses hypromellose drops intermittently. Episcleritis and scleritis are two distinct conditions, episcleritis being the milder condition often associated with allergic conditions and subsides spontaneously. The episclera has its own blood supply and is incompletely fixed to the underlying sclera. This is in contrast to the conjunctiva which is freely mobile over the episclera. Episcleritis is a benign, self-limiting condition that is usually nodular and unilateral. In rheumatoid arthritis, most of the episcleritis is of the diffuse type. The affected episcleral vessels are dilated within the affected area and the redness may be intense. Patients complain of irritation and redness rather than pain. Non-steroidal anti-inflammatory drugs or topical steroids lead to resolution. Scleritis must be taken seriously because it can lead to blindness [4]. It occurs in 0.6% of rheumatoid patients and is often associated with more severe disease. It is also a feature of other connective tissue diseases, particularly those with a vasculitic component; therefore, it is seen in systemic vasculitis, systemic lupus erythematosus (SLE) and Wegener's granulomatosis. In contrast to episcleritis, it is painful and does not subside spontaneously. Pain is the most prominent feature and may be very severe, and frequently radiates to the orbit and face. Scleritis may be anterior or posterior. Anterior scleritis occurs in three forms: diffuse, nodular and necrotizing with or without inflammation. Although posterior scleritis is relatively underdiagnosed, anterior scleritis is more common. Scleritis has an insidious onset and is recurrent, and further attacks can be

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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3 syndrome, one with pulmonary fibrosis, two with cutaneous vasculitis; there was also one patient with temporal arteritis and three with gout. Scleromalacia perforans is seen particularly in women with long-standing rheumatoid disease. The affected sclera becomes white because the underlying lesion is arteritic infarction. The underlying sclera becomes atrophic and the blue underlying choroid is clearly seen. This is partly due to thinning, but mainly due to reorientation of the collagen fibrils. This condition is painless. Appearances of Wegener's granulomatosis in the eye are distinct, 50% of patients with this condition develop eye problems, particularly those with limited disease. Marginal thinning with descemetocele and corneal perforation may occur, as it can in relapsing polychondritis and SLE. Breakdown of the corneal epithelium and corneal ulceration may occur, and the treatment includes immunosuppression with cyclophosphamide. In many cases, surgical intervention is necessary [6]. The aetiology of these melting disorders of the cornea is unclear. They usually occur predominantly in severe rheumatoid arthritis, and a vasculitis element is probably leading to collagenase secretion by infiltrating inflammatory cells and even by the corneal epithelium. Tissue damage is probably induced by activated cytolytic T cells or macrophages. This is the only systemic inflammatory disease that presents with orbital disease due to infiltration with granulomatous tissue. Patient 2: Mrs KH, date of birth 20.6.31 In 1971, this patient's ulcerative colitis was treated with sulphasalazine. In 1985, the dorsum of her hand was swollen, morning stiffness was present and there was tenderness of the metacarpophalangeal joints. In 1987, recurrent uveitis of the left eye developed and proctocolectomy was carried out. In 1989, she had uveitis 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, and was treated with prednisolone and azathioprine. A diagnosis ofrelapsingpolychondritis was made. Speech is still unaffected, but now she cannot sing, her hearing is impaired and she is still having recurrent anterior uveitis. The ocular findings in relapsing polychondritis were described in Ophthalmology 1986 [7], 57 of 112 patients had ocular involvement, 39% episcleritis, 14% scleritis, 9-30% uveitis, 9% retinopathy. Uveitis can be classified into: anterioriritis or iridocyclitis; intermediatecyclitis, vitritis or pars planitis; posteriorchoroiditis, chorido-retinitis or retinal vasculitis. The ophthalmological assessment of uveitis should be to initially identify the type of uveitis, then to assess the extent of disease within the eye and the presence of complicating factors, such as cataract, glaucoma, neovascularization and retinal detachment. Visual loss in an acute anterior uveitis is due to a combination of pathologies. There is an inflammatory infiltrate in the

minimized with prompt initial treatment. The course of diffuse and nodular scleritis is one of resolution with treatment, perhaps leading to some scleral thinning. The course of necrotizing scleritis is progressive, is associated with severe systemic disease and a high mortality if the underlying disease is not treated aggressively. Involvement of the posterior sclera leads to proptosis, serious retinal detachment and a swollen optic disc. Clinically differentiating episcleritis from scleritis may be difficult, but examination of the deep scleral vessels will show their involvement in scleritis. Recently, low-dose anterior segment fluorescein angiography has been demonstrated to be of value in determining the vascular pattern and in estimating the degree of vasculitis-related anterior scleral ischaemia. The pathogenesis of scleritis remains poorly understood. A review from Moorfield's indicates that patients usually remain with the same category ofdisease; diffuse scleritis was the least progressive, while visual loss was 74% in necrotizing disease. When scleral and conjunctival biopsies were examined, immune complex deposition and neutrophil invasion were seen in the vessels, suggesting an immune-complex deposition. The treatment of scleritis involves relieving the pain and halting the progression of the disease. Nonsteroidal anti-inflammatory drugs are helpful in non-necrotizing scleritis. Many patients require systemic steroids. High-dose corticosteroids are required for initial control of necrotizing scleritis, but in the long-term immunosuppressive therapy is necessary. Cyclosporin therapy can be very effective, and pulse therapy with methylprednisolone and cyclophosphamide may be necessary. Progressive destruction may still occur in necrotizing scleritis and scleral rupture may occur, and grafting is necessary. Corneo-scleral perforations are more common in patients with severe rheumatoid arthritis, in whom peripheral comeal ulceration is associated with labral and scleral inflammation. In these patients, a combined corneo-scleral graft may be required. If adjacent tissues are involved in the inflammatory process, additional signs and symptoms develop: spread to the cornea produces keratitis. Sclerosing keratitis is the most common comeal complication of scleritis. Pericorneal/limbus inflammation is associated with peripheral corneal vessels spreading across the central cornea preceded by stromal opacities. In nodular scleritis, the corneal involvement may be restricted to one segment, but in diffuse scleritis the entire cornea may be involved, producing a dense corneal leukoma; perforation of the cornea may occur. Treatment of the condition is the same as that for the underlying condition. A survey of the incidence of associated systemic disease in 100 patients attending the scleritis clinic in Moorfield's Hospital was carried out by Lachmann, Hazleman and Watson [5]. The average age of the patients was 46.6 yr. Nineteen patients with rheumatoid arthritis were seen, two with Sjogren's

