The Sclera and Systemic Disorders Peter G Watson, Brian L Hazleman, Peter McCluskey, Carlos E Pavésio
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Historical introductionChapter 1

‘Men, you are all marksmen—do not fire till you see the whites of their eyes.’ Perhaps this is the only really famous quotation relating to the sclera. These orders are reputed to have been given by General Israel Putnam (1718–90) at the Battle for Bunker Hill at Boston, Massachusetts in 1775 during the American War of Independence (Ketchum 1962) (Fig. 1.1). If all the British troops had had scleritis the course of history might have been changed!
How did the word sclera become used for the white of the eye? In 1865 a colleague of Thomas Windsor objected to the use of the word ‘sclera’ or ‘scleral’ rather than sclerotica; the term commonly in use at the time. Windsor (1865) responded by writing a paper on its etymology ‘because the purity of the language is so much to be desired that we do not think it will be a waste of time to endeavour to justify our use of these terms’. He was the ideal person to write such an article as he had acquired during his travels in Europe a large collection of ancient texts. All of these were annotated and were sent to his friend the Surgeon General in Washington, which is how these texts came to be in the library of the National Institutes of Health in Washington, DC.
The word sclera was certainly used by the Greeks and Romans. Aulus Cornelius Celsus who lived at the start of the Christian era used the same word κερατοειδεζ (Gr. keratoeides meaning ‘horn-like’) for both cornea and sclera. Galen (130 ad), in De Usu Partium used the term σκληρα μηνιγξ (Gr. sklera meninx meaning ‘hard membrane’) to describe how this thick membrane goes round the choroid in the same way that the dura mater covers the brain. It is not known how much of Galen's anatomical description derives from his own work or from his predecessors because the actual description of the anatomy of the eye has been lost. The descriptions available to us are the result of a complete translation of Galen's work into Arabic by Hunain (803–73) of Baghdad and retranslated by Max Simon (Simon 1906). Quotations before this date appear to be the result of unauthenticated texts or abstracts by Oribasius; these were widely quoted as it was felt that Galen's original text was ‘verbose and boring because he always put the teleological point of view into the foreground’. Oribasius, however, preserved the original meaning (Hirschberg 1887). Be that as it may, Galen's concepts of the anatomical coverings of the ‘most noble parts of the eye—those which constitute especially the organ of sight’ remained unquestioned through the Middle Ages into the 16th century.
Galen, the master anatomist and surgeon to the gladiators, knew of the fascial coats of the eye, calling them ‘tunica adnata’. He also introduced the term ‘rheumatism’ to designate pain which he believed to be caused by one of the four cardinal ‘humours’ of the human organism. The concept was that pain was in faulty combination with the other humours and was eliminated or discharged from the blood into one of the many cavities of the body, including the joints. It was in this way—a humour dripping into a joint cavity—that the word gout arose (L. gutta meaning ‘a drop’).
Galen lived long enough to lay only the basis of scientific medicine, and unfortunately this could not be developed sufficiently to cope with the plagues which followed migration to city life. As there was no scientific advance, the people's faith in doctors declined and care of the sick passed to the Church who viewed this as a moral obligation incumbent on its members, regardless of whether they were trained or not.
As both Christians and Arabs forbade dissection of the human corpse, no further anatomical advances were made until the 14th century when the Graeco–Roman era of speculation concerning the nature of disease (based on ‘humours’ of the organism) yielded slowly to reasoned observation in the early schools of anatomy by Leonardo da Vinci and Vesalius.
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Figure 1.1: ‘Do not fire till you see the whites of their eyes’—the orders of General Putnam (Old Put) in command of the battle. This scene shows the death of General Warren, a doctor who had fought in his best clothes. The British soldiers dislodged the American rebels, at a great cost, and trapped them on the narrow neck of land extending from Boston to the mainland. Nevertheless, this battle was a turning point in the development of American independence, proving that a rebel force could face a trained regular army. The Battle for Bunker Hill 1775 by John Trumbull. Private collection of HS Warren.
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This explains why Hippocrates (who was born in 460 bc and lived until he was about 100 years old) was familiar with the clinical signs of joint disease, but said little of the structural changes in the affected connective tissues—a reflection of the fact that anatomical dissection had not become accepted practice.
