THE VISUAL PROGNOSIS IN JUVENILE RHEUMATOID ARTHRITIS*
BY Harold F. Spalter, MD ALTHOUGH MIORE THAN 75 PERCENT OF THE CHILDREN WITH JUVENILE RHEUMATOID
arthritis (JRA) become disease-free with minimal or no joint limitations in adulthood, many of these children develop disabling and permanent visual loss. The current study of the visual prognosis in JRA was undertaken in an effort to identify and treat the ocular manifestations of this disease as early as possible. A prospective, rather than a retrospective, evaluation was performed to ascertain whether the historically high incidence of severe ocular complications might be reduced through early diagnosis and prompt treatment of the ocular inflammation. In the course of this study, 417 children with symptoms of arthritis were examined for a possible diagnosis of JRA by rheumatologists and the author. The diagnosis of JRA was made in 228 children. Evidence of ocular involvement was detected in 51 patients. Seventeen of these patients were excluded from the study because of previously treated ocular complications or early loss to followup. The remaining 34 children with ocular inflammation and the threat of visual loss form the key study group. HIISTORIC(AL REVIEW
Although the adult forms of rheumatism were identified and discussed
by Hippocrates in the fourth century B.C., it was not until the end of the nineteenth century that rheumatoid arthritis in children was identified as something other than septic, traumatic, or leutic arthritis. In 1896, the French physician Chauffard' published an article which recognized a syndrome of lymphadenopathy with rheumatoid arthritis in adults. The following year, George Still,2 in his classic study of the form of chronic joint disease in children which bears his name, acknowledged Chauffard's work and discussed a similar type of syndrome in children. His acknowledgement undoubtedly accounts for the persistence of the *Froim The Edward S. Harkness Instittite of Ophthalmology, 635 West 165 Street, New York, New York, 10032. Te Am. OPIITII Soc vol. LXXIII, 1975
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eponym Chauffard-Still's disease to describe in Europe what is more familiarly known in the English-speaking world as Still's disease. A severe, protracted polyarthritis with fever, splenomegaly, lymphadenopathy, and growth retardation, Still's disease is not a common form of JRA. Since the 1940's, numerous studies have documented the wide variety of signs and symptoms more characteristic of JRA than Still's original description.3-10 In 1966, Bywaters11 presented a detailed review of JRA. He concluded that Still's disease is a historical term and that international agreement upon criteria for diagnosing JRA was essential. These criteria have since been detailed in the monograph entitled "Criteria for the Classification of Juvenile Rheumatoid Arthritis," published in 1973 by the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association Section of the Arthritis Foundation. 12 In Still's original report no mention is made of ocular inflammation in the children studied. The first recorded cases of iridocyclitis and band keratopathy in Still's disease were published in the German literature between 1910 and 1922.13-18 The relationship between the uveal inflammation and the arthritis was not seriously examined, however. Of the four cases reported by Fuchs15 in 1918 with iridocvclitis and band keratopathy, three patients had joint disease. However, the cause was thought to be syphilis. In 1941, Blegvadt9 established the relationship between arthritis and iridocyclitis in childhood. Only 20 patients in his series of 896 cases of iridocyclitis were under 15 years of age. Remarkably, six of these children had a "distinct kind of childhood arthritis." Blegvad was also the first to record iridocyclitis and arthritis in childhood without concomitant band keratopathv. A decade later, Vesterdal and Surv,20 in a review of the literature to 1950, cited a total of 31 reported cases of iridocyclitis and band keratopathv in children with chronic joint disease. From a 30-year retrospective review of all case reports of all the ophthalmic departments in Copenhagen, these authors noted 34 additional cases of chronic iridocvclitis accompanying JRA. Subsequent clinical reports in the pediatric and ophthalmic literature have detailed the ocular problem, and finally, in 1967, a plea was made for routine slit lamp examination of patients with JRA. 21-30 DIAGN;osIs OF JRX
The patients in the currenit study fulfilled the criteria for the diagnlosis of JRA by the American Rheumatism Association. 12 Eleven authors
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S palter
representing centers of rheumatoid arthritis study collaborated for ten years to complete this important work. Their criteria were derived by "exercising clinical judgement and experience." In order to clarify the basis upon which the patients in the present study were identified as having JRA, a summary of the diagnostic guidelines follows: 1. Polyarthritis (two joints or more) or monoarticular arthritis of more than three months duration is sufficient for the diagnosis of JRA. 2. Polyarthritis present for more than six weeks but less than three months requires one or more of the following manifestations for a definite diagnosis of JRA; a. Skin Rash31 A characteristic evanescent salmon-pink macular rash. It may precede the arthritis and has been reported in 20 percent to 70 percent of patients. 32 b. Rheumatoid Factor33 Latex fixation and sensitized sheep cell serological tests are positive in 10 percent to 20 percent of patients. c. Iridocyclitis d. Cervical Vertebral Involvement Symptoms and signs involving the cervical spine are common, whereas involvement of the dorsal and lumbar spine is uncommon. 34 e. Pericarditis Occurs in 10 percent of children with JRA.35 It is usually associated with other systemic manifestations such as splenomegaly and lymphadenopathy. f. Tenosynovitis Involves the tendon sheaths, mainly in the wrists, hands, ankles, and feet. g. Intermittent Fever A persistent, intermittent fever with diurnal variation from 102 F to 106 F is suggestive of JRA. h. Morning Stiffness Often after periods of inactivity of sleep, there is difficulty in moving muscles.
The report of the Criteria Committee emphasizes the importance of excluding other childhood diseases resembling JRA. Table I lists the various initial differential diagnoses considered in the present study.
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MIODES OF EXPRESSION OF JRA
Over the past decade, JRA has come to be recognized as a broad disease spectrum. Three modes of expression of JRA can be distinguished.37 The implication of these groupings to the present study is of interest as each group is associated with a different incidence of ocular involvement (Table II). One mode of expression, systemic JRA, most resembles Still's disease. Characterized by severe polyarthritis, rash, fever, and a high incidence of systemic complications, this subgroup of JRA has a low incidence of iridocyclitis. At the other end of the clinical spectrum, the arthritis follows a benign course with minimal permanent joint impairment. Five or less joints (pauciarticular) are affected and the onset of the arthritis is often monoarticular. Although this mode of expression, pauciarticular JRA, has the lowest incidence of systemic manifestations, it has the highest incidence of iridocyclitis. The third disease pattern, polyarticular JRA, combines characteristics of the other two patterns. More than five joints (polyarticular) are involved with transient systemic manifestations and a moderate incidence of iridocyclitis. Systemic JRA comprises the smallest of the subgroups. In a pediatric review of 720 case records of JRA, 18 percent of the patients had systemic JRA.38 Two percent of those patients with systemic JRA had iridocyclitis. In the present study of 228 patients with JRA, 14 percent (32) of the patients had this form of the disease. None of these patients had iridocyclitis. The intermediate form, polyarticular JRA, occured in 22 percent of the patients in the previously referenced series. The incidence of iridocyclitis was 7 percent. In the present study, 38 percent (87) of the patients had this pattern of JRA, of which 8 percent (7) had iridocyclitis. The non-systemic form, pauciarticular JRA, is the most frequently encountered. In the report of 720 patients with JRA, 59 percent were categorized in this subgroup. The incidence of iridocyclitis was 8 percenit. In the present series, 48 percent (109) of the patients had this mild JRA pattern. Iridocyclitis was documented during the course of the present study in 25 percent (27) of these 109 patients.