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HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE anterior chamber, and an inflammatory infiltrate can coat the lens. There is disturbance of accommodation due to ciliary spasm and anterior synechiae (adhesions between the iris and posterior cornea) lead to an increase of intraocular pressure, causing corneal clouding. Posterior synechiae (adhesions between the iris and lens also form) and cataracts develop especially in children. Anterior uveitis is most frequently an acute, recurrent condition involving the iris and ciliary body. It is the most common form of uveitis; chronic forms also occur, as with juvenile arthritis, but are much less common. Typically, the patient presents with a moderately injected eye, variable pain and discomfort depending on the degree of ciliary muscle spasm and/or rise in intraocular pressure, and some degree of reduced vision. Inflammation of the ciliary body (cyclitis) causes difficulty in accommodation, affecting reading ability, in the presence of persistent inflammation; aqueous production by the ciliary body is affected which may lead to ocular hypotension. The appearance of uveitis in ankylosing spondylitis is well described, 25% of patients develop acute anterior uveitis. Uveitis is seen in 10-15% of patients with other seronegative arthropathies. Signs are identical regardless of the underlying disease. The attacks are usually unilateral and the posterior segment of the eye is uncommonly affected. Rothova [8] reported on 865 patients who presented with uveitis; 17% had a B27-associated uveitis, 7% sarcoidosis and 6% a B27 seronegative spondarthropathy. It appears that HLA-B27 positive patients with uveitis can be distinguished from HLA-B27-negative uveitis. Findings in the B27-positive patients include: male predominance, unilaterality with alternating recurrences, absence of 'mutton fat' keratitic precipitates, a high ocular complication rate and frequent association with spondylarthropathies. Rosenbaum in 1992 [9] described the appearances of uveitis associated with spondarthropathies. Onset was acute and unilateral, the recurrence in the contralateral eye was frequent, 55% of patients were B27 positive and there was associated joint disease in 84% of the B27-related iritis patients. Sarcoidosis leads to eye involvement in 30-40% of patients. It has common appearances of acute or chronic uveitis; 25% develop posterior uveitis and retinal vasculitis, and 5% of patients develop granulomatous optic neuropathy with profound visual loss which is steroid sensitive. It has been suggested that 70% of patients with sarcoidosis have cellular infiltrates and/or granulomatous lesions in the conjunctiva and the infiltrate is probably of a CD4positive T cell and that a conjunctival biopsy might be helpful in diagnosis, although this finding has not been widely reported. Patient 3: Master AD, date of birth 20.8.87 In September 1988, this patient developed a painful left eye. His haemoglobin was 10.7 g, ESR 51 mm/h

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and the ANA was 1/100 positive, rheumatoid factor negative. Treatment was with Naproxen. In 1990,flexiondeformity of the knee occurred with swelling of the proximal interphalangeal joints of the right hand. He developed swelling of both knees with injections required in 1991 and because of neck pain was given a soft collar. He developed a vaigus deformity of 10 in the left knee, flexion deformity of 5 and had overgrowth of 1 cm. He developed uveitis in 1991 and was treated with a topical steroid. His arthritis became polyarticular and he developed active synovitis of both wrists, metacarpal phalangeal and proximal interphalangeal joints. Treatment with methotrexate was successful. He developed recurrent uveitis which was treated with prednisolone 0.5% and cyclopentolate 0.5%. Affected children are mostly girls and are usually young at onset of arthritis (mean age 3 yr). Joint involvement is usually pauciarticular, although it may spread to become polyarticular; 90% of patients with chronic uveitis are ANA positive. In ANA-positive patients with pauciarticular onset before the age of 5 yr, there is a 60-70% risk of uveitis; 50% of uveitis patients present within 1 yr of onset. However, uveitis has been recorded before the onset of arthritis in 10% of patients. Whilst uveitis is usually detected within 7 yr of onset, it has developed 34 yr after the onset of joint symptoms. The eyes and joint disease evolve independently and the overall severity of each is likely to differ. Owing to the insidious nature of this inflammatory disorder, the visual consequence can be severe. The inflammation occurs predominantly as a low-grade cellular infiltrate. Extensive posterior synechiae, with cataract formation and secondary cystoid macular oedema, account for the visual loss, although only 10-20% of affected eyes become blind. Early onset of uveitis, either symptomatic or when picked up in routine screening within the first year of arthritis, and particularly if associated with posterior synechiae at the first examination, is associated with a worse prognosis for vision. A report published by a joint working party of the Royal College of Ophthalmologists and the British Paediatric Association has suggested that patients should be regarded as at risk of developing uveitis according to the following categories: high riskearly onset (under 6yr), pauciarticular onset, positive for ANA; medium riskpolyarticular onset, and positive for ANA or pauciarticular disease and negative for ANA; low risksystemic juvenile chronic arthritis, juvenile chronic arthritis associated with HLA-B27, or disease starting over the age of 11 yr. Patients in the high- and medium-risk categories should be screened every 3-6 months for 5 yr from the onset of juvenile chronic arthritis, with subsequent screening annually for lOyr after the onset or until the age of 12, whichever is shorter. Posterior uveitis presents with a wide variety of clinical syndromes of markedly different severity and visual consequences. It occurs in association with many