With the Renaissance new interest in the study of the human form arose in painting and sculpture. The study of anatomy thus became essential, producing a wealth of material not only from Leonardo da Vinci and tissues—a but also from Giovanni Ferrara, Gabriele Falloppio, Fabricius, and later Harvey. Because the configuration of the lids and the lustre of the eye is so important in facial expression, the changes which occur with age and suffering were intensively studied and accurately reproduced by the artists of the Renaissance. In spite of this no one from that era seems to have painted anyone with active scleral disease. However, during his Blue Period Picasso portayed many sad and handicapped people such as the blind guitarist. Another was Celestine, a procuress from Barcelona (Fig. 1.2). Her face suggests a history of chronic pain. She has a proptosed, divergent, cataractous blind eye and also seems to have an anterior stapyloma temporally very similar in appearance to Travers' illustration of the end result of chronic untreated scleral disease (Fig. 1.3).
It seems that the word ‘sclera’ was changed to ‘sclerotica’ in the Middle Ages (see Windsor 1865), possibly by Mundinius in 1325; Carpus said in 1535 ‘Posterior to the cornea is a membrane, not transparent but opaque and hard. So it is called sklerotica which covers the whole eye behind'. This change of the word was not entirely approved of, as indicated by Joubert (1585) in his dictionary ‘Sclerotique… by the Greeks called slderos which signifies hard, from this barbarians have invented the word sclerotica'. The word ‘sclerotica’ persisted in general use, however. Its use was discouraged first in German, in Kraus' medical dictionary (1844) which states ‘Sclerotica— μηνιγξ σκληρα (Gr. meninx sklera; the ‘hard membrane’)—die feste Augenhaut, von scleros: würde besser Sclera heissen!’
Some older anatomists continued to use terms like ‘dura oculi tunica of Vesalius’ or ‘dura tunica’: Regardless of this, the final nail in the coffin for ‘sclerotica’ came from Thomas Windsor (1865) who changed the word in English by pointing out that ‘sclera and sclerotica are both adjectives agreeing with tunica, understood. The tunica sclera would signify hard membrane, a denomination sufficiently expressive; the tunica sclerotica might mean hardening membrane, a term devoid of sense'. Modern scholars now say that ‘sclera’ has the form of a noun whereas ‘sclerotica’ can only be an adjective, and that the suffix ‘oticus’ conveys no notion of inception or progression. Furthermore, neither the Greek nor Latin form is used by any ancient author (Diggle 2001, Hirschberg 1982). Regardless of various objections, ‘sclera’ has become the word universally accepted as referring to the opaque collagenous coat of the eye.
In 1755, Zinn gave a long, detailed dissertation on the anatomy and relationships of the sclera and its surrounding structures, referring to many texts which are no longer available. In the text (translated by Eric Southern in 2001) he refers to the traditional Galenic coverings of the eye, the sclerotica, the choroid, the retina, and the ‘cellulose’ (the covering which contains the vessels of the sclera). In this remarkable description he not only describes for the first time the lamellar structure of the sclera, but also its intertwined nature to which he ascribes the whiteness of its appearance. He describes quite clearly how the tendons are inserted separately into the sclera and do not, as was originally thought, pass forward to a tendinous ring at the limbus (Fig. 1.4). After numerous anatomical dissections he states ‘My observations do not allow me to withdraw from the opinion of the ancients.’
He continues ‘The origin of transparent cornea is not so defined that the place where the cornea begins can be accurately determined. But the boundaries flow into each other and the fibres of the sclerotica—white, opaque now very close to the cornea—little by little and gradually more across the transparent cornea.’
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Figure 1.2: ‘Celestine’—Pablo Picasso 1903. Painted in Barcelona and said to depict the one-eyed procuress in the drama La Celestine by Fernando Rojas (1499) (Ravin & Perkins 2004). The appearances of the left eye are strikingly similar to the end stages of sleral disease as portrayed by Travers (Fig. 1.3) and others (Figs 1.81.10 and 11.23). Musee Picasso Paris.
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Figure 1.3: An illustration showing the end stage of scleritis with an anterior staphyloma, translucent sclera, cataract, and glaucoma. From Travers 1820. Plate 1; Figure 7. By kind permission of Mr John Winstanley, MC FRCS.
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Figure 1.4: Anatomical dissection of the eye. The tendinous portion of the recti muscles are shown to be gradually inserted into the sclera. The tendinous ring of the superior oblique has been dissected free from the bone. From Anatomy of Human Bodies by William Cowper, Oxford 1698 in Queens’ College Library Cambridge
He thus confirmed the observations of two French physicians—Pet-tit and Bissaeus—on the wedge-shaped limbus, the contiguity of the sclera and cornea, and the insertion of the conjunctiva into the limbus. Zinn (1755) went on further to describe the vascular anatomy in detail stating that ‘There are bigger vessels, and those especially conspicuous which run down behind the conjunctiva in the sclerotica itself, vessels ciliare, sometimes vein like, sometimes artery like, joined mutually in very many areas almost often the fashion of mesenteric vessels. These perforate the sclerotica at a distance close to the cornea's very root’ (Fig. 1.5). He goes on to say ‘I am persuaded that almost the whole of ophthalmia, certainly the more serious part, is owed not so much to the vessels of the conjunctiva but more to the inflamed vessels of the sclerotica'. It has taken modern technology to prove him right in almost every respect!
