Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Juvenile rheumatoid arthritis Jane Schaller To cite this article: Jane Schaller (1977) Juvenile rheumatoid arthritis, Postgraduate Medicine, 61:1, 177-184, DOI: 10.1080/00325481.1977.11714517 To link to this article: http://dx.doi.org/10.1080/00325481.1977.11714517

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• Great care should be taken in the initial evaluation of any child with chronic arthritis (that is, arthritis of three or more consecutive months' duration) to assure proper diagnosis. There are many causes of chronic arthritis in childhood; sorne of the more common ones are shown in table 1. Care must be taken to consider and exclude these diseases and disease processes before settling on a diagnosis of juvenile rheumatoid arthritis. 1 Additional causes of acute transient arthritis in childhood, such as viral-related arthritis, are not considered here. Discussion of chronic arthritis of childhood secondary to otherdiseases is outside the scope of this article. The arthritis of inflammatory bowel disease, Reiter's disease, and psoriatic arthritis occur occasionally in children but do not differ greatly from the adult forms, which are covered in other sections of this symposium. The majority of this discussion will be devoted to juvenile rheumatoid arthritis. What is called juvenile rheumatoid arthritis includes a diverse collection of chronic arthropathies in children in whom the other diseases and processes listed in table 1 have been excluded as far as possible. z-s Since ankylosing spondylitis may begin with peripheral arthritis in childhood, 5- 7 this disease may be impossible to distinguish early in its course from juvenile rheumatoid arthritis, and it is thus included in this discussion. Ali children with juvenile rheumatoid arthritis share the common property of chronic synovitis. However, several distinct subgroups of disease exist. These are summarized in table 2. lt can be seen that they differ in such important variables as sex of affected patient, age at disease onset, number and distribution of joints involved, types of extra-articular complications, results of serologie and genetic tests, and ultimate prognosis. The terminology for chronic arthritis of childhood is confusing. Chronic arthritis in children in whom other known disease entities have been excluded is lumped under the term "juvenile rheumatoid arthritis" in the United States. In En gland and Europe, the term "Still' s disease" is used in the same regard, although it does not include rheumatoid-factorpositive patients; and the term ''juvenile chronic polyarthritis'' is coming into use to include ali chronic arthritis in children, even that known to be associated with other dise ases. For

Vol. 61 • No. 1 • January 19n • POSTGRADUATE MEDICINE

juvenile rheumatoid arthritis Jane Schaller, MD University of Washington School of Medicine Seattle

con si der What clinical finding is common to ali forms of juvenile rheumatoid arthritis? Which type has the worst prognosis? With which type is chronic iridocyclitis associated?

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tabie 1. types of chronic arthritis of childhood Juvenile rheumatold arthrltls Systemic onset Polyarticular Seronegative Seropositive Pauciarticular Early onset (predominantly girls) Late onset (predominantly boys)

Ankyloslng spondylltls Arthrltls secondary to other lnflammstory dlseases

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Rheumatic diseases (eg, rheumatic fever, systemic lupus erythematosus, vasculitis, dermatomyositis, scleroderma) Other diseases (eg, Reiter's disease, psoriasis, inflammatory bowel disease)

Arthrltls related to other processes lnfectious diseases (eg, septic joint disease, osteomyelitis) Malignant diseases (eg, leukemia, neuroblastoma) Noninflammatory conditions of bones and joints (eg, trauma, avascular necrosis)

purposes of this discussion, the term ''juvenile rheumatoid arthritis'' (JRA) will be used. Types of Chronic Chlldhood Arthrltis (JRA)

Systemic-onset disease- This occurs in about 20% of JRA patients. Boys and girls are affected equally. There is no association with positive tests for rheumatoid factor or antinuclear antibodies, nor with histoco~pati­ bility antigen HLA-B27. 8 Disease may begin at any age during childhood. The hallmark of systemic-onset disease is the presence ofhigh intermittent fevers which reach levels of 103 F or greater for a number of consecutive weeks. 2 •5 .9 Temperature elevations occur once or twice daily, most often in the evening hours, and are followed by rapid retum of the temperature to normal or subnormal levels (figure 1). Shaking chills are frequently associated. Nearly ali patients with this type of fe ver also have a characteristic rheumatoid rash which may occur anywhere on the body, is ex tremel y evanescent, and is usually present during febrile periods. 2 •5 •10 Individual lesions are small (about 1 cm in diameter), pale, red macules, often with a central clearing (figure 2). The rash is occasionally pruritic.

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Other systemic manifestations are listed in table 3. Hepatosplenomegaly and lymphadenopathy may be dramatic in magnitude; lymph node histology may simulate that of lymphoma, and results of li ver function tests may be mildly aberrant. Pleuritis and pericarditis are generally mild; occasionally severe pericarditis or myocarditis occurs. 2 •5 •11 Abdominal pain may be troublesome in a few patients. Nearly ali patients have leukocytosis; sometimes white blO'Od cell counts exceed 50,000/cu mm. Profound anemia may be associated. Iridocyclitis is conspicuous by its absence. Systemic manifestations are generally present for periods of several consecutive months but then usually remit, often to recur months or years later. Nearly ali children with systemic-onset JRA also have musculoskeletal complaints, although these are easily overlooked in the presence of severe systemic disease. Most affected children have severe myalgia, arthralgia, or transient arthritis during febrile periods; these complaints often resolve dramatically when patients are afebrile. Within the first few months of disease, nearly ali affected children develop arthritis which persists in multiple joints. The pattern of joint involvement resembles that of polyarticular disease, described below. About 25% of children have chronic polyarthritis which exceeds the period of systemic disease manifestations. 2 •5 Polyarticular rheumatoid-factor-negative IRA-About 30% of children with JRA have arthritis which affects multiple joints but is unassociated with positive tests for rheumatoid factors. About 25% of these patients have positive tests for antinuclear antibodies. Girls are predominantly affected. The disease may begin at any time during childhood, frequently during early childhood. Extra-articular manifestations, such as low-grade fever, malaise, generalized growth retardation, mild anemia, and modest hepatosplenomegaly and lymphadenopathy, may occur during periods of active disease but are not as striking as those of systemiconset JRA. Any synovial joints of the body may be affected, except perhaps those of the lumbodorsal spine. The most characteristic involvement is a symmetric polyarthritis of