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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3 certain sequences from viral and fungal proteins. Treatment of experimental uveitis has included T-cell vaccination which protects against induction; feeding rats with retinal S antigen also prevents induction as do specific monoclonal antibodies [11]. Management of uveitis Anterior uveitis usually responds to topically applied steroids and mydriatics which prevent complications such as synechiae. It is important to give adequate treatment since the inflammation can escape control and 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 when symptoms are restricted to floaters, as occurs in mild pars planitis. Visual loss occurs with macular oedema, then macular and premacular fibrosis. Subretinal neovascular membranes cause permanent visual loss. Vitreous contraction may lead to retinal hole formation and detachment. Vitreous opacities can be removed, but usually reveal the true cause of visual lossmaculopathy. If vision is threatened in posterior uveitis and all infective causes have been excluded, then treatment with high-dose steroids and immunosuppressive drugs is usually indicated. Patient 4: Mrs EB, date of birth 10.7.27 In 1948, this patient developed seropositive rheumatoid arthritis. In 1958, she was treated with chloroquine sulphate 200 mg daily. In 1988, this was changed to hydroxychloroquine 400 mg daily. In 1990, there was good visual acuity, but blue haloes around point sources. She was not able to drive at night and had slight reduction of colour vision. A diagnosis of keratopathy was made. Electrodiagnostic testing in 1991 showed no hard evidence of retinal abnormality. EOG (pigment epithelium) was at the lower range of normal, the ERG (peripheral retina) was subnormal. The pattern ERG was also subnormal, but there were corneal opacities. The use of antimalarials raises the questions should ophthalmological screening be done? Who should screen? How often should the patient be screened and with what methods? Corneal toxicity leads to blurred vision and haloes around lights due to corneal deposits. There is transient loss of accommodation, poliosis, reduced corneal sensitivity and ocular muscle palsies. The major concern with antimalarials is the development of retinal toxicity. Chloroquine has a high affinity for melanin, including the retinal pigment epithelium. The retinal damage is related to malfunction of the phagolysosomes, resulting in faulty clearance of ageing photoreceptor membranes. The build-up of lamellar myelin bodies disturbs the metabolism of the retinal pigment epithelium. The consequences are as follows. 1. The corneal deposits disappear when the drug is stopped and are not related to retinal toxicity. These

systemic diseases; however, in a large prospective study of systemic disease linkage with uveitis, only 26% were found to have an association, of which the most common was sarcoidosis. It is important to differentiate uveitis associated with systemic disease from those forms of uveitis which have a clear infectious aetiology, such as herpes simplexinduced acute retinal necrosis, cytomegalovirus retinitis and toxoplasmosis retinochoroiditis. Behcet's disease leads to eye involvement in 70% of patients and up to 25% will lose sight. The anterior uveitis is typically recurrent, but can resolve spontaneously. The high incidence of blindness is due to the severity of the retinal changes, the characteristic features are sequential occlusions of branch retinal veins and retinal infiltrates resulting in progressive retinal ischaemia and optic disc atrophy. Pathological studies have shown little difference in the mechanism of tissue destruction that occurs with retinal vasculitis of Behcet's and retinal vasculitis in isolation. Involvement of the choroid in posterior uveitis is commonly a pars planitis with vitreous exudation [10]. The pathology of posterior uveitis consists of activated T cells present in the vitreous fluid, granulomatous lesions containing abundant macrophages and CD4 and CDS T cells. The CD4 T cells express the interleukin 2 receptor and dendritic cells are detected. There are good experimental models of posterior uveitis which resemble human disease and have assisted in defining the clinical heterogeneity of posterior uveitis. Several retinal antigens have been described, including retinal S antigen, interphotoreceptor retinal binding protein and rhodopsin. The best characterized of these antigens is S antigen which is also under study by other groups as a regulatory protein for phototransduction. These antigens can all induce a spectrum of uveitis severity which can be modified by the dose of antigen, the species of experimental animal and the state of immunosuppression of the animal. Inflammation induced in the model is assumed to be autoimmune in nature since the inflammation is inducible with heterologous, homologous and autologous antigen. The target cell has been identified as the photoreceptor cell, partly on the basis that the cells appear to home in on this layer of cells, and partly because most of the antigens derive from the photoreceptor/retinal pigment epithelium (RPE) interface. A major advantage of these models for human studies is that the earliest stage of the disease can be investigated. Thus, it has been shown that at the onset CD4 + T cells and macrophages predominate, while CD8+T cells appear later in the disease. B cells increase in number during the healing phase, while MHC Class II expression occurs on several cells from the earliest stages of the disease. Recent studies on peptides from retinal S antigen have suggested that there is a 'core sequence' within the protein which is essential for disease induction, and that this sequence has considerable homology for