Although Zinn noted the position of the vascular tree within the episclera, he did not consider the tissue in which they were contained to have very much value. It was left to Jacque René Tenon (1806) and later to Bonnet (1841) to describe the full extent and importance of the ‘tunica vaginalis oculi’ and its check ligaments and relationships. The full importance of this tissue in the disorder strabismus and in the pathology of inflammatory disease has only recently been recognised.
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Figure 1.5: The vessels of the eye and orbit, drawn by Joel Paul Kaltenhofer who worked as artist primarily for Haller. From Johann Gottfried Zinn 1755. Figure 1 III—VII.
The generic term ‘rheumatism’ was practically interchangeable with the term ‘catarrh’ until the time of Sydenham (1676) because it was believed that local collections of fluid within the body were due to discharge of a thin humour from the blood that also gave rise to pain, the onset of which was usually associated with changes in the weather. The word ‘rheum, the watery secretion of any tissue, was originally applied in the Middle Ages to normal secretions such as tears, but later came to describe any pathological state accompanied by excessive secretions, such as catarrhal colds. Rheumatism assumed an identity of its own through the work of the Parisian physician de Baillou (1643). He defined catarrh as a disease of the mucous membranes associated with inflammatory secretion, and he clearly separated from this ‘rheumatism’ as marked by migratory pains.
Germani (1964) suggested that the great Renaissance scientist and astronomer Galileo Galilei might have been the first person to have the combination of eye and rheumatic disease documented. The suggestion that he might also have had scleral disease is almost certainly incorrect (Fahie 1903, Watson 2009).
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Figure 1.6: An engraving of the mathematician and astronomer Galileo Galilei executed by Ottavio Leoni in 1624, drawn alla macchia (as he saw it). There is a swelling of the forehead and the eyelid above the upper inner part of the eye. In addition there is ptosis of the right upper eyelid, which is held open by contraction of the frontalis muscle. The right eye, his master eye, is depressed downwards and outwards. He is clearly using the left eye for fixation. These are the appearances of a mucocoele of the frontal sinus. His vision deteriorated rapidly between 1637 and 1640 by which time he was totally blind, probably from chronic angle closure glaucoma.Courtesy of Fitzwilliam Museum, University of Cambridge. Charrington Gift 1933.
From Gallileo's letters, still extant, it would seem that in the very hot summer of 1606 he and two noble friends took a siesta in a room cooled by an elaborate ducting system. This system used tumbling water from a stream which emerged from some caves adjacent to the villa to drive cool air through the room. When they awoke after a couple of hours they were stiff and aching, and developed severe headaches and ‘other discomforts'. They all became very ill. One friend died a few days later; the other became deaf and died a few weeks later; Galileo survived, but he became temporarily deaf in one ear. Thereafter he had bouts of illness in which he had acute pains in many parts of the body and ‘bloody discharges’ which worsened with changes in the weather. The attacks were accompanied by fever and eye problems in which his vision became reduced by ‘a very dense cloud’. Furthermore he saw ‘round the flame of a candle a luminous halo of a diameter of more than two feet’ which ‘hid from view all objects behind it’. These bouts would confine him to bed for as much as five days at a time. However, between episodes he was his usual exuberant and cheerful self and was described as having ‘blue and shining eyes’ (Figs 1.6 and 1.7).
It seems likely, therefore, that the initial illness which killed his colleagues was caused by an acute encephalitis of toxic or viral origin—in all probability due to food poisoning. Although he recovered from this acute illness he suffered from recurring bouts of illness thereafter, developing a reactive arthritis and, possibly, ulcerative colitis or Crohn's disease. The evidence suggests that he did not have the uveitis or scleritis and secondary glaucoma that is associated with these conditions but rather he had an chronic angle closure glaucoma so that he was able to retain accurate central vision to the last (Watson 2009).
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Figure 1.7: The sketch from which Fig. 1.6 was taken. Biblioteca Marucelliana, Florence.
