Ann Rheum Dis: first published as 10.1136/ard.15.1.21 on 1 March 1956. Downloaded from

Ann. rheum. Dis. (1956), 15, 21.

KERATO-CONJUNCTIVITIS SICCA AND RHEUMATOID ARTHRITIS BY MALCOLM THOMPSON* AND STELLA EADIE From the Rheumatic Unit, Northern General Hospital, Edinburgh, and the Edinburgh Royal Infirmary (RECEIVED FOR PUBLICATION OCTOBER 13, 1955) Although the ophthalmic lesions which constitute arthritis is an integral part of the symptom complex. kerato-conjunctivitis sicca have long been known, It is my feeling that the arthritis is an incidental the nature of the condition has remained obscure. finding." Ellman, Weber, and Goodier (1951) Duke-Elder (1930) reviewed those rare cases in remarked that: "rheumatoid arthritis is fairly which lesions of the lacrimal secretary nerves or of common among women, and that very few patients the gland parenchyma (including congenital aplasia, with rheumatoid arthritis ever manifest any symp- surgical extirpation, infiltrations by sarcoid, leu- toms resembling Sjogren's disease". They recorded kaemic or malignant tissue) resulted in deficient the case history and autopsy findings in a patient lacrimal secretion and the subsequent development who did suffer from rheumatoid arthritis, but in of corneal and conjunctival lesions of the sicca type. whom the symptoms of xerostoma, salivary gland These rare cases, however, accounted for only a enlargement, and ocular inflammation preceded the small proportion of all the patients suffering from development of the arthritis by several years. no However, Reader, Whyte, and Elmes (1951) con- kerato-conjunctivitis sicca, and in the majority copyright. local ophthalmic cause for deficient lacrimation and firmed the opinion of Holm (1949) that many sicca lesions could be found. patients who suffered from rheumatoid arthritis also Sjogren (1933) described in detail his observations had a deficiency of lacrimal secretion, as estimated on eighteen patients with idiopathic kerato-con- by Schirmer's test. Other workers have been more junctivitis sicca and drew attention to its frequent inclined to consider kerato-conjunctivitis sicca and association with such clinical features as poly- its allied pathology as part of the wider concept of arthritis, xerostoma, and salivary gland enlargement, rheumatoid disease; this view was expressed by occurring especially in middle-aged women. To Littler (1951), Gurling (1953), and Morgan (1954). http://ard.bmj.com/ this triad the name Sjogren's syndrome was given, During the past 3 years, we have treated eighteen but the variations and increasing complexity of the patients with severe or moderate kerato-conjunc- condition soon became apparent. Holm (1949) tivitis sicca, fourteen of whom (77 7 per cent.) had reviewing 440 cases of rheumatoid disease stated rheumatoid arthritis. An additional sixteen patients that "The conception of kerato-conjunctivitis sicca with milder symptoms and signs, consistent with a as a disease sui genesis (Sjogren) is fundamentally condition of conjunctivitis sicca, and also suffering

incorrect": but he considered that rheumatoid from rheumatoid arthritis, have also been examined on September 30, 2021 by guest. Protected arthritis was of importance as an aetiological factor. and treated. The high percentage of cases asso- The term Sjbgren's syndrome continued to be ciated with polyarthritis is due to the fact that most applied to any condition in which the classical of the cases were identified at a rheumatic unit. triad of kerato-conjunctivitis sicca, polyarthritis, The ophthalmic features, associated lesions, and and salivary gland enlargement was present, as complications noted in these patients have some well as those in which arthritis was absent (approxi- points of interest, and are recorded together with mately 40 per cent. of all cases of kerato-conjunc- some observations on the results of treatment of the tivitis sicca). Writers, however, remained cautious ocular lesions. of associating the condition with rheumatoid arth- Incidence ritis. Coverdale (1948) considered that "Sj6gren's Kerato-conjunctivitis sicca is not the rarity it was syndrome" indicated a general constitutional or once considered to be. It is, indeed, the commonest systemic disturbance of unknown origin, while ocular complication of rheumatoid arthritis. In a Henderson (1950) stated: "I do not feel that poly- recent study of 210 former in-patients of the Rheu- * Present address: Royal Victoria Infirmary, Newcastle-on-Tyne. matic Diseases Unit, Northern General Hospital, 21 Ann Rheum Dis: first published as 10.1136/ard.15.1.21 on 1 March 1956. Downloaded from