FORMtULATION OFT111E (tIMFIINTSTUDY1)Y
The current study was designed to detect iridocyclitis as early as possible in the course of JRA. Early therapy to prevenit the late comiiplicaitionis
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Spalter TABLE
I: IDIFFERENTIAL DIAGNOSIS (CONSIDERED IN 228 JRA PATIENTS
Disease Rheumatic fever Allergic reactions Trauma Infectious diseases Ankvlosing spondylitis Reiter's disease Systemic lupus erythematosis Ulcerative colitis Dermatomvositis Sickle cell disease Sarcoidosis Acute leukemia
No. of Times Listed 53 35 27 20 12 11 8 7 5 4 2 1
of ocular inflammation - advanced band keratopathy, dense posterior synechaie, complicated cataract, chronic panuveitis - is a reasonable clinical goal. If the ophthalmologist is to have the opportunity to diagnose and treat the asymptomatic ocular inflammation before visual loss develops, early ophthalmologic examination of children who manifest arthritic symptoms is necessary. The ophthalmologist is necessarily dependent on the clinical acumen of the general practitioner, pediatrician, or rheumatologist to be allowed early ophthalmic access to patients with suspected or proven JRA. Few pediatric rheumatology referral centers are available, even though 4 percent to 7 percent of rheumatoid arthritis patients are children.3940 In 1972, only nine fellowships in pediatric rheumatology were offered in the United States.41 The lack of training in the rheumatic diseases of childhood may account, in part, for the lack of emphasis on routine ophthalmic evaluation in all suspected or proven cases of JRA. Slit lamp examiniations of suspected or proven JRA patients, referred by the pediatric rheumatologist, were performed by the author at weekly intervals. JRA patients and suspects were also examined in the regular eye clinic and in the private offices. The slit lamp finding of iridocyclitis was classified by the amount of aqueous cells and flare on a semiquantitative basis. Mild, moderate, or severe anterior chamber inflammation TABILE1I: INCIDENCE OF IRI DOCY(CLITIS IN StTB(;HioU'PS OF JRA
Systemilie JRA Polvarticular JRA Pauiciartictilar Total
No. of Patients 32 ( 14%) 87 ( 38%) 109 ( 48%) 228 (100%)
No. of Patienits With Iridocyclitis 0/32 7/87 ( 8%) 27/109 (25%) 34/228 (15%)
559
Juvenile Rheumtatoid Arthritis TABLE III: RELATION OF TIMEF, OF DETECTION OF O(CULAIR INFLAMMATION TO INITIAL JOINT SYimPTrOMiS (34 PATIENTS)
No. of Patients Ocular iniflammationi detected before joint symptoms Ocular iniflammationi detected concomitant with joint svmptoms Ocular inflammation detected following joint symptoms
Time Interval
5 (15%)
1 - 14 moniths
8 (23%)
3 days - 6 months
21 (62%)
6 months - 9 xears
was noted as one-plus, two-plus, and three-plus respectively. Vitreous cells were similarly classified. The current study spans the period January, 1963 through June, 1973. Two hundred and twenty-eight patients were diagnosed as having JRA, satisfying the criteria previously summarized. Of these 228 patients, 51 (22 percent) were found to have iridocyclitis. Seventeen of the 51 patients were excluded from the study. Ten of the 17 excluded patients were referred because of previously diagnosed and treated ocular complications of JRA. Exclusion of these patients enables the study to maintain its prospective nature. Seven patients were excluded because of their loss to followup shortly after entering the study. The remaining 34 patients comprise the kev study group.
ANALYSIS OF KEY sT'I)Y (;iiouP
There were 30 females and 4 males which is a ratio well in excess of the more frequently quoted female to male ratios of 1.5 to 1 and 2.3 to 1 in JRA. 10(P17),32(P2) The racial distribution of 26 white, 5 black, and 3 hispanic patients is consistent with the demographic data for the referral area and reveals no racial predilection in JRA or in the uveitis associated with JRA. The average age at the onset of arthritic symptoms was 4.1 years (range 1 to 12 years). The average age at detection of the ocular inflammation was 5.3 years (range 21/2 to 11 years). The average duration of ophthalmologic followup was 5.9 years (range 2 to 10 years). Depending on the time relationship between the first observation of ocular inflammation and the onset of the first rheumaitic symptomlls, the key study group is divided into three subgroups (Table III). These are (1) patients in whom ocular inflammation was detected before the onset of recognizable joint symptoms; (2) patients whose ocular inflamllmation was detected concomitant with the first joint symptoms; and
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S palter
(3) patients in whom ocular inflammation was first detected six months or more after the onset of joint symptoms. Five patients are included in subgroup I. Iridocyclitis was detected in these children between one and fourteen months prior to the onset of the joint symptoms. They represent the only cases, in the entire group of 228 patients having JRA, which were referred by the ophthalmologist to the pediatric rheumatologist, instead of vice versa. Ocular signs and symptoms brought the uveitis to the parents' attention in all of these children. Three children had conjunctival hyperemia, one had photophobia, and one had irregular pupils. The initial diagnosis in each child was nongranulomatous uveitis of unknown etiology. Only with the development of arthralgias was JRA definitely diagnosed. When first examined, three children had bilateral iridocyclitis and two children unilateral iridocyclitis. The degree of ocular inflammation was mild in three patients and moderate in two patients. The two patients with the more intense inflammation had early band keratopathy, fine corneal precipitates, and one-plus vitreous cells. Unilateral posterior synechiae were also present in one patient. Subgroup II comprises eight children whose ocular inflammation was detected at the time of their initial diagnostic evaluation for possible JRA. This first slit lamp examination was performed from three days to six months after the onset of joint symptoms. In each child, the examination was accomplished within a week of the first pediatric rheumatology evaluation. In no case was the presenting complaint referrable to the eye. Four patients had bilateral and four patients unilateral ocular inflammation when first examined. Of these 12 inflamed eyes, four had posterior synechiae and one had minimal band keratopathy associated with a moderate degree of anterior chamber reaction. Vitreous cells were visible in these five eyes. The seven affected eyes in the remaining five patients had mild ocular inflammation with fine posterior synechiae detectible in one eye and occasional vitreous cells visible in another. Subgroup III comprises the remaining 21 patients, in whom the ocular inflammation was first detected 6 months to 9 years (average 2.1 years) after the appearance of arthritis. The inflammation was bilateral in 6 patients and unilateral in 15 patients when detected. In 5 of the 21 patients, previously unrecognized inflammatory complications were present on the first slit lamp examination. Three of these five children had band keratopathy, three had extensive synechiae, and two had cataracts (one bilateral). None of these children had ocular complaints and none of the parents were aware that any ocular problem existed. All five children had a history of mild arthralgias from one to
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561
five years previously with no interim joint or systemic complaints until a flare-up of the arthritis prompted referral to our clinic. The original medical evaluation for the arthralgias, performed elsewhere, did not include an ocular examination. The average delay between the onset of the original joint symptoms and the first slit lamp examination was 3.8 years. The four fellow eyes of the four severely diseased eyes in this group were free of inflammation at the time of the patients' entry into the study. Each of the fellow eyes developed ocular inflammation of mild to moderate degree, 15 months to 4 years after the initial slit lamp examination. In the remaining 16 patients in subgroup III, the initial slit lamp evaluation, performed as a part of the diagnostic workup for JRA, was negative. The ocular inflammation was diagnosed between six months and nine years after this negative examination. The longest interval between the immediately preceding negative slit lamp examination and the next subsequent examination which first detected the uveitis was seven months. In 10 of the 16 children, the arthritis was in remission when the uveitis was first detected. In three children, the arthritis had been completely inactive from four to seven years and the JRA was considered cured when the ocular inflammation was first diagnosed. Eight of these 16 children were routinely examined more frequently by the author than by the rheumatologist, even before the onset of the uveitis. In all of these 16 children, the ocular inflammation when detected was asymptomatic. The inflammation was mild in ten children and moderate in six children. None of the eyes had more than two-plus cells or twoplus flare, nor more than one-plus cells in the vitreous, when the iridocyclitis was first diagnosed. No band keratopathy was encountered at the time the ocular inflammation was first diagnosed. In the total group of 34 patients, ocular inflammatioin was bilateral in 13 patients and unilateral in 21 patients when first diagnosed (Table IV). In 13 of the 21 patients, the unilateral inflammation became bilateral in eight months to four years. Recurrent episodes of iridocyclitis were recorded in 19 patients and chronic iridocvclitis was preseInt in 8 patients. A single episode of ocular inflammation was observed in 7 patients, without recurrence, throughouit an average followup period of 4.4 xears (ranige 3 to 6 years). When therapy for ocular inflammiiatioin was started, slit lamiip examiniation was performed weekly unitil the anterior chamber was free of cells and flare. If an inflammation-free state was achieved, the friequency of slit lamp examinationi was reduced to bi-%veekly for three moniths, then