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HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE are the most frequent lesion and are dose related. The major problem is a maculopathy or retinopathy which can lead to visual field defects and a reduction in visual acuity. 2. A premaculopathy leads to development of visual field loss to a red target between 4 and 9 from fixation. The macular changes at this stage may be minimal and visual fields revert to normal if the drug is withdrawn. Identification at this stage is the goal of screening programmes, as cessation of treatment will usually prevent progression. 3. A maculopathy leads to a central scotoma and impaired visual acuity. The central part of the macula is hyperpigmented and the surrounding region hypopigmented (bull's-eye maculopathy). The maculopathy is irreversible and vision may worsen, which may occur months or years after the drug is withdrawn. Ocular changes are less likely to occur in patients receiving hydroxychloroquine than chloroquine. Toxicity is unlikely if the cumulative dose of hydroxychloroquine sulphate does not exceed 200 g. Chloroquine is said to cause a higher incidence of maculopathy, but this may have been due to the very high doses of this drug used in the 1960s. Very few cases of toxicity have been reported when the total dose has been less than 300 g of the phosphate. The retinal lesions described with hydroxychloroquine are not unique to hydroxychloroquine use. Cases of retinopathy including the classical bull's eye appearance occur in the absence of any predisposing cause. For instance, Scherbel et al. [12] found the incidence of pigmentary retinopathy in chloroquineand hydroxychloroquine-treated patients to be less than in untreated rheumatoid patients. The maculopathy in both groups was reported as being indistinguishable. The electro-octogram is considered to be a sensitive test of retinal function, but 20% of untreated rheumatoid arthritis patients have an abnormal result. One can conclude that cases of retinopathy have been described following hydroxychloroquine use and drug cessation seems to have prevented further deterioration. There is no single identifiable retinal pathology resulting from hydroxychloroquine use. The incidence of sight-threatening retinopathy on hydroxychloroquine at the recommended dose is extremely small and the incidence of retinopathy may not be higher than background population rates. In the light of these conclusions, the College of Ophthalmologists has recommended that patients have their eyes examined before treatment is started and any abnormality at this stage may require further ophthalmological supervision. Otherwise, patients can be given an Amsler chart with instructions on its use. This should be used monthly and the patient advised that if they note any abnormality they should stop the drug and seek advice. Special attention should be paid to higher risk patients: (1) those with hepatic/renal impairment; (2)

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those exceeding chloroquine base dose of 4 mg/kg lean body weight a day and hydroxychloroquine dose of 6.5 mg/kg lean body weight a day; (3) patients receiving treatment for more than 2yr, although this risk is small. The problems are that many patients at pretreatment may have macular abnormalities and there are no clinical features or tests, including electrodiagnostic tests, that can reliably detect the retinopathy at a reversible stage. Patient 5: Mrs JB, date of birth January 1947 This patient developed a tonic clonic seizure at the age of 20 during her first delivery. Eight years later, she developed arthralgia, an urticarial rash and absence seizures. Her rheumatoid factor was negative. Her ANA was weakly positive. She presented again aged 40 yr with a photosensitive rash and synovitis of the knees. Investigations then revealed a positive ANA with a homogeneous pattern and an elevated DNA of 100 units (normal <50) and immune complexes were elevated at 52%. She was initially treated with naproxen and hydroxychloroquine, but aged 42 yr developed a skin vasculitis at which time her DNA antibodies were 940 units and her ESR 78 mm/h; complement levels were still normal. She was treated with 40 mg prednisolone a day and azathioprine 100 mg daily, and improved. Two years later, she developed a severe and acute right ulnar neuropathy. She had axillary lymphadenopathy*. An EMG showed a left common perineal neuropathy in addition to a right ulnar neuropathy. An MRI scan showed enlarged axillary lymph nodes. A diagnosis of mononeuritis secondary to SLE was made. Despite high-dose oral prednisolone, a right median neuropathy supervened within 2 months. Treatment with pulsed i.v. methylprednisolone (10 mg/kg) and oral cyclophosphamide (15 mg/kg) was complicated by lymphopenia, oral candidiasis, staphylococcal dactylitis, alopecia and a lingual ulcer. DNA binding remained high (242 units), anti-cardiolipin antibody was 42% (normal <25%), platelet count and coagulation screen were normal. She deteriorated over the next month and developed a diffuse brainstem/cerebellar involvement characterized by a one-and-a-half syndrome, consistent with a lesion of the right paramedian pontine reticular formation, ataxia and a left lower motor neurone facial palsy. The MRI brain scan appearances were compatible with pontine microinfarcts. She received further i.v. methylprednisolone and cyclophosphamide without improvement, and then received IVIg ('Sandoglobulin'; Sandoz, Basle, infused at 400 mg/kg per day for 5 days), after which no new neurological deficit developed. Unfortunately, she developed hepatomegaly 2yr later; biopsy demonstrated lymphoma. She was treated with chemotherapy, but died within a year. The evidence for vasculitis as a cause of the neurological deterioration in this patient is indirect. However, this pathological cause seems likely in view of the stepwise presentation, particularly the multifocal