22 ANNALS OF THE RHEUMATIC DISEASES Edinburgh, we found evidence of lesions of the sicca symptoms of kerato-conjunctivitis sicca, the more -type in thirty patients, an incidence of 14 3 per cent. serious risks to vision have not been fully appreci- In comparison with this, there were only seven ated. In the present series, corneal ulceration was patients (3 3 per cent.) who showed signs of active noted in three cases. In two instances the ulcers or old uveitis. No cases of episcleritis, sclero- were of the small marginal type which healed without malacia perforans, or superficial punctate keratitis incident. The third patient, however, suffered from were identified in this series. These findings accord bilateral corneal ulceration, and was initially referred with those of Holm (1949), who diagnosed kerato- to hospital when perforation of a central corneal conjunctivitis sicca in 13 -4 per cent. of 440 rheuma- ulcer necessitated enucleation of the eye. One toid patients, and of Rosenberg (1949) who reported patient also had a small pannus involving the uveitis in 3 to 5 per cent. of cases. infero-lateral quadrant of the cornea. Of the thirty patients with kerato-conjunctivitis sicca in our series, all of whom had had ophthalmic Pathology.-Sjogren (1933) also described the symptoms, six had gross corneal and conjunctival histological features in the lacrimal and salivary lesions, eight had conjunctival lesions of moderate glands and in the conjunctiva. In the lacrimal severity and had only slight corneal changes in glands the changes consisted of round cell infiltra- addition, and sixteen had conjunctival lesions only, tions, atrophy and destruction of the acini, and and could be considered to be examples of con- replacement fibrosis in the later stages (Fig. 1). junctivitis sicca. Sex Ratio Sjogren (1933) stated that the syndrome occurred most commonly in middle-aged women. Holm (1949) found that female cases predominated, but that in his rheumatoid patients the sex incidence of kerato-conjunctivitis sicca paralleled the sex dis-

tribution of the arthritis, being approximately 2 5 copyright. females to 1 male. Of the thirty patients in our series, 26 were females, making a ratio of 6- 5 females to one male. The sex ratio of the 210 patients studied was only 2-7 females to one male. Description classical symptoms Ophthalmic Features.-The http://ard.bmj.com/ and signs of kerato-conjunctivitis sicca are those of conjunctivitis associated with filamentary keratitis and reduction oflacrimal secretion, and the diagnosis can be substantiated by Schirmer's test for lacrimal secretion and the staining reaction with 1 per cent. aqueous Rose-Bengal solution. In the present series, several ophthalmic features of interest were noted. The ocular symptoms ran on September 30, 2021 by guest. Protected a course of remissions and exacerbations, but symptoms were rarely completely absent in severe cases of kerato-conjunctivitis sicca. The waxing and waning of the ophthalmic symptoms in those who also had rheumatoid arthritis often patients Fig. 1.-Lacrimal gland showing atrophy of acini and extensive occurred independently of any changes in the round cell infiltration ( x 80). -arthritic condition. Furthermore, the severity of the ocular changes in such patients was not propor- The lesions in the lacrimal glands were considered tional to the severity of the arthritis, some of the to be mainly responsible for the dryness of the eyes most marked examples of kerato-conjunctivitis and the subsequent epithelial changes, but primary sicca being encountered in patients with mild or degenerative changes in the conjunctival epithelium quiescent rheumatoid arthritis. could also contribute to the developed appearances Although ocular discomfort, photophobia, and in kerato-conjunctivitis sicca. The histological mild impairment of vision are well recognized as changes in the lacrimal glands are similar to those Ann Rheum Dis: first published as 10.1136/ard.15.1.21 on 1 March 1956. Downloaded from