In 1722, St Yves gave a good description of what could easily be a staphyloma resulting from scleral inflammation. The difficulty with interpreting these early texts is that diseases of the cornea and sclera are regarded as the same. However, St Yves does distinguish between cold and hot abscesses, one containing mucilagenous material and the other accompanied by intense inflammation. He says that a cold abscess resolves slowly, and provided it is not treated with astringents or surgery, it will resorb leaving only an area of induration. This is indeed what occurs in some types of nodular scleritis. Most patients with scleral disease at this time would develop staphylomas, partly as a result of the disease itself, and partly as a result of the accompanying increase in intraocular pressure. This sometimes led to rupture of the globe (Fig. 1.8). All texts agree that corneal or scleral disease had a poor prognosis (Read 1717, Guerin 1759) and St Yves said ‘the word staphyloma is designated to signify an elevation on all the transparent cornea or part of it; experience however shows that it is often in the opaque cornea (i.e. sclera)’. He continued ‘this disease is very dangerous, for it brings on continual defluxations, great pains in the head, often want of sleep, abscesses in the inside of the eye; add to all these the deformity it causes the eye’ (Fig. 1.9).
Although Scarpa (1801) described both anterior and posterior staphyloma as the result of disease, his descriptions were mostly of pathological myopia. However, he does describe a young man (40 years old) whose eye increased to the size of a hazelnut and was accompanied by inflammation and ‘acute most hateful pain in the head. The sclera was reduced then as scarcely equal the thickness of writing paper’ (Fig. 1.10).
Along with accurate anatomical descriptions, there came accurate descriptions of diseases, but these overlapped with Galenic or mediaeval concepts of aetiology and their plethora of humours and vapours, making it difficult to discover what was meant by some of the descriptions of inflammatory disease. It was not until clinicopathological correlation became established practice under Morgagni (1761) that systemic pathological study of the connective tissue and rheumatic and ocular disease became widespread (Lawrence 1829, Dalrymple 1852).
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Figure 1.8: Spontaneous scleral rupture as a result of necrotising scleritis and raised intraocular pressure. From Ruete 1854. Plate 23; Figure 9.Courtesy of the Mayo Clinic.
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Figure 1.9: Quiescent anterior scleritis with a staphyloma and extreme thinning of the sclera. From Morgan 1839.Courtesy of Richard Keeler.
The first clinical description of scleral disease was probably that made in 1717 by Sir William Read, Royal Ophthalmologist to Queen Anne from 1702-1714, thus ‘For it is most certain that this horny membrane… by how much deeper the blister is hidden in the membrane… in danger to make an ulceration by breaking through the membrane, whereupon may ensue an utter loss and decay of all the humours’. Scleral inflammation was described as part of the ‘rheumatic diseases of the eye’ by Wardrop (1818a) but the term ‘rheumatic’ is imprecise and it is difficult to know whether or not he was describing the scleral changes in what we call now ‘rheumatoid arthritis’ He said that scleritis comes ‘from the patient's having kept wet clothes on his head when overheated. In another patient the disease came on after travelling during the night in a carriage with one side of his head close to an open window’. He added that scleritis occurs not infrequently ‘in patients who have previously had rheumatism in other parts of the body’. He stated: ‘Rheumatism may frequently be observed to attack a joint or part that has been injured. As rheumatism usually affects fibrous membranes in other parts of the body it is extremely probable that in Rheumatic Ophthalmia the disease is chiefly seated in the sclerotic coat; for when rheumatism attacks the eye I have frequently observed that the blood vessels on the white of the eye appear to be neither those of the conjunctiva inflamed nor the ciliary vessels but a general redness pervading the whole scleral coat’. Wardrop continued: ‘In corroboration of this opinion the sclerotic coat has generally lost its natural pearl whiteness and acquired a dingy yellow hue. The pain too in rheumatic ophthalmia is usually seated in the head and parts of the surrounding orbit probably arising from the similarity or, as some have supposed, from a continuation of structure between the sclerotic coat, dura mater and periosteum.’
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Figure 1.10: An anterior staphyloma and forward displacement of the eye as a result of scleritis, secondary glaucoma, and a large hypermature lens. From Ruete 1854. Plate 19; Figure 8.Courtesy of the Mayo Clinic.
He also recognised that scleritis could arise from other causes ‘but there are other kinds of inflammation which derive their characters not from the peculiarity of the texture inflamed, but from being produced from some specific virus’. (‘Virus’ is used here in the sense given in the third edition of the Shorter Oxford Dictionary: a morbid principle or poisonous substance produced in the body as a result of some disease, especially one capable of being introduced into other persons or animals.) ‘Hence the gonorrheal, the syphilitic, the scrofulous, the gouty and the rheumatic inflammations of the eye; all of which are accompanied with symptoms different from those of simple inflammation of one of the textures which compose that organ.’ He also noted ‘how difficult it is to distinguish in many instances between venereal, gouty and rheumatic affections of the joints.’
