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

KERATO-CONJUNCTIVITIS SICCA AND RHEUMATOIDARTHRITIS

BY

MALCOLM THOMPSON* AND STELLA EADIEFrom the Rheumatic Unit, Northern General Hospital, Edinburgh, and the Edinburgh Royal Infirmary

(RECEIVED FOR PUBLICATION OCTOBER 13, 1955)

Although the ophthalmic lesions which constitutekerato-conjunctivitis sicca have long been known,the nature of the condition has remained obscure.Duke-Elder (1930) reviewed those rare cases inwhich lesions of the lacrimal secretary nerves or ofthe gland parenchyma (including congenital aplasia,surgical extirpation, infiltrations by sarcoid, leu-kaemic or malignant tissue) resulted in deficientlacrimal secretion and the subsequent developmentof corneal and conjunctival lesions of the sicca type.These rare cases, however, accounted for only asmall proportion of all the patients suffering fromkerato-conjunctivitis sicca, and in the majority nolocal ophthalmic cause for deficient lacrimation andsicca lesions could be found.

Sjogren (1933) described in detail his observationson eighteen patients with idiopathic kerato-con-junctivitis sicca and drew attention to its frequentassociation with such clinical features as poly-arthritis, xerostoma, and salivary gland enlargement,occurring especially in middle-aged women. Tothis triad the name Sjogren's syndrome was given,but the variations and increasing complexity of thecondition soon became apparent. Holm (1949)reviewing 440 cases of rheumatoid disease statedthat "The conception of kerato-conjunctivitis siccaas a disease sui genesis (Sjogren) is fundamentallyincorrect": but he considered that rheumatoidarthritis was of importance as an aetiological factor.The term Sjbgren's syndrome continued to be

applied to any condition in which the classicaltriad of kerato-conjunctivitis sicca, polyarthritis,and salivary gland enlargement was present, aswell as those in which arthritis was absent (approxi-mately 40 per cent. of all cases of kerato-conjunc-tivitis sicca). Writers, however, remained cautiousof associating the condition with rheumatoid arth-ritis. Coverdale (1948) considered that "Sj6gren'ssyndrome" indicated a general constitutional orsystemic disturbance of unknown origin, whileHenderson (1950) stated: "I do not feel that poly-

* Present address: Royal Victoria Infirmary, Newcastle-on-Tyne.21

arthritis is an integral part of the symptom complex.It is my feeling that the arthritis is an incidentalfinding." Ellman, Weber, and Goodier (1951)remarked that: "rheumatoid arthritis is fairlycommon among women, and that very few patientswith rheumatoid arthritis ever manifest any symp-toms resembling Sjogren's disease". They recordedthe case history and autopsy findings in a patientwho did suffer from rheumatoid arthritis, but inwhom the symptoms of xerostoma, salivary glandenlargement, and ocular inflammation preceded thedevelopment of the arthritis by several years.However, Reader, Whyte, and Elmes (1951) con-

firmed the opinion of Holm (1949) that manypatients who suffered from rheumatoid arthritis alsohad a deficiency of lacrimal secretion, as estimatedby Schirmer's test. Other workers have been moreinclined to consider kerato-conjunctivitis sicca andits allied pathology as part of the wider concept ofrheumatoid disease; this view was expressed byLittler (1951), Gurling (1953), and Morgan (1954).During the past 3 years, we have treated eighteen

patients with severe or moderate kerato-conjunc-tivitis sicca, fourteen of whom (77 7 per cent.) hadrheumatoid arthritis. An additional sixteen patientswith milder symptoms and signs, consistent with acondition of conjunctivitis sicca, and also sufferingfrom rheumatoid arthritis, have also been examinedand treated. The high percentage of cases asso-ciated with polyarthritis is due to the fact that mostof the cases were identified at a rheumatic unit.The ophthalmic features, associated lesions, andcomplications noted in these patients have somepoints of interest, and are recorded together withsome observations on the results of treatment of theocular lesions.