KERATO-CONJUNCTIVITIS SICCA AND RHEUMATOID ARTHRITIS 23 noted in the salivary glands, but one important evidence of arthritis comprised one man and three difference is that while secretary ducts may be women. In only two instances had ocular symptoms blocked in the salivary glands, this does not occur been noticed before the age of 40 years. The nail in the lacrimal glands (Morgan, 1954). This is in changes and otitis externa noted in the present keeping with the clinical observation that enlarge- series are worthy of special mention. ment of the salivary glands is not uncommon in The nail lesions, seen in both fingers and toes, Sjogren's syndrome, but that enlargement of the consisted of dry, longitudinally fissured nails lacrimal glands is never seen. (onychorrhexis), stained brownish-yellow. Those most severely involved were rough and irregularly Associated Clinical Features.-The principal con- heaped up, due to subungual hyperkeratosis, and ditions, already recorded as associated with kerato- such nails grew slowly, gradually separated and conjunctivitis sicca, and accepted as components of sloughed (onycholysis) and then further nail growth Sj6gren's syndrome, are shown in Table I. commenced from the irregular nail bed. Similar TABLE I changes in the nails have been recorded in rheuma- are CLINICAL FEATURES ALREADY REPORTED IN toid arthritis (Ragan, 1954), but only rarely ASSOCIATION WITH KERATO-CONJUNCTIVITIS SICCA encountered, so that their frequency in the present Rheumatoid polyarthritis series is especially noteworthy. The most severe Xerostoma and salivary gland enlargement a Laryngo-pharyngo-rhinitis sicca nail lesions occurred in patient who also had Bronchitis and pulmonary atelectasis arthritis, alopecia totalis, and several other features Achlorhydria Vaginitis of the syndrome. This patient received oral Alopecia nail Peripheral vascular symptoms cortisone, 100 mg. daily, and normal growth Ichthyosis was restored (Fig. 2), but there was no improvement Generalized lymphadenopathy Felty's syndrome in the alopecia. Anaemia Raised erythrocyte sedimentation rate

It is exceptional for a patient to exhibit most or copyright. even many of these features, and usually only poly- arthritis and xerostoma are seen. Many of the associated features can be attributed to a deficiency of epithelial glandular secretions and consequent dryness of cutaneous and mucosal surfaces. The co-existence of Sjogren's syndrome and Felty's syndrome, previously noted by Gurling (1953), is further evidence of the common identity of Sjogren's http://ard.bmj.com/ syndrome and rheumatoid disease. The clinical features in our eighteen cases of severe or moderate kerato-conjunctivitis sicca are shown in Table II. Fourteen of the patients, of whom thirteen were women, had associated rheu- matoid polyarthritis. The four patients who had no on September 30, 2021 by guest. Protected TABLE II CLINICAL FEATURES IN EIGHTEEN CASES OF KERATO-CONJUNCTIVITIS SICCA Fig. 2.-Close-up of left hand of a patient suffering from rheumatoid arthritis, who also exhibited many of the features of Sjogren's syn- Rheumatoid polyarthritis .. 14 drome, taken after 2 months' treatment with cortisone, 100 mg. daily. Xerostoma .. 14 There is a clear line of demarcation between the former discoloured Salivary gland enlargement .. 6 nail and the apparently normal new nail formation. Laryngo-pharyngo-rhinitis sicca..12 Achloihydria (five cases examined) 5 Bronchitis and pulmonary atelectasis 5 The occurrence of external otitis in three patients Alopecia. 5 is probably a significant finding in a syndrome where Peripheral vascular symptoms . 4 Felty's syndrome I deficiency of epithelial secretions is common. Persistent leucopenia. Hepatic cirrhosis Deficient secretion of cerumen and resultant impair- Marginal corneal ulceration..2 ment of normal lubrication of the outer ear passages Central corneal ulceration I Pannus .... I would predispose to dryness and irritation by dust. Trophic nail changes.4 Otitis externa 3 The appearances in the affected cases were those of dry, sore ears with small, tender fissures in the Ann Rheum Dis: first published as 10.1136/ard.15.1.21 on 1 March 1956. Downloaded from