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Spalter TABLE IV: CHARACTERISTICS OF OCULAR INFLAMMATION (34 JRA PATIENTS)
Unilateral Bilateral Initially bilateral Initially unilateral Initerval from unilateral to bilateral Symptomatic Asymptomatic Single episode Recurrent episodes
Chronic iniflammation
No. of Patients 8 26 13 13 (8 months - 41/2 years) 5 29 8 19 8
monthly for three months. If the anterior chamber remained clear, routine, periodic slit lamp examinations were resumed at three month to six mointh intervals. Non-chronic ocular inflammation characterized by single or recurrent episodes of mild iridocyclitis responded satisfactorily to topical steroids and mvdriatic drops. Patients with more severe, recurrent iridocyclitis or chronic iridocyclitis required systemic steroid therapy. A large dosage was used to control the inflammation as quickly as possible. The total daily dosage was doubled but was given only on alternate days when a clinical response was obtained. With continued favorable response, the steroid dosage was reduced over a six to ten week period. If prolonged use of systemic steroids was necessary, the total weekly amount of steroid was (livided into thirds and administered on three consecutive days of each week with a four day lapse. During high dosage steroid therapy, recognition of systemic complications was the responsibility of the pediatric rheumatologist. Recognition of steroid effectiveness was the responsibility of the ophthalmologist. Frequenit communlicationi took place between both clinicians. The author was therefore allowed a broad freedom of action with prompt anid aggressive therapeutic measures, that is, the use of high dosage systemic steroids. Immediate availability of consultation and mutual support among the concerned specialists is necessary to preserve vision in severe ocular inflaimimationi in JRA. Chronic glaucoma, a documented complication of systemic steroid therapy, occured in two children requiring long term steroid therapy.42 In none of the children with chroinic uveitis requiring systemic steroid therapy, could the development of cataracts be catagorized as a steroid coi-nplication. 43
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PREDICTING OCULAR INFLAMMATION
In general, patients with JRA who develop ocular inflammation tend to have mild arthritic disease with minimal systemic manifestations. This observation has no predictive value for the individual patient or for the severity of the uveitis. At present, it is impossible to foresee which child will develop ocular inflammation or at what point in the course of the arthritis this will occur. No clinical factor - patient age; duration of the arthritis; the presence of active joint inflammation, rheumatoid rash, or intermittent fever; or the use of systemic anti-inflammatory agents for the arthritis, such as acetylsalicylic acid or steroids singly or in combination - demonstrates a positive correlation with the development of the ocular inflammation. The laboratory tests for erythrocyte sedimentation rate (ESR) and rheumatoid factor commonly employed have not proven helpful in identifying the ocular risk group. New laboratory studies to improve the definition of the antibody mechanisms involved in JRA may prove to be reliable, however. The test most frequently performed on JRA patients is the ESR. Although a useful indicator of arthritic activity, the ESR is of no value in predicting the onset or evaluating the activity of ocular inflammation. ESR levels were recorded in all 34 patients in the key study group, during episodes of active arthritis, both with and without concurrent ocular inflammation, and during episodes of ocular inflammation with and without concurrent arthritis activity. Abnormal values had a positive correlation only with arthritic activity. A second laboratory test is the latex fixation variant of this sensitized sheep cell agglutination, Rose-Waaler, test. This technique is used to identify the rheumatoid factor in the serum. In JRA, the incidence of positive results of this test is low (10 percent to 20 percent), whereas in adult rheumatoid arthritis it is high (50 percent to 85 percent).33 In the course of the present study, latex fixation tests were performed in 32 of the 34 patients. Results were negative in 29 patients anid positive in three. Two of the sero-negative children became sero-positive when they reached their teens. The role of serum immunoglobulins and serum complemeint is being studied in JRA.4446 The more active and chronic JRA is, the more illmmunoglobulin factors are found and the more serum complement depression is detected. In the key study group, ten patients were tested for quantitative serum levels of immunoglobulins and for the serumil complement activity. The ten patients had mild arthritis. Seven patients had mild to moderate recurrent uveitis aind three patieints had
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chronic uveitis, resistant to therapy. None of the patients had abnormal serum immunoglobulin values or abnormal serum complement depression.
Epstein and associates47 have investigated the presence of antibodies to double-stranded ribonucleic acids (RNA) in JRA patients with uveitis. These investigators found that less than half their patients with uveitis but no specific concomitant systemic disease had positive anti-RNA antibodies. But they observed significantly positive titers in all five children in their study group who had JRA and uveitis. Antinuclear antibodies (ANA) have been reported in 22 percent of JRA patients.48 At the 1972 meeting of the American Rheumatism Association, a verbal report recorded a positive ANA test in 75 percent of a series of JRA patients with iridocyclitis.49 Of the 11 patients with JRA in the key study group of the present series tested for ANA, 6 were positive. Too few tests of JRA patients without ocular inflammation have been performed to permit any conclusions as to the sensitivity of ANA to the presence of ocular inflammation. This laboratory test will continue to be investigated. As knowledge of immunopathologic mechanisms increases, the enigma of collagen-like rheumatoid disease may be resolved. There is an evident need for a laboratory test with predictive value to alert the rheumatologist to those JRA children who will develop carditis, crippling arthritis, or iridocyclitis. For the ophthalmologist seeking to reduce the ocular morbidity of JRA, such a test would reduce the time required for detection of eye signs. VISUAL OUTCOME
Visual results in JRA have heretofore been uniformly poor. A retrospective study of 162 cases of JRA, diagnosed in Copenhagen between 1920 and 1949, was published in 1950.20 Of 61 eyes with iridocyclitis, 31 eyes had band keratopathy and 30 eyes had cataracts. Phthisis bulbi was reported in 5 eyes. Even with the advent of steroid therapy, the visual prognosis in patients with ocular manifestations of JRA is still usually poor. In 485 cases of JRA, studied between 1951 and 1961, uveal inflammation was detected in 27 patients.50 Fully a third of these children were blind, five in one eye and four in both eyes. In contrast, fewer than 30 percent of the total study group experienced long-term joint disability. Another report on ocular findings based on a seven-year reveiw of 183 cases of JRA at the Juvenile Rheumatism Unit of the Canadian Red Cross