Similar observations about scleritis were made by Benjamin Travers (1820) who also observed that ‘the colour of the eye is usually a dull red like that of brick dust. Now and then I have observed it to be rather of a purple hue. In mild cases the redness is often confined to a small space, irregular in figure, perhaps not exceeding an inch in circumference’ (Fig. 1.3). The absolutely characteristic pain experienced by patients with scleritis was described in 1840 by Frederick Tyrell who in the section of his book Sclerotitis—Rheumatic Ophthalmia, describes the ‘dull aching pain which becomes more severe towards evening or morning, with a sense of fullness of the globe and a degree of tenderness as if the organ had been bruised; and such tenderness is much increased during the accession of pain at which is not confined to the globe alone but usually extends to the temple, forehead and cheek.’6
It is surprising how little mention there is of affections of the locomotor system, other than gout, in the medical articles of the past. Why should it be that physicians did not consider these disorders worthy of more than perfunctory mention? It may have been due to a feeling of therapeutic helplessness on their part, as all emphasis was concentrated on the discovery of a specific medicine for each disease, and the concepts of patient management or physical treatment were seldom considered.
In the 17th century, Sydenham in England and Böerhaave in The Netherlands revived the Hippocratic ideals for close clinical observation of patients and their symptoms. This approach was in preference to that of physicians relying purely academically on the recorded opinions of their forerunners, and the revival facilitated the recognition of specific disease syndromes. Following the lead of the famous botanist Linnaeus, who was busy classifying the plant world, medical men such as William Cullen were soon producing overelaborate classifications of disease; gout and the allied rheumatic disorders accounted for nearly 20 categories. In contrast, his classification of ophthalmology amounted to two pages out of four volumes (Cullen 1784). In his opinion all eye diseases were caused by trauma, frequent intoxication, or too much exercise of the eye in viewing small objects.
Sydenham (1624-89) distinguished between ‘chronic’ rheumatism and gout, although the latter term continued to embrace a large and undefined collection of syndromes throughout most of the 18th century. Sydenham's classic description of the acute and chronic ravages of gout, which he described after 30 years of painful personal experience, has never been bettered. In his Treatise on Gout (1683) he showed how to differentiate between gout and rheumatic fever. He also noted and rationalised the connection of the gout with the formation of gravel and calculus. For treatment he advised dietetic restriction, particularly of meat, and regular exercise.
True gout has influenced the course of history. It caused the Roman General, Agrippa, to commit suicide; it soured the disposition of the great reformer, Martin Luther. It is also said to have been instrumental in the loss of the American colonies by the British, in that Prime Minister William Pitt—who could have dealt with the crisis—was prevented from going to the House of Commons because of an acute attack of gout. A major step forward came in 1848 when Sir Alfred Garrod (1819-1907) showed that the gouty tophus consisted of sodium biurate; his classic thread test demonstration proved that the blood of the gouty patient contained an excess of uric acid. Wollaston (1797) had previously shown that the tophaceous material from his own gouty ear contained sodium biurate. Garrod showed that uric acid left in the serum overnight crystallised along a cotton thread as reported in The Nature and Treatment of Gout and Rheumatic Gout (1859). In this book he also differentiated between the various arthritic conditions, saying: ‘The term “rheumatic gout” is widely used by the medical profession of a disease having a special pathology in no way related to true gout and not necessarily rheumatism’. He added: ‘Although unwilling to add to the number of names… perhaps “rheumatoid arthritis” would answer the object, by which term I would wish to imply an inflammatory condition of the joints not unlike rheumatism in some of its characters, but differing materially from it.’
Later, his son Sir Archibald Garrod (1857-1936) differentiated the pathological characteristics of rheumatoid arthritis from those of osteoarthritis in A Treatise on Rheumatism and Rheumatoid Arthritis (1890).
‘Rheumatoid arthritis’ was first clearly described as an entity by Landré-Beauvais in 1800; he was physician to the Saltpetriére Hospital in Paris and published observations in a doctoral thesis. He noticed that the condition mostly affected women, and described its most striking clinical features under the name of ‘goutte asthénique primitive des jointures’. Further precision was given to the concept of chronic arthritis by the work of Heberden (1802). Jean Charcot (1867) gave a further description in a doctoral thesis of what we now know as rheumatoid arthritis. This was illustrated by Charcot himself, showing the types of joint contractures which may be produced. He still appeared to favour the hypothesis that the underlying aetiology was ‘gouty: As Stockman pointed out, in 1920, from the earliest times until recently medical writers made little or no distinction between the different types of ‘chronic rheumatic arthritis’ so that today it is practically impossible to disentangle their descriptions.