IncidenceKerato-conjunctivitis sicca is not the rarity it was

once considered to be. It is, indeed, the commonestocular complication of rheumatoid arthritis. In arecent study of 210 former in-patients of the Rheu-matic Diseases Unit, Northern General Hospital,

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Edinburgh, we found evidence of lesions of the sicca-type in thirty patients, an incidence of 14 3 per cent.In comparison with this, there were only sevenpatients (3 3 per cent.) who showed signs of activeor old uveitis. No cases of episcleritis, sclero-malacia perforans, or superficial punctate keratitiswere identified in this series. These findings accordwith those of Holm (1949), who diagnosed kerato-conjunctivitis sicca in 13 -4 per cent. of 440 rheuma-toid patients, and of Rosenberg (1949) who reporteduveitis in 3 to 5 per cent. of cases.Of the thirty patients with kerato-conjunctivitis

sicca in our series, all of whom had had ophthalmicsymptoms, six had gross corneal and conjunctivallesions, eight had conjunctival lesions of moderateseverity and had only slight corneal changes inaddition, and sixteen had conjunctival lesions only,and could be considered to be examples of con-junctivitis sicca.

Sex RatioSjogren (1933) stated that the syndrome occurred

most commonly in middle-aged women. Holm(1949) found that female cases predominated, butthat in his rheumatoid patients the sex incidence ofkerato-conjunctivitis sicca paralleled the sex dis-tribution of the arthritis, being approximately 2 5females to 1 male. Of the thirty patients in ourseries, 26 were females, making a ratio of 6- 5 femalesto one male. The sex ratio of the 210 patientsstudied was only 2- 7 females to one male.

DescriptionOphthalmic Features.-The classical symptoms

and signs of kerato-conjunctivitis sicca are those ofconjunctivitis associated with filamentary keratitisand reduction of lacrimal secretion, and the diagnosiscan be substantiated by Schirmer's test for lacrimalsecretion and the staining reaction with 1 per cent.aqueous Rose-Bengal solution.

In the present series, several ophthalmic featuresof interest were noted. The ocular symptoms rana course of remissions and exacerbations, butsymptoms were rarely completely absent in severecases of kerato-conjunctivitis sicca. The waxingand waning of the ophthalmic symptoms in thosepatients who also had rheumatoid arthritis oftenoccurred independently of any changes in the-arthritic condition. Furthermore, the severity ofthe ocular changes in such patients was not propor-tional to the severity of the arthritis, some of themost marked examples of kerato-conjunctivitissicca being encountered in patients with mild orquiescent rheumatoid arthritis.Although ocular discomfort, photophobia, and

mild impairment of vision are well recognized as

symptoms of kerato-conjunctivitis sicca, the moreserious risks to vision have not been fully appreci-ated. In the present series, corneal ulceration wasnoted in three cases. In two instances the ulcerswere of the small marginal type which healed withoutincident. The third patient, however, suffered frombilateral corneal ulceration, and was initially referredto hospital when perforation of a central cornealulcer necessitated enucleation of the eye. Onepatient also had a small pannus involving theinfero-lateral quadrant of the cornea.

Pathology.-Sjogren (1933) also described thehistological features in the lacrimal and salivaryglands and in the conjunctiva. In the lacrimalglands the changes consisted of round cell infiltra-tions, atrophy and destruction of the acini, andreplacement fibrosis in the later stages (Fig. 1).

Fig. 1.-Lacrimal gland showing atrophy of acini and extensive

round cell infiltration (x 80).

The lesions in the lacrimal glands were consideredto be mainly responsible for the dryness of the eyesand the subsequent epithelial changes, but primarydegenerative changes in the conjunctival epitheliumcould also contribute to the developed appearancesin kerato-conjunctivitis sicca. The histologicalchanges in the lacrimal glands are similar to those

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noted in the salivary glands, but one importantdifference is that while secretary ducts may beblocked in the salivary glands, this does not occurin the lacrimal glands (Morgan, 1954). This is inkeeping with the clinical observation that enlarge-ment of the salivary glands is not uncommon inSjogren's syndrome, but that enlargement of thelacrimal glands is never seen.