5065 Juvenile Rheumatoid Arthritis Memorial Hospital in Taplow, England, noted that seven of ten children with iridocyclitis had serious complications of ophthalmic inflammation when they were first examined ophthalmoscopically.25 Another ocular report, published in 1969, cited significant eye damage in six of eight patients with JRA and iridocyclitis followed for four years. 51 In a more recent detailed review of 124 cases of JRA, 10 of 14 patients with iridocyclitis developed some degree of permanent visual loss.37 The first book devoted to JRA appeared in 1962. 10 This work summarized 110 patients stjsdied and treated at the Presbyterian Hospital in New York City between 1924 and 1959. Total blindness was present in two of nine children with ocular involvement. The authors concluded that immediate ophthalmological consultation should be obtained "at the first sign of uveal tract inflammation." The current study was stimulated by this recommendation. Uveal tract involvement in patients with JRA is asymptomatic, however. These children almost never experience ocular pain or photophobia, and ciliary flush is rarely detected. Visible signs such as band keratopathy, posterior synechiae, and cataract represent already established complications of inflammation. Ophthalmological consultation is therefore required before the first sign of uveal inflammation. To reduce the incidence of blindness of JRA, ophthalmological examination should commence in anticipation of ocular inflammation. The visual prognosis of patients in the current prospective study is significantly better than that cited in the literature. Thirty-four of the 228 children with JRA, or 15 percent, had ocular inflammation. Five children had previously unrecognized visual loss at entry into the current study. Twenty-five of 29 patients with normal vision on entry into the study have retained normal vision for an average followup period of 5.7 years. Since the presence or absence of signs of ocular inflammation, at the time of the first examination, may affect the visual outcome, these patients have been divided into two groups (Table V). These are (a) patients with evidence of ocular inflammation on the first slit lamp examination - this group includes all patients in subgroups I and II of the earlier analysis and the five patients with previously undetected ocular complications from subgroup III: (b) patients who developed ocular inflammation after an initially negative slit lamp examination - this group includes the remaining patients in subgroup III. Of the 18 children in group A, 13 had ocular inflammation prior (5 children) to or concurrent (8 children) with initial joint complaints. In the other five children, severe ocular inflammation was detected on the
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Spalter TABLE V: VISUAL OUTCOME (34 PATIENTS; 68 EYES)
Group A: initial slit lamp exam positive for signs of ocular inflammation (18 patients; 36 eyes) Group B: initial slit lamp exam negative for signs of ocular inflammation (16 patients; 32 eyes) Total
No. of eyes with normal visual acuity on initial examination
No. of eyes with ocular inflammation
during study
No. of eyes with normal visual acuity at conclusion of study
30
34
29
32
26 60/68
29 58/68
62/68
first slit lamp examination - an examination not performed until one to five years after the initial- joint symptoms were reported. When first examined, six eyes of five patients in group A had visual loss, ranging from 20/70 to light perception. Visual acuity in one patient improved after bilateral cataract surgery from light perception and 20/300 to 20/200 and 20/70. The four remaining eyes with initially defective vision remained unimproved at the conclusion of the study. Despite intensive management with systemic steroids, these eyes were considered irreversibly damaged because of secondary glaucoma and early phthisis. Twenty-eight of the remaining 30 eyes - all with initial normal visual acuity - in group A had documented episodes of uveal inflammation during the study period. Normal visual acuity was retained in 27 of these 28 eyes. Visual acuity in one eye deteriorated to 20/400. Visual failure in this eye was due to cystoid macular edema associated with chronic iridocyclitis, refractory to steroid therapy. Two of the 36 eyes in group A, had no signs of ocular inflammation during the study period. None of the 32 eyes in the 16 patients in group B had slit lamp signs of current or antecedent ocular inflammation when first examined. Normal visual acuity was recorded in all of the 32 eyes, at the time of entry into the study. Twenty-six of these 32 eyes subsequently developed ocular inflammation. In 23 of these 26 eyes, the visual outcome had been excellent. Three eyes were visual failures. One eye, in a child temporarily lost to followup, developed a dense cataract and glaucoma. Only light perception was present in the eye upon reentry into the study. The other two eyes developed irreversible visual loss because of steroid-induced glaucoma. In summary (Table VI), normal visual acuity was present in 62 of 68 eyes in the 34 patients on entry into the current study. The six eyes
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TABLE VI: VISUAL OUTCOME OF EYES AT RISK OF VISUAL LOSS
No. of Eyes 62
Normal vision at entry into study Normal vision at entry into study with no ocular 8 inflammation during study Normal vision at entry into study with ocular inflammation during study (eyes at risk 54 of visual loss) Eyes at risk of visual loss with retained normal 50/54 (93%) vision at conclusion of study
with previously unrecognized inflammatory damage were considered unavoidable visual failures in the context of this prospective study. No slit lamp signs of inflammation were present in 8 of the 62 eyes with initial normal visual acuity, throughout the duration of the study. Therefore, a total of 54 eyes with initial normal visual acuity and documented ocular inflammation of JRA were at risk of visual loss. Fifty of the 54 eyes, or 93 percent, have retained normal vision over a followup period ranging from two to nine years. Only four of the at risk eyes, or 7 percent, have become functionally blind. CONCLUSIONS
Two hundred twenty-eight patients with juvenile rheumatoid arthritis were examined for ocular inflammation between 1963 and 1973. Slit lamp examinations of these patients detected 34 children with uveal inflammation. In 60 of these 68 eyes, active inflammation was observed and treated during the course of this study. Six of these eyes evidenced previously unrecognized visual damage; 54 had normal visual acuity when they were first examined, but were at risk of visual loss from the complications frequently associated with ocular manifestations of JRA. Only four of these eyes developed irreversible visual loss during the course of this
study. The improvement in the visual prognosis of JRA which the current study demonstrates, in contrast to the poor visual results cited in the ophthalmic and pediatric literature, is a reasonable clinical goal. Its achievement, however, depends upon the active participation of an ophthalmologist, both in the initial workup and during the long-term followup of all children with a possible or proven diagnosis of JRA. Since ocular inflammation is more likely to occur in children with the mildest expression of the arthritis, and since these children tend to require less medical surveillance, the risk of undetected ocular inflammation is
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particularly high in this group of patients. Until a laboratory test predicting the ocular manifestations of JRA is developed, frequent slit lamp examination of these children will be necessary. These examinations should be continued after the arthritis becomes clinically inactive. How long these examinations should be continued is a question that remains unanswered. ACKNOWLEDGEMENTS
I would like to thank Dr. Jerry C. Jacobs, of Babies Hospital, at ColumbiaPresbyterian Medical Center for his professional guidance during this study. Mrs. Josie S. Spalter rendered invaluable editorial aid. I would also like to acknowledge the technical assistance of Mrs. Valerie Ramsdell and Mr. Scott Wong.
REFERENCES
1. Chauffard A, Ramond F: Des adenopathies dans le rheumatisme chronique infectieux. Rev de Med, 1896, p 345. 2. Still GF: On a form of chronic joint disease in children. Med Chir Trans 80:47, 1897. 3. Edstrom G: Rheumatoid arthritis in children: A clinical study. Acta Paediatr Scand 34:334, 1947. 4. Pickard NS: Rheumatoid arthritis in children: Clinical study. Arch Intern Med 80:771, 1947. 5. Coss JA, Jr, Boots RH: Juvenile rheumatoid arthritis: A study of 56 cases with a note on skeletal changes. J Pediatr 29:143, 1948. 6. Middlemiss JH: Juvenile rheumatoid arthritis (Still's disease). Proc Roy Soc Med 44:805, 1951. 7. Sury B: Rheumatoid arthritis in children: A clinical study, Thesis. Copenhagen, Munksgaard, 1952. 8. Edstrom G, Gredda PO: Clinical and prognosis of rheumatoid arthritis in children. Acta Rheum Scand 3:129, 1957. 9. Ansell BM, Bywaters EGL: Prognosis in Still's disease. Bull Rheum Dis 9:189, 1959. 10. Groekest AW, Snyder Al, Schlaeger R: Juvenile Rheumatoid Arthritis. Boston, Little Brown and Co, 1962. 11. Bywaters EGL: Categorization in medicine: A survey of Still's disease. Ann Rheum Dis 26:185, 1967. 12. Brewer EJ, Jr, et al: Criteria for the classification of juvenile rheumatoid arthritis. Bull Rheum Dis 23:721, 1973. 13. Ohm J: Bandformige Hornhauttrubung bei einem neunjahrigen Madchen und ihre Behandlung mit subconjunctivalen Jodaliumeinspirtzungen. Klin Monatsbl Augenheilk 48:243, 1910. 14. Unthoff W: Ein Fall von typischer bandforminger Trubung der Hornhaut auf beiden Augen bei einem 8-jahrigen Madchen mit teilweiser erhaltener Sehkraft und hinteren Synechien: anatomische Untersuchung. Klin Monatsbl Augenheilk 60:11, 1918. 15. Fuchs E: Uber grutelformige Hornhauttrubung. Klin MonatsblAugenheilk 61:10, 1918. 16. Behman A: Zwei Falle von bandformiger Hornhauttrubung an sehenden Augen von jugendlichen Patieten. Klin Monatsbl Augenheilk 66:450, 1921.