There is certainly no convincing description of rheumatoid arthritis in mediaeval writing (Short 1974) except perhaps the description of arthritis in Constantine IX (980-1055) who suffered from a progressive inflammatory polyarthritis, with involvement of the soft tissues and increasing deformities (Caughey 1974, Short 1974). Although Garrod introduced the term rheumatoid arthritis in 1859, there was no clear clinical recognition until 1906 when a physician from Bath, Bannatyne, stated in the fourth edition of his monograph that the disease affected joints in a manner different from osteoarthrosis. He reproduced the first ever X-ray photograph in a medical book. Indeed, Virchow (1858) and Charcot (1867) positively delayed progress by insisting on the unity of degenerate and rheumatoid joint disease under the misleading title of ‘arthritis deformans: It was not until 1857 that Robert Adams of Dublin convincingly separated the osteoarthritic type of arthropathy from the others (Adams 1857).
Several authors have commented on the absence of rheumatoid deformities in paintings or sculptures before 1800 (Boyle & Buchanan 1971, Snorrason 1952). Recently Dequeker (1975) examined hands seen in Flemish paintings done between 1400 and 1700; although changes suggestive of rheumatoid-like lesions were seen in five paintings, there was no totally convincing evidence of symmetrical rheumatoid arthritis (the most convincing was that of a serving maid in Jacob Jordaens’ Painter's Family) (Fig. 1.11).
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Figure 1.11: The artist and his family in a garden Jacob Jordaens (1593—1678), Museo del Prado, Madrid. The hands of the maid holding the basket of fruit (insert) show the classical deformation of the hands and wrists seen in rheumatoid arthritis (see Figs 3.21, 3.22, and 3.25).
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Perhaps the most famous example of a rheumatic disease in a painting is that of temporal arteritis in Canon van der Paele by Jan van Eyck (1385-1440). According to records of the cathedral, whilst the Canon was having his portrait painted he began to have difficulty in performing his duties as a result of morning stiffness, weakness, and general ill health (Fig. 1.12).
The anatomical features of rheumatoid arthritis did not appear to engage the interest of surgeons preoccupied with tuberculous and other forms of infective joint disease, many of whom are described as having ocular inflammation in one form or another (Brodie 1813, 1818). It seems very likely that the superficial similarities of the diseases, the frequency and occurrence of tuberculous arthritis, and the low mean expectation of life in the years when Hunter, Brodie, Badlie, and other great pioneers of morbid anatomy were at work effectively disguised the problem of rheumatoid arthritis—a disorder much more conspicuous in ageing populations such as our own, among which infectious arthritis is now rare.
Paleopathology consists of the study of disease in human populations as revealed by their mummified and skeletal remains. Whether rheumatoid arthritis has been demonstrated in ancient skeletons has been the subject of debate. Recent demonstration of erosive polyarthritis in ancient Indian skeletons in North American has fuelled speculation that rheumatoid arthritis had its origins in the New World. However, a number of joint diseases, including the seronegative arthropathies, can cause an erosive polyarthritis.
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Figure 1.12: Temporal arteritis. Madonna met Kanunnik Joris Van der Paele (1436) by Jan van Eyck (detail). The Canon of the cathedral had difficulty performing his duties on account of general ill health, weakness, and morning stiffness. The detail from the painting shows the knotted temporal arteries extending to the crown of the head. This is also one of the earliest pictures illustrating the use of spectacles.Courtesy of Groeningemuseum Ghent, Belgium.
Archaeological evidence exists that ankylosing spondylitis affected the human race from prehistoric times and it was recognised by Hippocrates. It must have been relatively common after this. Certainly certain members of the English Royal Family in Plantagenet times suffered from it, so it is surprising that there is no written description of the disease before the end of the 17th century, when Connor (1691) described a skeleton with signs of the condition. Widespread clinical recognition of the disorder did not materialise until the 19th century, when the Russian neurologist von Bechterew (1893), Strumpell (1897), and Charcot's successor Marie (1898) reported several cases. Benjamin Brodie (1813) included descriptions of joint changes in ankylosing spondylitis together with what is apparently the first description of the triad of urethritis, arthritis, and conjunctivitis—now called Reiter's syndrome (Reiter's 1916) or reactive arthritis. Cazenave (1850) drew attention to the skin changes of discoid lupus erythematosus, and Kaposi (1872) subsequently described the disseminated form of this disease and emphasised the widespread involvement of viscera. The first clear recognition of polyarteritis nodosa came at almost the same time (Kussmaul & Maier 1866).