24 ANNALS OF THE RHEUMATIC DISEASES external meatus and helix. The ear wax was dry and the symptoms, and in no instance has any undesir- powdery, but there was no suppuration or damage able side-effect been noted as a result of this treat- to the ear drum. The changes may be described as ment. Hydrocortisone drops and cortisone eye an otitis externa sicca, comparable to rhinitis sicca. ointment were used in the treatment of some patients, but did not appear to confer any extra benefit. The Treatment local application of these hormones has been shown General treatment, by such measures as large to be effective solely by virtue of their anti-inflam- doses of vitamins, thyroid extract, and oestrogens, matory action, as no increase in lacrimal secretion has not proved to be of any value. Local treat- has been noted during their use. ments have been directed towards relieving the The operation of sealing both lacrimal puncta, in ocular symptoms. Gifford, Puntenney, and Bellows order to conserve diminished secretions, was intro- (1943) employed parasympathomimetic drugs such duced by Beetham (1935), and has proved to be an as pilocarpine nitrate and prostigmine hydro- effective surgical procedure. Gifford and others bromide, in an attempt to stimulate lacrimal (1943) have reported favourably on its value, and secretion, and reported success in the treatment of we have found it to be helpful in more severe cases early cases. However, the results have not been of kerato-conjunctivitis sicca that were not impressive in more severe cases, and intestinal adequately controlled by local cortisone therapy. cramps limit the dosage of such drugs. This operation, conveniently done by thermal Saline and antibiotic eye drops are not usually cauterization of the canaliculus, should not be per- helpful because of rapid evaporation. In our formed in early or mild cases in whom a remission experience, artificial tears, which do not evaporate may be expected, as subsequent improvement in so rapidly, have been of benefit in many mild cases. lacrimation would lead to epiphora. In some cases Methylcellulose drops have been used, and another only slight increase in lacrimal secretion, as measured suitable preparation, suggested by Gifford and by Schirmer's filter-paper may occur after operation, others (1943), is: but in spite of this there may be an appreciable subjective and objective improvement in the eyes. Gelatin ...... 03 g. copyright. Chlorbutal .. . . 0-3 g. In very severe cases of kerato-conjunctivitis sicca Locke's solution .. .. 30 ml. adjuvant therapy with cortisone eye drops or artificial One drop of these "tears" can be instilled into the tears may be necessary even after sealing of the conjunctiva, three to six times daily. lacrimal puncta. Deep x-ray therapy has been used successfully in Summary reducing the size of the enlarged parotid glands, but The clinical features of kerato-conjunctivitis sicca no constant improvement has been noted after have been described and its occurrence in patients treatment of the lacrimal glands (Beetham, 1935). suffering from rheumatoid arthritis has been studied. http://ard.bmj.com/ ACTH and cortisone have been administered It is considered to be the most common ocular systemically with conflicting reports of their effect complication of this disease, having been identified upon lacrimal secretion. In early cases some in 14-3 per cent. of a series of 210 patients. Mild return of lacrimal secretion has been noted, but side- cases of kerato-conjunctivitis sicca are especially effects and complications, common to the pro- common, and the minor, recurrent, conjunctival longed administration of high doses of these hor- inflammation noted in many patients with rheuma-

mones, have limited the value of this form of treat- toid arthritis is conjunctivitis sicca, without corneal on September 30, 2021 by guest. Protected ment. In severe and chronic cases of kerato- lesions. conjunctivitis sicca the systemic administration of The associated clinical findings have been des- steroid hormones may relieve the ocular symptoms cribed in a series of eighteen patients who exhibited even though unsuccessful in increasing lacrimal the features of Sjogren's syndrome. Changes in the secretion. nails and otitis externa sicca have been described. Topical administration of cortisone and hydro- The hazard to vision resulting from corneal ulcera- cortisone has, in our experience, proved to be a safe tion has been emphasized. The treatment of the and useful means of treating mild and moderate ocular symptoms has been discussed. cases of kerato-conjunctivitis sicca (Eadie and We gratefully acknowledge the invaluable advice and Thompson, 1955). The eye drops may be prepared co-operation of Dr. J. J. R. Duthie of the Northern in strengths ranging from 0 5 to 2 per cent., and we General Hospital, Edinburgh, and of Professor G. 1. employed a saline suspension of cortisone acetate Scott of the Edinburgh Royal Infirmary. During the diluted in a buffered base. The drops were instilled period when this work was undertaken the Rheumatic three to six times daily, according to the severity of Unit, Northern General Hospital, Edinburgh, was in Ann Rheum Dis: first published as 10.1136/ard.15.1.21 on 1 March 1956. Downloaded from