Associated Clinical Features.-The principal con-ditions, already recorded as associated with kerato-conjunctivitis sicca, and accepted as components ofSj6gren's syndrome, are shown in Table I.

TABLE I

CLINICAL FEATURES ALREADY REPORTED INASSOCIATION WITH KERATO-CONJUNCTIVITIS SICCA

Rheumatoid polyarthritisXerostoma and salivary gland enlargementLaryngo-pharyngo-rhinitis siccaBronchitis and pulmonary atelectasisAchlorhydriaVaginitisAlopeciaPeripheral vascular symptomsIchthyosisGeneralized lymphadenopathyFelty's syndromeAnaemiaRaised erythrocyte sedimentation rate

It is exceptional for a patient to exhibit most oreven many of these features, and usually only poly-arthritis and xerostoma are seen. Many of theassociated features can be attributed to a deficiencyof epithelial glandular secretions and consequentdryness of cutaneous and mucosal surfaces. Theco-existence of Sjogren's syndrome and Felty'ssyndrome, previously noted by Gurling (1953), isfurther evidence of the common identity of Sjogren'ssyndrome and rheumatoid disease.The clinical features in our eighteen cases of

severe or moderate kerato-conjunctivitis sicca areshown in Table II. Fourteen of the patients, ofwhom thirteen were women, had associated rheu-matoid polyarthritis. The four patients who had no

TABLE II

CLINICAL FEATURES IN EIGHTEEN CASES OFKERATO-CONJUNCTIVITIS SICCA

Rheumatoid polyarthritis .. 14Xerostoma .. 14Salivary gland enlargement .. 6Laryngo-pharyngo-rhinitis sicca..12Achloihydria (five cases examined) 5Bronchitis and pulmonary atelectasis 5Alopecia. 5Peripheral vascular symptoms . 4Felty's syndrome IPersistentleucopenia.Hepatic cirrhosisMarginal corneal ulceration..2Central corneal ulceration IPannus .... ITrophic nail changes.4Otitis externa 3

evidence of arthritis comprised one man and threewomen. In only two instances had ocular symptomsbeen noticed before the age of 40 years. The nailchanges and otitis externa noted in the presentseries are worthy of special mention.The nail lesions, seen in both fingers and toes,

consisted of dry, longitudinally fissured nails(onychorrhexis), stained brownish-yellow. Thosemost severely involved were rough and irregularlyheaped up, due to subungual hyperkeratosis, andsuch nails grew slowly, gradually separated andsloughed (onycholysis) and then further nail growthcommenced from the irregular nail bed. Similarchanges in the nails have been recorded in rheuma-toid arthritis (Ragan, 1954), but are only rarelyencountered, so that their frequency in the presentseries is especially noteworthy. The most severenail lesions occurred in a patient who also hadarthritis, alopecia totalis, and several other featuresof the syndrome. This patient received oralcortisone, 100 mg. daily, and normal nail growthwas restored (Fig. 2), but there was no improvementin the alopecia.

Fig. 2.-Close-up of left hand of a patient suffering from rheumatoidarthritis, who also exhibited many of the features of Sjogren's syn-drome, taken after 2 months' treatment with cortisone, 100 mg. daily.There is a clear line of demarcation between the former discoloured

nail and the apparently normal new nail formation.

The occurrence of external otitis in three patientsis probably a significant finding in a syndrome wheredeficiency of epithelial secretions is common.

Deficient secretion of cerumen and resultant impair-ment of normal lubrication of the outer ear passageswould predispose to dryness and irritation by dust.The appearances in the affected cases were those ofdry, sore ears with small, tender fissures in the

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external meatus and helix. The ear wax was dry andpowdery, but there was no suppuration or damageto the ear drum. The changes may be described asan otitis externa sicca, comparable to rhinitis sicca.