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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3 occupying lesions, 10 for liver disease, 11 for neoplasia, 12 for anaemia and nine for a pyrexia of unknown origin [16]. Healey and Wilske [17] documented the presenting complaints of 50 consecutive patients with biopsyproven GCA; 16 presented with polymyalgia rheumatica, 13 with symptoms of temporal arteritis, eight with weight loss and malaise and a flu-like illness, five with fever of undermined origin, two with loss of vision, two with anaemia, two with headaches and one with leg claudication. Clinical manifestations at late stages included 31 with symptoms of polymyalgia rheumatica, 31 having symptoms of temporal arteritis, 15 having a fever greater than 100T, 14 developed visual manifestations, 10 jaw pain, six developed a peripheral neuropathy, four developed leg claudication and one patient died with a ruptured aortic aneurysm. It has been suggested that if cranial arteritis is to become clinically apparent it will do so within 1 yr of the onset of general symptoms; however, examples of cranial arteritis developing 2 yr or longer after systemic symptoms have been described. GCA has a peak age of onset between the ages of 60 and 75 yr. The annual incidence of biopsy-positive patients is 6.7:100 000. The annual incidence rate over patients of 50yr of age is 18.3:100000. It is a disease that affects mainly northern Europeans and northern states of the USA. Biopsy studies from Olmstead County [18] have shown an increase in incidence of biopsy-positive patients in females, but not in men between 1965 and 1985. Ostberg [19] examined the temporal arteries and aorta of all adults who died in Mahno throughout 1 yr, and found evidence of previous arteritis in 1.7% of the 889 cases. Patient 6: Mrs MW, date of birth 21.6.22 In January 1989, she developed pain of the neck and shoulder girdles and both buttocks and thighs. There were no headaches, her general health was good. Haemoglobin was 11.6g/dl, ESR 45mm/h, C-reactive protein 29 mg/1. A diagnosis of polymyalgia rheumatica was made. She was treated with 15mg prednisolone a day and her symptoms resolved. In January 1990, she was receiving prednisolone 5mg alternating with 7.5 mg. She developed three episodes lasting 10 min of loss of vision of the left eye with pain in the jaw on chewing and pain around the left eye. Her ESR was 18mm/h, her C-reactive protein 7.8 mg/1. Her prednisolone was increased to 40 mg a day and a temporal artery biopsy was carried out. This showed characteristic changes of GCA with narrowing of the lumen, intimal proliferation and medial infiltration of lymphocytes and plasma cells, and disruption of internal elastic lamina. She is now well and requires 3-5 mg prednisolone daily. She has had some recurrence of limb girdle stiffness and jaw pain, and pain around the left eye and left temple. These symptoms have responded to a temporary small increase of corticosteroid dosage. In 1991 Wise et at. [20] described the characteristics of patients with temporal arteritis and a low ESR. The

peripheral nerve involvement, MRI appearance and the associated scrological abnormalities. In addition, cutaneous vasculitis had been previously present Corticosteroids did not arrest the development of new neurological lesions and the brainstem syndrome developed after the first i.v. pulse of cyclophosphamide. Disease progression was apparently only halted when FVlg was used, suggesting that this treatment may be added to existing therapeutic strategies for vasculitic neurological manifestations of SLE. FVIg has been used with benefit in other systemic vasculitides, and for non-neurological complications of SLE. The mechanism of action is uncertain, but it is considered that it alters idiotypic networks. Manifestations of neurolupus include non-focal cerebral dysfunction (35-60%), organic brain syndrome, psychosis, affective disorder and neurosis. Seizures are seen in 15-35%, focal deficits in 10-35%, cranial neuropathies in 10-35%. Peripheral neuropathies are seen in 10-15%. Aseptic meningitis, Eaton-Lambert syndrome, myasthenia gravis and infectious complications have been described. Ocular symptoms are common in patients with SLE. Scleritis can been seen at some stage in 10% of patients. Its presence indicates active systemic disease and may require an increase in systemic therapy. Uveitis is only seen in association with severe scleritis. Patients may suffer from dry eye, as well as peripheral corneal thinning Double vision may result from involvement of the extraocular muscles. The hallmark of retinal involvement is the cytoid body, which is the descriptive term used in systemic lupus for cotton-wool spot Retinal haemorrhages and occlusions of central and branch retinal arteries may occur, and are due to the deposition of immune complexes rather than vasculitis. The patients may also show signs of hypertensive retinopathy, with occlusions of branch retinal veins [13]. GIANT CELL ARTERITIS Giant cell arteritis was initially described by Jonathan Hutchinson in 1890 [14]. The patient Rumbold was described as developing red streaks on his head which were painful and prevented him from wearing his hat The term 'arteritis of the aged' was used. The Archives of Internal Medicine 1993 [15] suggests that Adolf Hitler suffered from GCA; he is described 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 anaemia and an elevated ESR. Whereas the symptoms and signs of polymyalgia,, rheumatica and GCA are usually readily identifiable, general symptoms of night sweats, depression, anorexia, malaise, fever and weight loss can lead to delay in diagnosis, as can laboratory abnormalities, particularly the raised alkaline phosphatase and anaemia. In a survey at Addenbrooke's Hospital [8] of 108 patients admitted as medical in-patients, initial diagnoses included neoplastic polymyositis; four were investigated for space-

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HAZLEMAN: RHEUMATIC DISORDERS OF THE EYE low-ESR group were more likely to have previous polymyalgia rheumatica or to have received steroid therapy. It is thought that the reason for failure of the ESR and CRP to increase may be due to downregulation of the acute-phase response in chronic inflammation. In patients with uveitis, Yorston et al. [21] have described smaller response in the ESR if there have been several previous attacks of uveitis despite a similar level of inflammation. Kyle et al. [22] have followed ESR and C-reactive protein in patients prospectively, and ~ 50% of patients flare without a rise in C-reactive protein or ESR. There seems to be no advantage of measuring C-reactive protein in addition to ESR. Pountain and colleagues [23] have not been able to demonstrate a prolonged fall in CD8-positive T cells in patients with active polymyalgia rheumatica and GCA, and cannot confirm that measurement of CD8 T cells helps in monitoring disease activity. A transient fall is seen which we have attributed to initiation of steroid therapy. However, a measurement of a-1 antichymotrypsin levels may help in management [24]. These levels are raised in active disease and fall with remission, and then patients can be successfully weaned offcorticosteroid therapy. There is a wide distribution of ESR in patients with polymyalgia rheumatica and GCA. However, the ESR is usually greatly elevated and provides a useful means of monitoring treatment, although it must be appreciated that some elevation of the ESR may occur in otherwise healthy elderly people. Establishing a raised ESR is the key investigation, although a normal ESR is occasionally found in patients with active biopsy-proven disease. Patient 7: Mr TP, age 74 yr This patient presented with 2 months' depression, anorexia, weight loss and headaches, eased by diazepam and analgesics. Bilateral carotid and femoral bruits were present. ESR was 20mm/h, the gamma glutamyl transferase was elevated at 110 /x/1. The patient was advised to stop smoking and drinking, with improvement. Two months later, he presented with pain and loss of central vision in the right eye. Two weeks previously he had developed a tender scalp which was thought to be due to herpes zoster. He then developed three episodes of obscured vision lasting 15 s which were thought to be atheromatous anterior ischaemic optic atrophy. Five days later, he lost vision in both eyes. At that time, a temporal artery biopsy was carried out and was positive. Unfortunately, despite a huge volume of literature on visual loss and other ocular manifestations of GCA, such cases are still seen. My experience over the last 25 yr, like that of many others, has shown that if the disease is detected early, and managed adequately, blindness is almost totally preventable. This makes early diagnosis and management of the disease all important. Ocular temporal arteritis was described by Simmons and Cogan in 1962 [25]. Patients developed sudden painless visual loss in one eye; 30% went blind in the other eye without treatment, in most cases within 7