In the latter half of the 19th century, progress in understanding the pathology of these diseases was slow. Perhaps because of the introduction of the compound microscope by Charles Chevalier (1804–59) and the identification of microorganisms as the cause of disease by Pasteur from 1857, interest was diverted to those diseases with a bacteriological basis; and lack of any direct evidence that the rheumatic diseases were infective discouraged further investigation.
Virchow (1858) expounded the doctrine of ‘omnus cellula e cellula’. The idea that the seat of disease should always be sought in the cell has been the basis of investigation into this group of diseases and their eye complications ever since.
The first and easiest search was for the role of microorganisms as a cause of eye disease. This started as soon as methods for their detection became readily available; tuberculosis was soon added as a cause of scleral disease to those chronic granulomatous conditions already recognised. Koch (1843-1910) had shown the difficulty of recognising certain organisms, even when cultured under ideal conditions (Koch 1882). Therefore it was not regarded as strange that no organisms could be cultured from the chronic granulomas found in the sclera.
Similarly, when streptococci were identified by Ogston (1881) and Poynton & Paine (1913) they conducted an extensive series of investigations to see whether rheumatic fever was the result of an infection. By the time their monograph was published, an immune origin for the disease was suspected. Klinge (1933) established an association between an immune arthritis in rabbits injected with horse serum and the presence of fibrinoid material in the affected tissues. This classic work laid the foundations for the theory which postulates the existence of systemic collagen or connective tissue diseases (Klemperer et al 1942).
Klemperer described widespread foci of fibrinoid change in connective tissues in systemic lupus erythematosus and systemic sclerosis and suggested that both diseases be regarded as diffuse disorders of connective tissue. As rheumatic fever, rheumatoid arthritis, dermatomyositis, and polyarteritis nodosa have similar basic changes, they were also grouped together.
From the foundations laid by Ehrlich (1854-1915), Pfeiffer (1858-1945), and many others, and by drawing analogies from other 8affected tissues (e.g. the joints), it became clear that most reactions seen as a result of scleral disease could result from immune processes of a similar type.
In 1950 Klemperer used the term ‘collagen disease’, but later in 1954 he emphasised that he had intended to refer in his original description to the complete intercellular connective tissue, both fibres and ground substance, but had used the word collagen in a nonspecific sense for the sake of brevity (Klemperer 1954, 1955). He also pointed out the danger that the term ‘diffuse collagen disease’ may be applied to any illness with puzzling clinical and anatomical features, rather than conditions which affect connective tissue.
This group of diseases was then considered to arise from a derangement of the immune response. The demonstration of serum antibodies which reacted with antigens present in their own tissues led to the idea that these antibodies could damage host tissues. This concept has been based largely on the work of Sir Macfarlane Burnet (1959). It is considered that a ‘forbidden’ clone of cells arising from a single immunocyte, on account of a combination of somatic mutation and genetically determined characteristics, proliferates and produces antibody. This was claimed to be the basic abnormality leading to the initiation of autoimmune disease.
Having produced a reasonable explanation for the pathological changes seen in both eye and joint, the search has continued for trigger factors which might initiate and perpetuate changes, and for the factors which determine the particular features of each disease. The search, which has implicated trauma, bacteria, mycoplasma, viruses, genetic factors, or combinations of these, still continues. The primary antigen may not be an infectious agent or a specific antigen produced in response to it, but may be other components of connective tissue which have been immunologically altered by the inflammatory response to a virus or other agent. Indeed the interaction of viruses with cells can lead to the release of hydrolytic enzymes from sub-lethally infected cells; these enzymes could be the first autoantigens towards which immune responses are directed.
Although there is no clear evidence of their Mendelian inheritance, the inflammatory rheumatic diseases which affect the eye do cluster in families. Presumably this reflects the action of environmental factors against a background of genetic susceptibility. If we were able to define the main genes involved, and determine how their products differ from those of unaffected individuals, we would be in a better position to understand how these conditions arise, and eventually how to prevent or manage them.
The term ‘new genetics’ was first used by the editor of the American Journal of Human Genetics, commenting on an article which described a new DNA analytical approach to mapping the human genome. The term is usually used to describe the study of inheritance at the molecular level, either of single-gene disorders or of common polygenic disorders, such as autoimmune diseases. An understanding of the underlying genetic factors is important because epidemiological studies of putative environmental factors have not revealed the cause of common diseases such as rheumatoid arthritis.