KERATO-CONJUNCTIVITIS SICCA AND RHEUMATOID ARTHRITIS 25 receipt of grants from the Nuffield Foundation and sujets atteints d'arthrite rhumatismale. On consider Medical Research Council, and one of us (S.E.) received que c'est la complication oculaire la plus frequente, a grant from the W. H. Ross Foundation (Scotland) for l'ayant identified dans 14,3% d'une serie de 210 malades. Des cas benins de kerato-conjonctivite seche sont the Prevention of Blindness. particulierement repandus et l'inflammation mineure et The cortisone and ACTH used in the treatment of recurrente des conjonctives, observee chez nombreux several of these patients was supplied by the Medical rhumatisants est, en reality, une conjonctivite seche sans Research Council, to whom we are indebted. lesions de la cornee. On decrit les manifestations cliniques secondaires REFERENCES chez 18 malades presentant des traits du syndrome de Beetham, W. P. (1935). Trans. Amer. ophthal. Soc., 33, 413. en particulier les alterations des ongles et Coverdale, H. (1948). Brit. J. Ophthal., 32, 669. Sjogren, Duke-Elder, S. (1930). Ibid., 14, 61. l'otite externe seche. On souligne le danger de l'ulcera- Eadie, S., and Thompson, M. (1955). Ibid., 39, 90. tion de la cornee et on discute le traitement oculaire. Ellman, P., Weber, F. Parks, and Goodier, T. E. W. (1951). Quart. J. Med., n.s. 20, 33. Gifford, S. R., Puntenney, I., and Bellows, J. (1943). Arch. Ophthal. (Chicago), 30, 207. La kerato-conjunctivitis sicca y la artritis Gurling, K. J. (1953). Annals of the Rheumatic Diseases, 12, 212. reumatoide Henderson, J. W. (1950). Amer. J. Ophthal., 33, 197. Holm, S. (1949). Acta ophthal. (Kbh.), Suppl. 33. SUMARIO Littler, T. R. (1951). Annals of the Rheumatic Diseases, 10, 405. Morgan, W. S. (1954). New Engl. J. Med., 251, 5. Se describen los rasgos clinicos de la kerato-con- Ragan, C. (1953). In "Comroe's Arthritis and Allied Conditions", ed. J. L. Hollander, 5th ed., p. 156. Kimpton, London. junctivitis sicca y se estudia su ocurrencia en sujetos con Reader, S. R., Whyte, H. M., and Elmes, P. C. (1951). Annals of the artritis reumatoide. Se consider que se trata aqui de la Rheumatic Diseases, 10, 288. complicaci6n ocular la mas frecuente, habiendola Rosenberg, E. F. (1949). In "Comroe's Arthritis and Allied Con- ditions", ed. J. L. Hollander, 4th ed., p. 173. Kimpton, identificado en el 14,3% de una serie de 210 enfermos. London. Casos benignos de kerato-conjunctivitis sicca se ven Sjogren, H. (1933). Acta ophthal. (Kbh.), Suppl. 2. (Trans. J. Bruce corrientemente y la inflamaci6n menor y recurrente de Hamilton, 1943. Australasian Medical Publishing Co., las conjuntivas observada en numerosos enfermos con Sydney.) artritis reumatoide represents realmente una con- juntivitis seca sin lesiones de la cornea. La k6rato-conjonctivite seche et l'arthrite Se describen las manifestaciones clinicas secundarias rhumatismale en 18 enfermos presentando rasgos del sindrome de RESUME Sjogren, particularmente las alteraciones unguales y la

On decrit les caracteres cliniques de la kerato-con- otitis externa seca. Se subraya el peligro de la ulceracion copyright. onctivite seche et on etudie sa frequence parmi les de la cornea y se discute el tratamiento ocular. http://ard.bmj.com/ on September 30, 2021 by guest. Protected