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days, but it could occur as early as 24 h. Many ocular lesions can be seen in GCA, these are essentially due to occlusion of the various orbital or ocular arteries. The incidence of various ocular manifestations given in the literature varies widely because the incidence depends on a number of factors, the most important of which is how early the diagnosis of GCA is established and the treatment started. It also depends upon the rigour with which cases are diagnosed; for example, it is not uncommon to find that the diagnosis has been made solely on clinical grounds. The most common lesion is optic nerve ischaemia, these can be anterior which is the most common lesion, they can be partial but usually leads to complete visual loss. They can occasionally be posterior which can lead to partial or complete loss. Extraocular motility disorders are usually transient and not associated with visual loss. Pupillary abnormalities can be seen secondary to visual loss. Cerebral ischaemic lesions producing visual loss are rare, as are anterior segment ischaemic lesions and choroidal infarcts. Retinal ischaemic lesions can affect the central retinal artery, this is associated with severe visual loss. The cilioretinal artery can be occluded, but is invariably associated with anterior ischaemic optic neuropathy (AION) [26]. Hayreh in 1990 [27] described his experience of ~800 patients with AION, 12% had arteritic AION and 88% non-arteritic. He suggested that the features suggesting arteritic AION and helping to differentiate it from non-arteritic AION were systemic symptoms and an elevated ESR. Amaurosis fugax was rarely seen in non-arteritic AION. Arteritic AION was usually associated with early visual loss. A chalky white disk was highly suggestive of arteritic AION. Optic disc oedema was associated with cilioretinal occlusion and was due to arteritis. Early non-filling of the choroid on angiography was also associated with arteritis. Does the temporal artery biopsy influence treatment? It can be useful in patients with symptoms of GCA and is particularly reassuring if patients respond poorly to corticosteroid therapy. It is not usually of value in patients with polymyalgia rheumatica alone, but is crucial in making the diagnosis of GCA in patients with non-specific constitutional symptoms alone. Positive biopsy indicates the need for steroid therapy in higher doses than those used for polymyalgia rheumatica, more intense follow-up and commits a physician to treatment despite steroid complications. Clinicians vary greatly in their approach to temporal artery biopsy. Some consider it emphasizes the value of a positive histological diagnosis, especially months or years later, when side-effects of the steroid treatment have developed. Others feel that a high false-negative rate diminishes the value of the procedure. In most instances, the high false-negative rate can be attributed to the focal nature and involvement of the superficial temporal artery by the inflammatory process. In 1976 Klein el al. [28] demonstrated 'skip' lesions in 17 of 60 temporal artery biopsies; some segments showing active disease were as short as 350 //m. The rate of false-negative biopsies depends on many variables,