TreatmentGeneral treatment, by such measures as large

doses of vitamins, thyroid extract, and oestrogens,has not proved to be of any value. Local treat-ments have been directed towards relieving theocular symptoms. Gifford, Puntenney, and Bellows(1943) employed parasympathomimetic drugs suchas pilocarpine nitrate and prostigmine hydro-bromide, in an attempt to stimulate lacrimalsecretion, and reported success in the treatment ofearly cases. However, the results have not beenimpressive in more severe cases, and intestinalcramps limit the dosage of such drugs.

Saline and antibiotic eye drops are not usuallyhelpful because of rapid evaporation. In ourexperience, artificial tears, which do not evaporateso rapidly, have been of benefit in many mild cases.Methylcellulose drops have been used, and anothersuitable preparation, suggested by Gifford andothers (1943), is:

Gelatin .. .. .. 03 g.Chlorbutal .. . . 0-3 g.Locke's solution .. .. 30 ml.

One drop of these "tears" can be instilled into theconjunctiva, three to six times daily.Deep x-ray therapy has been used successfully in

reducing the size of the enlarged parotid glands, butno constant improvement has been noted aftertreatment of the lacrimal glands (Beetham, 1935).ACTH and cortisone have been administered

systemically with conflicting reports of their effectupon lacrimal secretion. In early cases somereturn of lacrimal secretion has been noted, but side-effects and complications, common to the pro-longed administration of high doses of these hor-mones, have limited the value of this form of treat-ment. In severe and chronic cases of kerato-conjunctivitis sicca the systemic administration ofsteroid hormones may relieve the ocular symptomseven though unsuccessful in increasing lacrimalsecretion.

Topical administration of cortisone and hydro-cortisone has, in our experience, proved to be a safeand useful means of treating mild and moderatecases of kerato-conjunctivitis sicca (Eadie andThompson, 1955). The eye drops may be preparedin strengths ranging from 0 5 to 2 per cent., and weemployed a saline suspension of cortisone acetatediluted in a buffered base. The drops were instilledthree to six times daily, according to the severity of

the symptoms, and in no instance has any undesir-able side-effect been noted as a result of this treat-ment. Hydrocortisone drops and cortisone eyeointment were used in the treatment ofsome patients,but did not appear to confer any extra benefit. Thelocal application of these hormones has been shownto be effective solely by virtue of their anti-inflam-matory action, as no increase in lacrimal secretionhas been noted during their use.The operation of sealing both lacrimal puncta, in

order to conserve diminished secretions, was intro-duced by Beetham (1935), and has proved to be aneffective surgical procedure. Gifford and others(1943) have reported favourably on its value, andwe have found it to be helpful in more severe casesof kerato-conjunctivitis sicca that were notadequately controlled by local cortisone therapy.This operation, conveniently done by thermalcauterization of the canaliculus, should not be per-formed in early or mild cases in whom a remissionmay be expected, as subsequent improvement inlacrimation would lead to epiphora. In some casesonly slight increase in lacrimal secretion, as measuredby Schirmer's filter-paper may occur after operation,but in spite of this there may be an appreciablesubjective and objective improvement in the eyes.In very severe cases of kerato-conjunctivitis siccaadjuvant therapy with cortisone eye drops or artificialtears may be necessary even after sealing of thelacrimal puncta.

SummaryThe clinical features of kerato-conjunctivitis sicca

have been described and its occurrence in patientssuffering from rheumatoid arthritis has been studied.It is considered to be the most common ocularcomplication of this disease, having been identifiedin 14-3 per cent. of a series of 210 patients. Mildcases of kerato-conjunctivitis sicca are especiallycommon, and the minor, recurrent, conjunctivalinflammation noted in many patients with rheuma-toid arthritis is conjunctivitis sicca, without corneallesions.The associated clinical findings have been des-

cribed in a series of eighteen patients who exhibitedthe features of Sjogren's syndrome. Changes in thenails and otitis externa sicca have been described.The hazard to vision resulting from corneal ulcera-tion has been emphasized. The treatment of theocular symptoms has been discussed.We gratefully acknowledge the invaluable advice and

co-operation of Dr. J. J. R. Duthie of the NorthernGeneral Hospital, Edinburgh, and of Professor G. 1.Scott of the Edinburgh Royal Infirmary. During theperiod when this work was undertaken the RheumaticUnit, Northern General Hospital, Edinburgh, was in