Rheumatoid arthritis (but not necessarily the scleral involvement in the disease) is an example of a polygenic disease, where it is likely that the combined effects of several genes can allow a number of environmental triggers to produce a similar clinical condition. Rheumatoid arthritis is prevalent among many racial groups and epidemological studies have shown that it is not like an infectious disease with a single causative agent.
There is a drive to unravel the genes which are important in polygenic diseases, because their identification will allow us to understand the biochemical bases of why these diseases occur (e.g. complement deficiencies and immune complex diseases). As a result, more rational methods of disease prevention and management may be developed.
There are two approaches to defining the genes involved in a particular disease: the candidate gene approach, and the establishment of linkage using large families.
In inflammatory eye diseases and rheumatic diseases the search for candidate genes has been favoured historically, with considerable effort expanded in the analysis of the major histocompatibility complex (MHC) genes and more recently, the T-cell-receptor genes. The hypothesis is that the trimolecular complex of the human leukocyte antigen (HLA), peptide, and T-cell receptors in presenting antigen is central to pathogenesis of disease.
More recent studies have concerned candidate genes other than those coding for the antigen-presenting trimolecular complex. For example, the inflammatory cytokines, which are mediators of the inflammatory and immune responses seen in rheumatic disorders.
Current molecular techniques have led to major advances in the last 30 years. In 1982, three interleukins had been characterised; now the number is approaching 20. To these can be added the cytokines such as tumour necrosis factor, onconstatin-M, leukaemia inhibitory factor, and many others. Most have names which fail to indicate their wide-ranging involvement in inflammation and immunity.
Around 40 cytokines have been defined. The predominant actions of chemokines are on neutrophils, monocytes, or lymphocytes. An expanding family of receptors for these factors is also being defined. The most recent chemokines and chemokine receptors are examples of ‘reverse genetics’ with the discovery coming from DNA sequences rather than biological activity. Among the newer chemokines are factors with important roles in establishing the architecture of the immune system, for instance, attracting cells into germinal centres.
At one time, the interests of cellular immunologists were almost entirely focused on events at the cell surface. Now the many signalling pathways have been defined in detail and shown to be very complex. Examples include signalling from T-and B-cell receptors, from co-stimulatory molecules and cytokine receptors, and the signalling mechanisms which mediate programmed cell death (apoptosis). Increasing knowledge of signalling pathways is likely to be particularly important because it is often more realistic to manipulate the immune system by interfering with signalling pathways, rather than to use biological agents which act primarily on cellular interactions.
Most connective tissue disorders occur in the context of an immune system which is generally competent—patients are able to protect themselves adequately from pathogens—but some minor defect may lead to disaster. These defects have not generally been defined but might include overexuberant responses to environmental antigens in terms of cytokine production where there is confusion between similar epitopes on foreign and self-antigens.
Our therapeutic repertoire has involved shutting down the whole immune system substantially, which inevitably leads to vulnerability from infectious agents. It is hoped that in future more subtle manipulation of the immune system might achieve the desired effects on autoimmune/chronic inflammatory diseases, while maintaining intact defences against pathogens.
Before the cause of any disease can be established, it must fulfil the criteria laid down by Koch (1882), who postulated:
  1. The organism must be demonstrated in the blood or tissues of the diseased animal.
  2. The organism, so demonstrated, must be capable of artificial cultivation in suitable media outside the body and successive generations of pure culture obtained.
  3. Such pure culture must, when introduced into a healthy and susceptible animal, produce the given disease.
    9
  4. The organism must again be found in the circulation or tissues of the inoculated animal.
  5. The claims of organisms which fail to meet these demands must be set aside to await further proof.
Alternatively, if the condition is thought to be autoimmune, it must fulfil the criteria defined by Milgrom and Witebsky (1962); these criteria have not been satisfied for any of the connective tissue diseases or for any of the nonspecific causes of scleral disease.
Our understanding of the molecular basis of immune-mediated diseases has advanced considerably over the past two decades. However, much work needs to be done to translate this knowledge to the benefit of patients in the clinic.
For example, how can we best apply our knowledge to introduce into the clinical setting immunological biomarkers to facilitate diagnosis and monitor the impact of our therapeutic interventions?
Now we are entering an age where technology threatens to overwhelm clinical medicine. We would all do well to reflect on how much can be achieved by observation alone. As Sir William Osler (1849–1919) said in his introductory lecture at the 45th session of the Medical Faculty McGill University: ‘Remember you enter upon a glorious heritage: you will reap where you have not sown and gotten where you have not strived and the knowledge which is your privilege today to acquire so early has cost others. We are, all of us, debtors to our profession.’
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