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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3 periorbital oedema and tenderness of the right temporal artery with bilateral carotid and right subclavian bruits. An ESR was elevated at 91 mm/h. Arch aortogram was normal. He was treated initially with prednisolone 60 mg then increased to 100 mg a day to control his symptoms. In November 1990, he lost vision on two occasions following exercise, at that time an ESR was 40 mm/h and a carotid angiogram was normal. In March 1990, he was treated with hydrochloride and also in March 1990 he presented with three episodes of loss of vision in the right eye, his ESR was elevated at 85 mm/h. He was treated with pulse methylprednisolone and the dosage of prednisolone was 60 mg/day and of azathioprine 300 mg/day. It is probable that he has Uhthoff's symptom. This was described by Raymond et al. in 1980 [33]. The symptoms are a reduction of visual acuity with exercise or heat The syndrome is associated with multiple sclerosis and neurological disease. Raymond described two patients with vascular disease, one who had GCA, another patient had total carotid occlusion.
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including the size of the biopsy, the number of levels examined, whether biopsies were taken from one or both sides of the scalp, and the duration of steroid therapy before the procedure. Three papers examine the value of temporal artery biopsy. In 1981 AJlsop and Gallagher [29] described 58% of patients with clinical arteritis having histological confirmation. This figure rose to 66% in the late 1980s. In up to 6% of all biopsies, the original reporting pathologist had mistaken the usual feature of ageing (arteriosclerosis) as evidence of active or healed cranial arteritis. In a single case, the histological evidence of arteritis had been overlooked. Hall et al., in the Lancet of 1983 [30], subsequently in 1984 concluded that a normal biopsy predicted the absence of need for corticosteroid therapy in 91% of patients, but a 4-6 cm artery specimen was needed to say that the artery was not clearly abnormal; 86% of patients were diagnosed by unilateral biopsy, but 14% of patients required examination of the other side. Wilkinson and Russell [31] have also shown a clear correlation between the amount of elastic tissue in the head and neck vessels and the susceptibility to arteritis, and some transient visual disturbance may be due to microemboli arising from arteritis of vertebral arteries. There have been anecdotal reports of the use of chloroquine, dapsone and cyclosporin and cyclophosphamide in the treatment of GCA. Widespread studies looking at the use of prednisolone in combination with methotrexate or azathioprine have demonstrated them to have weak steroid-sparing properties. Clearly, the use of steroids leads to better symptom control and reduced incidence of blindness, but it is uncertain whether their use shortens the disease duration. There are few clinical trials to help decide on the correct initial dose and the rate of corticosteroid reduction once initial symptoms are controlled. Kyle and Hazleman [32] have carried out a prospective study looking at dosage and length of treatment, and suggested that 15-20 mg prednisolone initially is usually sufficient for the treatment of polymyalgia rheumatica, aiming to reduce the dosage after a month to about 10 mg by 2 months. An initial dose of 40 mg prednisolone for GCA is usually sufficient, reducing the dose after a month to ~20mg by 2 months, a maintenance dose of ~ 10 mg by 6 months and 7.5 mg by a year. Most patients will need 3-4 yr of treatment, but withdrawal after 2 yr is worth attempting. The risk of relapse, particularly with arteritic complications, has to be balanced against the risks of corticosteroid-associated side-effects. Between one-fifth and a half of patients may experience serious sideeffects. There is an increased risk if there is a high initial dose ( > 30 mg of prednisolone), a maintenance dose of > 10 mg prednisolone and high cumulative dosages and increased duration of therapy. Maintenance doses of < 5 mg seem relatively safe. Patient 8: Mr RB, date of birth 12.6.42 In December 1989, this patient presented with pain in the head, face, neck and difficulty eating. He had

Patient 9: Mrs EB, age 72 This 72-yr-old retired cleaner had a hysterectomy and repair in May 1984. Her histology showed GCA of the myometrial arteries [34]. She was referred to the rheumatology clinic in July 1985 with coldness of the right hand, her right arm was aching after use, she had stiffness of the buttocks and groins, she was tired, there was weight loss of 18 lbs and she had described occasional visual blurring for a year. An arteriogram showed almost total occlusion of the axillary artery and her symptoms gradually improved with corticosteroid therapy; it is characteristic that these symptoms are slow to improve. Clinical evidence of large artery involvement is present in 10-15% of cases, and in some instances aortic dissection and rupture occur. Bruits are often present over large arteries and there may be tenderness, particularly over the subclavian artery. An early sign of arteritis is increased sensitivity of the carotid sinus. Light pressure will often lead to transient asystole for two or more beats, so it is advisable for the patient to be lying down when examined. Patient 10: Mrs JT, age 85 The last patient presented in 1978 at the age of 70 yr with 2 weeks temporal headaches and scalp tenderness. There was no visual disturbance, no joint pains and no night sweats or symptoms of polymyalgia rheumatica, but a 4 month history of lethargy and ill-health. Investigations showed a haemoglobin of 11 g/dl, an elevated ESR of 94 mm/h and an elevated alkaline phosphatase of 120 n(\ (normal range 30-92/i/1). Immune complexes were elevated at 6 1 % (normal range 0-24) and acute-phase proteins were elevated. Chest X-ray showed a slight left ventricular enlargement with the aorta unfolding. Temporal artery biopsy was normal. In December 1979, she was asymptomatic on prednisolone 5 mg/day, atenolol and a diuretic; blood

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pressure was 150-80. Her ESR was 21 mm/h. In January 1980, she presented with interscapular and right shoulder pain. Her right arm was cold with absent pulses. There were no bruits or radial femoral delay. Her apex beat was displaced. An angiogram demonstrated a dissecting aortic aneurysm. Her aortic aneurysm was treated with an arterial graft and the biopsy of the aorta showed active GCA [35]. GCA as a cause of aortic dissection has been recorded rarely at autopsy, and most exceptionally during life. This elderly patient with a dear symptom complex of polymyalgia rheumatica subsequently presented as an emergency with chest pain. The diagnosis of GCA causing dissection of the aorta with survival of the patient is most unusual. Most of the patients reported had a history of hypertension or features of hypertensive disease at autopsy. In addition, there is a higher proportion of females than is found in GCA. This case serves to illustrate that the clinician should be aware of potential life-threatening largevessel disease in GCA, particularly in female patients with hypertension. In both clinical and histological terms, cranial arteritis is one of the most distinctive of all vascular disorders. Although ultrastructural and immunohistochemical studies have provided some insight into the underlying pathological changes, they have not contributed directly to the diagnosis of cranial arteritis. Immunological studies have suggested that a cellmediated immune reaction, possibly against an autologous antigen, occurs locally in the arteritic lesions. The observed HLA-DR expression can be accounted for by the sum of macrophages and activated T cells, the macrophages being the most probable antigen-presenting cells. The interdigitating reticulum cells may also be involved in antigen presentation. What the antigen(s) may be is, however, still unknown, as are the factors initiating the inflammatory process. In this presentation, the association between eye disease and connective disorders has been described. Failure to be aware of the ocular problems is not uncommon, but these are of particular importance because slight disturbances of function cause symptoms, because progressive lesions may result in blindness with its devastating consequences, because they are often thefirsttissues to be involved and because any pathological changes in the eye can readily be visualized and monitored with slitlamp or ophthalmoscope. This is uniquely fascinating for the clinician who can only get a superficia] view of skin, synovia or epithelia and has to depend on histological sections for an entirely static view of events occurring in the tissues.
REFERENCES

4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20.