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17. Waubke H: Zur Kenntnis der bandformigen Hornhauttrubung in seheden. Augen. Klin Monatsbl Augenheilk 69:78, 1922. 18. Hauptvogel J: Uber bandformige Hornhauttrubung. Klin Monatsbl Augenheilk 69:763, 1922. 19. Blegvad 0: Iridocyclitis and disease of the joints in children. Acta Ophthalmol (Kbh) 19:219, 1941. 20. Vesterdal E, Sury B: Iridocyclitis and band-shaped corneal opacity in juvenile rheumatoid arthritis. Acta Ophthalmol Kbh 28:321, 1950. 21. Franceschetti A, Blum JD, Bamatter F: Diagnostic value of ocular symptoms in juvenile chronic polyarthritis (Still's Disease). Trans Ophthalmol Soc UK 71:17, 1951. 22. Davis MD: Endogenous uveitis in children: Associated band-shaped keratopathy and rheumatoid arthritis. Arch Ophthalmol 50:443, 1953. 23. Francois J, Haustrate L: Les Manifestations oculares de la maladie de Still. Bull Soc Belge Ophthalmol 107:383, 1954. 24. Hogan MJ, Kimura SJ, Thygeson P: Uveitis in association with rheumatism. Arch Ophthalmol 57:400, 1957. 25. Smiley WK, May E, Bywaters EGL: Ocular presentations of Still's disease and their treatment. Ann Rheum Dis 16:371, 1957. 26. Dubowitz V: Ocular involvement in juvenile rheumatoid arthritis (Still's Disease). Clin Pediatr 3:274, 1964. 27. Haut J: Manifestations oculaires de la maladie de Still. Gaz Med Fr 72:633, 1965. 28. Stewart AJ, Hill RH: Ocular manifestations in juvenile rheumatoid arthritis. Canad J Ophthalmol 2:58, 1967. 29. Kimura SJ, et al: Uveitis and joint diseases: Clinical findings in 191 cases. Arch Ophthalmol 72:309, 1967. 30. Calabro JJ, Marchesano JM: Juvenile rheumatoid arthritis. N Engl J Med 277:746, 1967. 31. Calabro JJ, Marchesano JM: Rash with juvenile rheumatoid arthritis. J Pediatr 72:611, 1968. 32. Brewer EJJR: Juvenile Rheumatoid Arthritis. Philadelphia, WB Saunders and Co, 1970. 33. Bywaters EGL, Carter ME, Scott FET: Comparison of differential agglutination titre in juvenile and adult rheumatoid arthritis. Ann Rheum Dis 18:233, 1959. 34. Lorenz K, Berger G: Roentgen diagnosis of juvenile rheumatoid arthritis. Radiol Diagn (Berl) 10:647, 1969. 35. Lietman PS, Bywaters EGL: Pericarditis in juvenile rheumatoid arthritis. Pediatrics 32:855, 1963. 36. Calabro JJ, Marchesano JM: Fever associated with juvenile rheumatoid arthritis. N Eng J Med 276:11, 1967. 37. Schaller J, Wedgwood RJ: Juvenile rheumatoid arthritis: A review. Pediatrics 50:940, 1972. 38. Kolle G: Klinisches Bild und Verlauf Der juvenilen rheumatoiden arthritis und des Still syndromes. Monatsschr Kinderheilkd 118:488, 1970. 39. Barkin RE: The clinical course of juvenile rheumatoid arthritis. Bull Rheum Dis 3:37, 1952. 40. Edstrom G: Rheumatoid arthritis and Still's disease in children: A survey of 161 cases. Arthritis Rheum 1:497, 1958. 41. Residencies and fellowships. J Pediatr 81:639, 1972. 42. Covell L: Glaucoma induced by systemic steroid therapy. Am J Ophthalmoi 45:108, 1959. 43. Bihari M, Grossman BJ: Posterior subcapsular cataracts related to long-term corticosteroid treatment in children. Am J Dis Child 116:604, 1968. 44. Schur PH, Austen KF: Complement in the rheumatic diseases. Bull Rheum Dis 22:666, 1972.
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45. Stage DE, Mannik M: Rheumatoid factors in rheumatoid arthritis. Bull Rheum Dis 23:720, 1973. 46. Bianco NE, et al: Immunologic studies of juvenile rheumatoid arthritis. Arthritis Rheum 14:685, 1971. 47. Epstein WV, Tan M, Easterbrook M: Serum antibody to double-stranded RNA and DNA in patients with idiopathic and secondary uveitis. N Eng J Med 285:000, 1971. 48. Kornreich HK, Drexler E, Hanson V: Antinuclear factors in childhood rheumatoid diseases. J Pediatr 69:1039, 1966. 49. Schaller J, et al: Antinuclear antibodies (ANA) in patients with iridocyclitis and juvenile rheumatoid arthritis. Read before the American Rheumatism Association, Pittsburgh, Pa., Dec 8-9, 1972. 50. Laaksonen AL: Prognostic study of juvenile rheumatoid arthritis: Analysis of 544 cases. Acta Paediatr Scand [SuppI] 166, 168, 1966. 51. Schaller J, Kupfer C, Wedgwood RJ: Iridocycitis in juvenile rheumatoid arthritis. Pediatrics 44:92, 1969.
BY Harold F. Spalter, MD ALTHOUGH MIORE THAN 75 PERCENT OF THE CHILDREN WITH JUVENILE RHEUMATOID
arthritis (JRA) become disease-free with minimal or no joint limitations in adulthood, many of these children develop disabling and permanent visual loss. The current study of the visual prognosis in JRA was undertaken in an effort to identify and treat the ocular manifestations of this disease as early as possible. A prospective, rather than a retrospective, evaluation was performed to ascertain whether the historically high incidence of severe ocular complications might be reduced through early diagnosis and prompt treatment of the ocular inflammation. In the course of this study, 417 children with symptoms of arthritis were examined for a possible diagnosis of JRA by rheumatologists and the author. The diagnosis of JRA was made in 228 children. Evidence of ocular involvement was detected in 51 patients. Seventeen of these patients were excluded from the study because of previously treated ocular complications or early loss to followup. The remaining 34 children with ocular inflammation and the threat of visual loss form the key study group. HIISTORIC(AL REVIEW
Although the adult forms of rheumatism were identified and discussed
by Hippocrates in the fourth century B.C., it was not until the end of the nineteenth century that rheumatoid arthritis in children was identified as something other than septic, traumatic, or leutic arthritis. In 1896, the French physician Chauffard' published an article which recognized a syndrome of lymphadenopathy with rheumatoid arthritis in adults. The following year, George Still,2 in his classic study of the form of chronic joint disease in children which bears his name, acknowledged Chauffard's work and discussed a similar type of syndrome in children. His acknowledgement undoubtedly accounts for the persistence of the *Froim The Edward S. Harkness Instittite of Ophthalmology, 635 West 165 Street, New York, New York, 10032. Te Am. OPIITII Soc vol. LXXIII, 1975
Juvenile Rheumatoid Arthritis
555
eponym Chauffard-Still's disease to describe in Europe what is more familiarly known in the English-speaking world as Still's disease. A severe, protracted polyarthritis with fever, splenomegaly, lymphadenopathy, and growth retardation, Still's disease is not a common form of JRA. Since the 1940's, numerous studies have documented the wide variety of signs and symptoms more characteristic of JRA than Still's original description.3-10 In 1966, Bywaters11 presented a detailed review of JRA. He concluded that Still's disease is a historical term and that international agreement upon criteria for diagnosing JRA was essential. These criteria have since been detailed in the monograph entitled "Criteria for the Classification of Juvenile Rheumatoid Arthritis," published in 1973 by the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association Section of the Arthritis Foundation. 12 In Still's original report no mention is made of ocular inflammation in the children studied. The first recorded cases of iridocyclitis and band keratopathy in Still's disease were published in the German literature between 1910 and 1922.13-18 The relationship between the uveal inflammation and the arthritis was not seriously examined, however. Of the four cases reported by Fuchs15 in 1918 with iridocvclitis and band keratopathy, three patients had joint disease. However, the cause was thought to be syphilis. In 1941, Blegvadt9 established the relationship between arthritis and iridocyclitis in childhood. Only 20 patients in his series of 896 cases of iridocyclitis were under 15 years of age. Remarkably, six of these children had a "distinct kind of childhood arthritis." Blegvad was also the first to record iridocyclitis and arthritis in childhood without concomitant band keratopathv. A decade later, Vesterdal and Surv,20 in a review of the literature to 1950, cited a total of 31 reported cases of iridocyclitis and band keratopathv in children with chronic joint disease. From a 30-year retrospective review of all case reports of all the ophthalmic departments in Copenhagen, these authors noted 34 additional cases of chronic iridocvclitis accompanying JRA. Subsequent clinical reports in the pediatric and ophthalmic literature have detailed the ocular problem, and finally, in 1967, a plea was made for routine slit lamp examination of patients with JRA. 21-30 DIAGN;osIs OF JRX
The patients in the currenit study fulfilled the criteria for the diagnlosis of JRA by the American Rheumatism Association. 12 Eleven authors
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S palter
representing centers of rheumatoid arthritis study collaborated for ten years to complete this important work. Their criteria were derived by "exercising clinical judgement and experience." In order to clarify the basis upon which the patients in the present study were identified as having JRA, a summary of the diagnostic guidelines follows: 1. Polyarthritis (two joints or more) or monoarticular arthritis of more than three months duration is sufficient for the diagnosis of JRA. 2. Polyarthritis present for more than six weeks but less than three months requires one or more of the following manifestations for a definite diagnosis of JRA; a. Skin Rash31 A characteristic evanescent salmon-pink macular rash. It may precede the arthritis and has been reported in 20 percent to 70 percent of patients. 32 b. Rheumatoid Factor33 Latex fixation and sensitized sheep cell serological tests are positive in 10 percent to 20 percent of patients. c. Iridocyclitis d. Cervical Vertebral Involvement Symptoms and signs involving the cervical spine are common, whereas involvement of the dorsal and lumbar spine is uncommon. 34 e. Pericarditis Occurs in 10 percent of children with JRA.35 It is usually associated with other systemic manifestations such as splenomegaly and lymphadenopathy. f. Tenosynovitis Involves the tendon sheaths, mainly in the wrists, hands, ankles, and feet. g. Intermittent Fever A persistent, intermittent fever with diurnal variation from 102 F to 106 F is suggestive of JRA. h. Morning Stiffness Often after periods of inactivity of sleep, there is difficulty in moving muscles.