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receipt of grants from the Nuffield Foundation andMedical Research Council, and one of us (S.E.) receiveda grant from the W. H. Ross Foundation (Scotland) forthe Prevention of Blindness.The cortisone and ACTH used in the treatment of

several of these patients was supplied by the MedicalResearch Council, to whom we are indebted.

REFERENCESBeetham, W. P. (1935). Trans. Amer. ophthal. Soc., 33, 413.Coverdale, H. (1948). Brit. J. Ophthal., 32, 669.Duke-Elder, S. (1930). Ibid., 14, 61.Eadie, S., and Thompson, M. (1955). Ibid., 39, 90.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.Gurling, K. J. (1953). Annals of the Rheumatic Diseases, 12, 212.Henderson, J. W. (1950). Amer. J. Ophthal., 33, 197.Holm, S. (1949). Acta ophthal. (Kbh.), Suppl. 33.Littler, T. R. (1951). Annals of the Rheumatic Diseases, 10, 405.Morgan, W. S. (1954). New Engl. J. Med., 251, 5.Ragan, C. (1953). In "Comroe's Arthritis and Allied Conditions",

ed. J. L. Hollander, 5th ed., p. 156. Kimpton, London.Reader, S. R., Whyte, H. M., and Elmes, P. C. (1951). Annals of the

Rheumatic Diseases, 10, 288.Rosenberg, E. F. (1949). In "Comroe's Arthritis and Allied Con-

ditions", ed. J. L. Hollander, 4th ed., p. 173. Kimpton,London.

Sjogren, H. (1933). Acta ophthal. (Kbh.), Suppl. 2. (Trans. J. BruceHamilton, 1943. Australasian Medical Publishing Co.,Sydney.)

La k6rato-conjonctivite seche et l'arthriterhumatismale

RESUMEOn decrit les caracteres cliniques de la kerato-con-

onctivite seche et on etudie sa frequence parmi les

sujets atteints d'arthrite rhumatismale. On considerque c'est la complication oculaire la plus frequente,l'ayant identified dans 14,3% d'une serie de 210 malades.Des cas benins de kerato-conjonctivite seche sontparticulierement repandus et l'inflammation mineure etrecurrente des conjonctives, observee chez nombreuxrhumatisants est, en reality, une conjonctivite seche sanslesions de la cornee.On decrit les manifestations cliniques secondaires

chez 18 malades presentant des traits du syndrome deSjogren, en particulier les alterations des ongles etl'otite externe seche. On souligne le danger de l'ulcera-tion de la cornee et on discute le traitement oculaire.

La kerato-conjunctivitis sicca y la artritisreumatoideSUMARIO

Se describen los rasgos clinicos de la kerato-con-junctivitis sicca y se estudia su ocurrencia en sujetos conartritis reumatoide. Se consider que se trata aqui de lacomplicaci6n ocular la mas frecuente, habiendolaidentificado en el 14,3% de una serie de 210 enfermos.Casos benignos de kerato-conjunctivitis sicca se vencorrientemente y la inflamaci6n menor y recurrente delas conjuntivas observada en numerosos enfermos conartritis reumatoide represents realmente una con-juntivitis seca sin lesiones de la cornea.

Se describen las manifestaciones clinicas secundariasen 18 enfermos presentando rasgos del sindrome deSjogren, particularmente las alteraciones unguales y laotitis externa seca. Se subraya el peligro de la ulceracionde la cornea y se discute el tratamiento ocular.

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