21. 22.

23.

24.

25. 26. 27.

1. Heberden E. William Heberden. Physician of the age of reason. London: Royal Society of Medicine, 1989. 2. Moll HMH. The Heberden Society. London: Chapman and Hall, 1987. 3. Rook A, Carlton M, Cannon W. The history of Adden-

brooke's Hospital, Cambridge. Cambridge: Cambridge University Press, 1991. Watson P, Hazelman B. The sclera and systemic disorders. London: W. B. Saunders, 1973. Lachmann S, Hazleman B, Watson P. Scleritis and associated diseases. Br Med J 1978;1:88. Bullen CL, Liesegang TJ, McDonald Y et al. Ocular complications of Wegener's granulomatosis. Ophthalmology 1983;9(h279-9O. Isaak BL, Liesegang TJ, Michet CJ Jr. Ocularfindingsin relapsing polychondritis. Ophthalmology 1986;93:681-9. Rothova A, Buitenhuis HJ, Meenken C et al. Uveitis and systemic disease. Br J Ophthalmol 1992;76:137-41. Rosenbaum JT. Acute anterior uveitis and spondyloarthropathies. Rheum Dis Clin North Am 1992;18: 143-51. O'Duffy JD. Behcets syndrome. N Engl J Med 1990; 322:326-8. Forrester JV. New concepts on the role of autoimmunity in the pathogenesis of uveitis. Eye 1992;6:433-46. Scherbel AL, MacKenzie AH, Nousek JE, Atdjlan M. Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy. N Engl J Med 1963^73:360-6. Coppeto J, Lessel S. Retinopathy in systemic lupus erythematosus. Arch Ophthalmol 1977^)5:794-7. Hutchinson J. On a peculiar form of thrombotic arteritis of the aged which is sometimes productive of gangrene. Arch Surg 1890;l:323-7. Redlich F. A new medical diagnosis of Adolf Hitler. Arch Intern Med 1993;153:693-7. Jones JG, Hazleman BL. Prognoses and management of polymyalgia rheumatica. Ann Rheum Dis 1981;4(hl-5. Healey LA, Wilske KR. Manifestations of giant cell arteritis. Med Clin North Am 1977;61:261-70. Bengtsson BA. Epidemiology of giant cell arteritis. In: Hazleman BL, Bengtsson BA, eds. Giant cell arteritis. London: Bailliere Tindall, 1991. Ostberg G. On arteritis with special reference to polymyalgia arteritica. Ada Pathol Microbiol Scand 1973;237(suppl.):l-59. Wise CM, Agudelo CA, Chmelewski W, McKnight K. Temporal arteritis with low erythrocyte sedimentation rate. A review of five cases. Arthritis Rheum 1991; 34:1571-4. Yorston D, Whicher J, Chambers R et al. The acute phase response in acute anterior uveitis. Trans Ophthalmol Soc UK 1985;104:166-70. Kyle MV, Cawston TE, Hazleman BL. ESR and Creactive protein in the assessment of polymyalgia rheumatica/giant cell arteritis on presentation and during follow-up. Ann Rheum Dis 1989;48:667-71. Pountain GD, Keogan MT, Brown DL, Hazleman BL. Circulating T cell subtypes in polymyalgia rheumatica and giant cell arteritis: variation in the percentage of CD8 + cells with prednisolone treatment. Ann Rheum Dis 1993;52:730-3. Pountain GD, Calvin J, Hazleman BL. al-antichymotrypsin, C-rcactive protein and erythrocyte sedimentation rate in PMR/GCA. Br J Rheumatol 1994; 33:550-4. Simmons RJ, Cogan DG. Occult temporal arteritis. Arch Ophthalmol 1962;68:8-18. Hayreh SS. Ophthalmic features. In: Hazleman BL, Bengtsson BA. Giant cell arteritis. London: Bailliere Tindall, 1991. Hayreh SS. Anterior ischaemia optic neuropathy.

Downloaded from rheumatology.oxfordjournals.org by guest on May 15, 2011

268

BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 3

28. 29. 30. 31.

Differentiation of arteritis from non-arteritic type and its management. Eye 1990;4:25-41. Klein RCT, Campbell RJ, Hunder GG, Carey J. Ship lessons in temporal arteritis. Mayo Clinic Proc 1976; 51:504. Allsop CJ, Gallagher PJ. Temporal artery biopsy in giant cell arteritis, a reappraisal. Am J Surg Pathol 1981; 5:317-23. Hall S, l i e J, Kierland L. The therapeutic impact of temporal artery biopsy. Lancet 1983^11:12217-20. Wilkinson IMS, Russell RWR. Arteries of the head and neck in giant cell arteritis. A pathological study to show the pattern of arterial involvement. Arch Neurol 1972^7^78-82.

32. Kyle MV, Hazleman BL. Treatment of PMR/GCA. I Steroid regimes in the first two months. Ann Rheum Dis 1989;48:658-61. 33. Raymond L, Sachs J, Choromokos E, Khodadad G. Short posterior ciliary artery insufficiency with hyperthermia (UhthofTs Symptoms). Am J Ophthalmol 1980^0:615-23. 34. Kyle V, Hamilton Dutoit S, Elias Jones J, Hazleman BL. Giant cell arteritis of myometrial and axillary arteries and polvmyalgia rheumatica. Ann Rheum Dis 1987; 46:256-8. 35. Salisbury RS, Hazleman BL. Successful treatment of dissecting aortic aneurysm due to giant cell arteritis. Ann Rheum Dis 1981;40:507-8.

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