The report of the Criteria Committee emphasizes the importance of excluding other childhood diseases resembling JRA. Table I lists the various initial differential diagnoses considered in the present study.
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557
MIODES OF EXPRESSION OF JRA
Over the past decade, JRA has come to be recognized as a broad disease spectrum. Three modes of expression of JRA can be distinguished.37 The implication of these groupings to the present study is of interest as each group is associated with a different incidence of ocular involvement (Table II). One mode of expression, systemic JRA, most resembles Still's disease. Characterized by severe polyarthritis, rash, fever, and a high incidence of systemic complications, this subgroup of JRA has a low incidence of iridocyclitis. At the other end of the clinical spectrum, the arthritis follows a benign course with minimal permanent joint impairment. Five or less joints (pauciarticular) are affected and the onset of the arthritis is often monoarticular. Although this mode of expression, pauciarticular JRA, has the lowest incidence of systemic manifestations, it has the highest incidence of iridocyclitis. The third disease pattern, polyarticular JRA, combines characteristics of the other two patterns. More than five joints (polyarticular) are involved with transient systemic manifestations and a moderate incidence of iridocyclitis. Systemic JRA comprises the smallest of the subgroups. In a pediatric review of 720 case records of JRA, 18 percent of the patients had systemic JRA.38 Two percent of those patients with systemic JRA had iridocyclitis. In the present study of 228 patients with JRA, 14 percent (32) of the patients had this form of the disease. None of these patients had iridocyclitis. The intermediate form, polyarticular JRA, occured in 22 percent of the patients in the previously referenced series. The incidence of iridocyclitis was 7 percent. In the present study, 38 percent (87) of the patients had this pattern of JRA, of which 8 percent (7) had iridocyclitis. The non-systemic form, pauciarticular JRA, is the most frequently encountered. In the report of 720 patients with JRA, 59 percent were categorized in this subgroup. The incidence of iridocyclitis was 8 percenit. In the present series, 48 percent (109) of the patients had this mild JRA pattern. Iridocyclitis was documented during the course of the present study in 25 percent (27) of these 109 patients.
FORMtULATION OFT111E (tIMFIINTSTUDY1)Y
The current study was designed to detect iridocyclitis as early as possible in the course of JRA. Early therapy to prevenit the late comiiplicaitionis
558
Spalter TABLE
I: IDIFFERENTIAL DIAGNOSIS (CONSIDERED IN 228 JRA PATIENTS
Disease Rheumatic fever Allergic reactions Trauma Infectious diseases Ankvlosing spondylitis Reiter's disease Systemic lupus erythematosis Ulcerative colitis Dermatomvositis Sickle cell disease Sarcoidosis Acute leukemia
No. of Times Listed 53 35 27 20 12 11 8 7 5 4 2 1
of ocular inflammation - advanced band keratopathy, dense posterior synechaie, complicated cataract, chronic panuveitis - is a reasonable clinical goal. If the ophthalmologist is to have the opportunity to diagnose and treat the asymptomatic ocular inflammation before visual loss develops, early ophthalmologic examination of children who manifest arthritic symptoms is necessary. The ophthalmologist is necessarily dependent on the clinical acumen of the general practitioner, pediatrician, or rheumatologist to be allowed early ophthalmic access to patients with suspected or proven JRA. Few pediatric rheumatology referral centers are available, even though 4 percent to 7 percent of rheumatoid arthritis patients are children.3940 In 1972, only nine fellowships in pediatric rheumatology were offered in the United States.41 The lack of training in the rheumatic diseases of childhood may account, in part, for the lack of emphasis on routine ophthalmic evaluation in all suspected or proven cases of JRA. Slit lamp examiniations of suspected or proven JRA patients, referred by the pediatric rheumatologist, were performed by the author at weekly intervals. JRA patients and suspects were also examined in the regular eye clinic and in the private offices. The slit lamp finding of iridocyclitis was classified by the amount of aqueous cells and flare on a semiquantitative basis. Mild, moderate, or severe anterior chamber inflammation TABILE1I: INCIDENCE OF IRI DOCY(CLITIS IN StTB(;HioU'PS OF JRA
Systemilie JRA Polvarticular JRA Pauiciartictilar Total
No. of Patients 32 ( 14%) 87 ( 38%) 109 ( 48%) 228 (100%)
No. of Patienits With Iridocyclitis 0/32 7/87 ( 8%) 27/109 (25%) 34/228 (15%)
559
Juvenile Rheumtatoid Arthritis TABLE III: RELATION OF TIMEF, OF DETECTION OF O(CULAIR INFLAMMATION TO INITIAL JOINT SYimPTrOMiS (34 PATIENTS)
No. of Patients Ocular iniflammationi detected before joint symptoms Ocular iniflammationi detected concomitant with joint svmptoms Ocular inflammation detected following joint symptoms
Time Interval
5 (15%)
1 - 14 moniths
8 (23%)
3 days - 6 months
21 (62%)
6 months - 9 xears
was noted as one-plus, two-plus, and three-plus respectively. Vitreous cells were similarly classified. The current study spans the period January, 1963 through June, 1973. Two hundred and twenty-eight patients were diagnosed as having JRA, satisfying the criteria previously summarized. Of these 228 patients, 51 (22 percent) were found to have iridocyclitis. Seventeen of the 51 patients were excluded from the study. Ten of the 17 excluded patients were referred because of previously diagnosed and treated ocular complications of JRA. Exclusion of these patients enables the study to maintain its prospective nature. Seven patients were excluded because of their loss to followup shortly after entering the study. The remaining 34 patients comprise the kev study group.
ANALYSIS OF KEY sT'I)Y (;iiouP
There were 30 females and 4 males which is a ratio well in excess of the more frequently quoted female to male ratios of 1.5 to 1 and 2.3 to 1 in JRA. 10(P17),32(P2) The racial distribution of 26 white, 5 black, and 3 hispanic patients is consistent with the demographic data for the referral area and reveals no racial predilection in JRA or in the uveitis associated with JRA. The average age at the onset of arthritic symptoms was 4.1 years (range 1 to 12 years). The average age at detection of the ocular inflammation was 5.3 years (range 21/2 to 11 years). The average duration of ophthalmologic followup was 5.9 years (range 2 to 10 years). Depending on the time relationship between the first observation of ocular inflammation and the onset of the first rheumaitic symptomlls, the key study group is divided into three subgroups (Table III). These are (1) patients in whom ocular inflammation was detected before the onset of recognizable joint symptoms; (2) patients whose ocular inflamllmation was detected concomitant with the first joint symptoms; and
560
S palter
(3) patients in whom ocular inflammation was first detected six months or more after the onset of joint symptoms. Five patients are included in subgroup I. Iridocyclitis was detected in these children between one and fourteen months prior to the onset of the joint symptoms. They represent the only cases, in the entire group of 228 patients having JRA, which were referred by the ophthalmologist to the pediatric rheumatologist, instead of vice versa. Ocular signs and symptoms brought the uveitis to the parents' attention in all of these children. Three children had conjunctival hyperemia, one had photophobia, and one had irregular pupils. The initial diagnosis in each child was nongranulomatous uveitis of unknown etiology. Only with the development of arthralgias was JRA definitely diagnosed. When first examined, three children had bilateral iridocyclitis and two children unilateral iridocyclitis. The degree of ocular inflammation was mild in three patients and moderate in two patients. The two patients with the more intense inflammation had early band keratopathy, fine corneal precipitates, and one-plus vitreous cells. Unilateral posterior synechiae were also present in one patient. Subgroup II comprises eight children whose ocular inflammation was detected at the time of their initial diagnostic evaluation for possible JRA. This first slit lamp examination was performed from three days to six months after the onset of joint symptoms. In each child, the examination was accomplished within a week of the first pediatric rheumatology evaluation. In no case was the presenting complaint referrable to the eye. Four patients had bilateral and four patients unilateral ocular inflammation when first examined. Of these 12 inflamed eyes, four had posterior synechiae and one had minimal band keratopathy associated with a moderate degree of anterior chamber reaction. Vitreous cells were visible in these five eyes. The seven affected eyes in the remaining five patients had mild ocular inflammation with fine posterior synechiae detectible in one eye and occasional vitreous cells visible in another. Subgroup III comprises the remaining 21 patients, in whom the ocular inflammation was first detected 6 months to 9 years (average 2.1 years) after the appearance of arthritis. The inflammation was bilateral in 6 patients and unilateral in 15 patients when detected. In 5 of the 21 patients, previously unrecognized inflammatory complications were present on the first slit lamp examination. Three of these five children had band keratopathy, three had extensive synechiae, and two had cataracts (one bilateral). None of these children had ocular complaints and none of the parents were aware that any ocular problem existed. All five children had a history of mild arthralgias from one to
Juvenile Rheumatoid Arthritis
561
five years previously with no interim joint or systemic complaints until a flare-up of the arthritis prompted referral to our clinic. The original medical evaluation for the arthralgias, performed elsewhere, did not include an ocular examination. The average delay between the onset of the original joint symptoms and the first slit lamp examination was 3.8 years. The four fellow eyes of the four severely diseased eyes in this group were free of inflammation at the time of the patients' entry into the study. Each of the fellow eyes developed ocular inflammation of mild to moderate degree, 15 months to 4 years after the initial slit lamp examination. In the remaining 16 patients in subgroup III, the initial slit lamp evaluation, performed as a part of the diagnostic workup for JRA, was negative. The ocular inflammation was diagnosed between six months and nine years after this negative examination. The longest interval between the immediately preceding negative slit lamp examination and the next subsequent examination which first detected the uveitis was seven months. In 10 of the 16 children, the arthritis was in remission when the uveitis was first detected. In three children, the arthritis had been completely inactive from four to seven years and the JRA was considered cured when the ocular inflammation was first diagnosed. Eight of these 16 children were routinely examined more frequently by the author than by the rheumatologist, even before the onset of the uveitis. In all of these 16 children, the ocular inflammation when detected was asymptomatic. The inflammation was mild in ten children and moderate in six children. None of the eyes had more than two-plus cells or twoplus flare, nor more than one-plus cells in the vitreous, when the iridocyclitis was first diagnosed. No band keratopathy was encountered at the time the ocular inflammation was first diagnosed. In the total group of 34 patients, ocular inflammatioin was bilateral in 13 patients and unilateral in 21 patients when first diagnosed (Table IV). In 13 of the 21 patients, the unilateral inflammation became bilateral in eight months to four years. Recurrent episodes of iridocyclitis were recorded in 19 patients and chronic iridocvclitis was preseInt in 8 patients. A single episode of ocular inflammation was observed in 7 patients, without recurrence, throughouit an average followup period of 4.4 xears (ranige 3 to 6 years). When therapy for ocular inflammiiatioin was started, slit lamiip examiniation was performed weekly unitil the anterior chamber was free of cells and flare. If an inflammation-free state was achieved, the friequency of slit lamp examinationi was reduced to bi-%veekly for three moniths, then
562
Spalter TABLE IV: CHARACTERISTICS OF OCULAR INFLAMMATION (34 JRA PATIENTS)
Unilateral Bilateral Initially bilateral Initially unilateral Initerval from unilateral to bilateral Symptomatic Asymptomatic Single episode Recurrent episodes
Chronic iniflammation
No. of Patients 8 26 13 13 (8 months - 41/2 years) 5 29 8 19 8
monthly for three months. If the anterior chamber remained clear, routine, periodic slit lamp examinations were resumed at three month to six mointh intervals. Non-chronic ocular inflammation characterized by single or recurrent episodes of mild iridocyclitis responded satisfactorily to topical steroids and mvdriatic drops. Patients with more severe, recurrent iridocyclitis or chronic iridocyclitis required systemic steroid therapy. A large dosage was used to control the inflammation as quickly as possible. The total daily dosage was doubled but was given only on alternate days when a clinical response was obtained. With continued favorable response, the steroid dosage was reduced over a six to ten week period. If prolonged use of systemic steroids was necessary, the total weekly amount of steroid was (livided into thirds and administered on three consecutive days of each week with a four day lapse. During high dosage steroid therapy, recognition of systemic complications was the responsibility of the pediatric rheumatologist. Recognition of steroid effectiveness was the responsibility of the ophthalmologist. Frequenit communlicationi took place between both clinicians. The author was therefore allowed a broad freedom of action with prompt anid aggressive therapeutic measures, that is, the use of high dosage systemic steroids. Immediate availability of consultation and mutual support among the concerned specialists is necessary to preserve vision in severe ocular inflaimimationi in JRA. Chronic glaucoma, a documented complication of systemic steroid therapy, occured in two children requiring long term steroid therapy.42 In none of the children with chroinic uveitis requiring systemic steroid therapy, could the development of cataracts be catagorized as a steroid coi-nplication. 43
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PREDICTING OCULAR INFLAMMATION
In general, patients with JRA who develop ocular inflammation tend to have mild arthritic disease with minimal systemic manifestations. This observation has no predictive value for the individual patient or for the severity of the uveitis. At present, it is impossible to foresee which child will develop ocular inflammation or at what point in the course of the arthritis this will occur. No clinical factor - patient age; duration of the arthritis; the presence of active joint inflammation, rheumatoid rash, or intermittent fever; or the use of systemic anti-inflammatory agents for the arthritis, such as acetylsalicylic acid or steroids singly or in combination - demonstrates a positive correlation with the development of the ocular inflammation. The laboratory tests for erythrocyte sedimentation rate (ESR) and rheumatoid factor commonly employed have not proven helpful in identifying the ocular risk group. New laboratory studies to improve the definition of the antibody mechanisms involved in JRA may prove to be reliable, however. The test most frequently performed on JRA patients is the ESR. Although a useful indicator of arthritic activity, the ESR is of no value in predicting the onset or evaluating the activity of ocular inflammation. ESR levels were recorded in all 34 patients in the key study group, during episodes of active arthritis, both with and without concurrent ocular inflammation, and during episodes of ocular inflammation with and without concurrent arthritis activity. Abnormal values had a positive correlation only with arthritic activity. A second laboratory test is the latex fixation variant of this sensitized sheep cell agglutination, Rose-Waaler, test. This technique is used to identify the rheumatoid factor in the serum. In JRA, the incidence of positive results of this test is low (10 percent to 20 percent), whereas in adult rheumatoid arthritis it is high (50 percent to 85 percent).33 In the course of the present study, latex fixation tests were performed in 32 of the 34 patients. Results were negative in 29 patients anid positive in three. Two of the sero-negative children became sero-positive when they reached their teens. The role of serum immunoglobulins and serum complemeint is being studied in JRA.4446 The more active and chronic JRA is, the more illmmunoglobulin factors are found and the more serum complement depression is detected. In the key study group, ten patients were tested for quantitative serum levels of immunoglobulins and for the serumil complement activity. The ten patients had mild arthritis. Seven patients had mild to moderate recurrent uveitis aind three patieints had
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Spalter
chronic uveitis, resistant to therapy. None of the patients had abnormal serum immunoglobulin values or abnormal serum complement depression.
Epstein and associates47 have investigated the presence of antibodies to double-stranded ribonucleic acids (RNA) in JRA patients with uveitis. These investigators found that less than half their patients with uveitis but no specific concomitant systemic disease had positive anti-RNA antibodies. But they observed significantly positive titers in all five children in their study group who had JRA and uveitis. Antinuclear antibodies (ANA) have been reported in 22 percent of JRA patients.48 At the 1972 meeting of the American Rheumatism Association, a verbal report recorded a positive ANA test in 75 percent of a series of JRA patients with iridocyclitis.49 Of the 11 patients with JRA in the key study group of the present series tested for ANA, 6 were positive. Too few tests of JRA patients without ocular inflammation have been performed to permit any conclusions as to the sensitivity of ANA to the presence of ocular inflammation. This laboratory test will continue to be investigated. As knowledge of immunopathologic mechanisms increases, the enigma of collagen-like rheumatoid disease may be resolved. There is an evident need for a laboratory test with predictive value to alert the rheumatologist to those JRA children who will develop carditis, crippling arthritis, or iridocyclitis. For the ophthalmologist seeking to reduce the ocular morbidity of JRA, such a test would reduce the time required for detection of eye signs. VISUAL OUTCOME
Visual results in JRA have heretofore been uniformly poor. A retrospective study of 162 cases of JRA, diagnosed in Copenhagen between 1920 and 1949, was published in 1950.20 Of 61 eyes with iridocyclitis, 31 eyes had band keratopathy and 30 eyes had cataracts. Phthisis bulbi was reported in 5 eyes. Even with the advent of steroid therapy, the visual prognosis in patients with ocular manifestations of JRA is still usually poor. In 485 cases of JRA, studied between 1951 and 1961, uveal inflammation was detected in 27 patients.50 Fully a third of these children were blind, five in one eye and four in both eyes. In contrast, fewer than 30 percent of the total study group experienced long-term joint disability. Another report on ocular findings based on a seven-year reveiw of 183 cases of JRA at the Juvenile Rheumatism Unit of the Canadian Red Cross
5065 Juvenile Rheumatoid Arthritis Memorial Hospital in Taplow, England, noted that seven of ten children with iridocyclitis had serious complications of ophthalmic inflammation when they were first examined ophthalmoscopically.25 Another ocular report, published in 1969, cited significant eye damage in six of eight patients with JRA and iridocyclitis followed for four years. 51 In a more recent detailed review of 124 cases of JRA, 10 of 14 patients with iridocyclitis developed some degree of permanent visual loss.37 The first book devoted to JRA appeared in 1962. 10 This work summarized 110 patients stjsdied and treated at the Presbyterian Hospital in New York City between 1924 and 1959. Total blindness was present in two of nine children with ocular involvement. The authors concluded that immediate ophthalmological consultation should be obtained "at the first sign of uveal tract inflammation." The current study was stimulated by this recommendation. Uveal tract involvement in patients with JRA is asymptomatic, however. These children almost never experience ocular pain or photophobia, and ciliary flush is rarely detected. Visible signs such as band keratopathy, posterior synechiae, and cataract represent already established complications of inflammation. Ophthalmological consultation is therefore required before the first sign of uveal inflammation. To reduce the incidence of blindness of JRA, ophthalmological examination should commence in anticipation of ocular inflammation. The visual prognosis of patients in the current prospective study is significantly better than that cited in the literature. Thirty-four of the 228 children with JRA, or 15 percent, had ocular inflammation. Five children had previously unrecognized visual loss at entry into the current study. Twenty-five of 29 patients with normal vision on entry into the study have retained normal vision for an average followup period of 5.7 years. Since the presence or absence of signs of ocular inflammation, at the time of the first examination, may affect the visual outcome, these patients have been divided into two groups (Table V). These are (a) patients with evidence of ocular inflammation on the first slit lamp examination - this group includes all patients in subgroups I and II of the earlier analysis and the five patients with previously undetected ocular complications from subgroup III: (b) patients who developed ocular inflammation after an initially negative slit lamp examination - this group includes the remaining patients in subgroup III. Of the 18 children in group A, 13 had ocular inflammation prior (5 children) to or concurrent (8 children) with initial joint complaints. In the other five children, severe ocular inflammation was detected on the
566
Spalter TABLE V: VISUAL OUTCOME (34 PATIENTS; 68 EYES)
Group A: initial slit lamp exam positive for signs of ocular inflammation (18 patients; 36 eyes) Group B: initial slit lamp exam negative for signs of ocular inflammation (16 patients; 32 eyes) Total
No. of eyes with normal visual acuity on initial examination
No. of eyes with ocular inflammation
during study
No. of eyes with normal visual acuity at conclusion of study
30
34
29
32
26 60/68
29 58/68
62/68
first slit lamp examination - an examination not performed until one to five years after the initial- joint symptoms were reported. When first examined, six eyes of five patients in group A had visual loss, ranging from 20/70 to light perception. Visual acuity in one patient improved after bilateral cataract surgery from light perception and 20/300 to 20/200 and 20/70. The four remaining eyes with initially defective vision remained unimproved at the conclusion of the study. Despite intensive management with systemic steroids, these eyes were considered irreversibly damaged because of secondary glaucoma and early phthisis. Twenty-eight of the remaining 30 eyes - all with initial normal visual acuity - in group A had documented episodes of uveal inflammation during the study period. Normal visual acuity was retained in 27 of these 28 eyes. Visual acuity in one eye deteriorated to 20/400. Visual failure in this eye was due to cystoid macular edema associated with chronic iridocyclitis, refractory to steroid therapy. Two of the 36 eyes in group A, had no signs of ocular inflammation during the study period. None of the 32 eyes in the 16 patients in group B had slit lamp signs of current or antecedent ocular inflammation when first examined. Normal visual acuity was recorded in all of the 32 eyes, at the time of entry into the study. Twenty-six of these 32 eyes subsequently developed ocular inflammation. In 23 of these 26 eyes, the visual outcome had been excellent. Three eyes were visual failures. One eye, in a child temporarily lost to followup, developed a dense cataract and glaucoma. Only light perception was present in the eye upon reentry into the study. The other two eyes developed irreversible visual loss because of steroid-induced glaucoma. In summary (Table VI), normal visual acuity was present in 62 of 68 eyes in the 34 patients on entry into the current study. The six eyes
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TABLE VI: VISUAL OUTCOME OF EYES AT RISK OF VISUAL LOSS
No. of Eyes 62
Normal vision at entry into study Normal vision at entry into study with no ocular 8 inflammation during study Normal vision at entry into study with ocular inflammation during study (eyes at risk 54 of visual loss) Eyes at risk of visual loss with retained normal 50/54 (93%) vision at conclusion of study
with previously unrecognized inflammatory damage were considered unavoidable visual failures in the context of this prospective study. No slit lamp signs of inflammation were present in 8 of the 62 eyes with initial normal visual acuity, throughout the duration of the study. Therefore, a total of 54 eyes with initial normal visual acuity and documented ocular inflammation of JRA were at risk of visual loss. Fifty of the 54 eyes, or 93 percent, have retained normal vision over a followup period ranging from two to nine years. Only four of the at risk eyes, or 7 percent, have become functionally blind. CONCLUSIONS
Two hundred twenty-eight patients with juvenile rheumatoid arthritis were examined for ocular inflammation between 1963 and 1973. Slit lamp examinations of these patients detected 34 children with uveal inflammation. In 60 of these 68 eyes, active inflammation was observed and treated during the course of this study. Six of these eyes evidenced previously unrecognized visual damage; 54 had normal visual acuity when they were first examined, but were at risk of visual loss from the complications frequently associated with ocular manifestations of JRA. Only four of these eyes developed irreversible visual loss during the course of this
study. The improvement in the visual prognosis of JRA which the current study demonstrates, in contrast to the poor visual results cited in the ophthalmic and pediatric literature, is a reasonable clinical goal. Its achievement, however, depends upon the active participation of an ophthalmologist, both in the initial workup and during the long-term followup of all children with a possible or proven diagnosis of JRA. Since ocular inflammation is more likely to occur in children with the mildest expression of the arthritis, and since these children tend to require less medical surveillance, the risk of undetected ocular inflammation is
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particularly high in this group of patients. Until a laboratory test predicting the ocular manifestations of JRA is developed, frequent slit lamp examination of these children will be necessary. These examinations should be continued after the arthritis becomes clinically inactive. How long these examinations should be continued is a question that remains unanswered. ACKNOWLEDGEMENTS
I would like to thank Dr. Jerry C. Jacobs, of Babies Hospital, at ColumbiaPresbyterian Medical Center for his professional guidance during this study. Mrs. Josie S. Spalter rendered invaluable editorial aid. I would also like to acknowledge the technical assistance of Mrs. Valerie Ramsdell and Mr. Scott Wong.
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