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table 2. characteristics of subtypes of juvenile rheumatoid arthritis (JRA) Type of dlsease

Girl/boy Age at % of ali JRA ratio onset

Joints affected

Serologie flndlngs

Extra-artlcular manifestations

Prognosls

Systemic on set

20

8:10

Any age

Any joint

ANA neg RF neg

See table 3

20% severe arthritis

Polyarticular, seronegative

30

8:1

Any age

Any joint

ANA 25% RF neg

Low-grade fever, mild anemia, malaise

10% severe arthritis

Polyarticular, seropositive

10

6:1

Late Any joint childhood

ANA 75% RF 100%

Mild fever, anemia, malaise, rheumatoid nodules

>50% severe arthritis

Pauciarticular, 25 early onset

7:1

Early Few large joints, childhood hips and sacroiliac joint spared

ANA 50% RF neg

Chronic iridocyclitis in 50%

Severe arthritis rare, 10% to 20% ocular damage

Pauciarticular, 15 late onset

1:10

Late Few large joints, childhood hip girdle and sacroiliac joint involvement

ANA neg Acute iridocyclitis Ankylosing RF neg in 5% to 10% spondylitis HLA-827 75% sometimes found at follow-up

ANA, antinuclear antibodies; RF, rheumatoid factor.

small joints of the bands, particularly the proximal interphalangeal joints and the metacarpal phalangeal joints (figure 3). Distal interphalangeal joints are also occasionally affected. Knees, ankles, elbows, and feet are affected in the majority of patients. About half of patients also have arthritis in the temporomandibular joints, neck, hips, and shoulders. Severe hip disease is the major cause of late disability. Iridocyclitis and pericarditis are rare, and rheumatoid nodules are not usually found. Severe destructive arthritis occurs in only about 10% of patients; the majority ultimately do weil. 2 .a.s Rheumatoid-factor-positive polyarthritis -About l 0% of children with JRA have positive agglutination tests for rheumatoid factor, almost always first present during the first year of disease. These patients have a pattern of joint distribution similar to that of the seronegative patients discussed above. However, they differ in several regards from the seronegative group. 2 •5 •8 Disease onset is almost always in late childhood, and patients frequently have associated rheumatoid nodules. Unfortunately, severe destructive arthritis is common, occurring in more than 50% of the patients in this group. Girls are

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predominantly affected. Seventy-five percent of patients also have positive tests for antinuclear antibodies. lridocyclitis is not associated. Occasionally rheumatoid vasculitis and rheumatoid lung disease occur. This type of positive disease closely resembles severe adult-onset rheumatoid arthritis. Pauciarticular arthritis-About 40% of children with JRA have arthritis which does not affect multiple joints symmetrically, but affects a few joints (pauci, Latin few; articulus, Latin joint) asymmetrically. Usually the large joints are affected, particularly the knee, ankle, and elbow. Isolated fmger and toe joints are occasionally involved, as are the cervical spine and the wrist. This type of disease is difficult to define according to the total number of joints involved, since patients may conform to the pattern and type of joint involvement but have as many as eight or nine joints affected. Current American Rheumatism Association criteria specify four or fewer joints for pauciarticular arthritis. 1 Two distinct subgroups of patients are included un der the designation of pauciarticular arthritis (table 2). 5 •8 • 12 These will be considered separately. .,..

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Figure 1. Typical high intermittent fever of systemic-onset juvenile rheumatoid arthritis. Febrile periods generally continue for weeks to months before remission.

The first group is composed of patients who are mostly young at disease onset (5 years of age or younger) and predominantly girls. This group includes about 25% of ali JRA patients. These patients rarely have hip involvement and do not have sacroiliitis found at time of follow-up; HLA-B27 is not associated. Although their arthritis may be long-lasting, the prognosis for ultimate joint function is good. At least half of them have positive tests for antinuclear antibodies; rheumatoid factors are not associated. About half of this group of patients will develop chronic "ïridocyclitis sometime during the first ten years of disease. This insidious, potentially scarring type of eye disease, which is associated with few early symptoms or signs, is the major cause of disability among this group of patients.13'15 Photophobia, eye pain, and eye redness are not usual complaints early in disease, and diagnosis can be made earl y only if routine slit-lamp examinations are done. Nearly ali children with chronic iridocyclitis

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also have positive tests for antinuclear antibodies. 14 ·16 Sequelae of chronic iridocyclitis include posterior synechiae, band keratopathy, cataract formation, and secondacy glaucoma. Early recognition and trealment of this complication are extremely important to the preservation of vision. The second group of pauciarticular patients, including about 15% of total JRA patients, is composed of children mostly past the age of 8 years at disease onset and predominant!y boys. These patients, in addition to having pauciarticular arthritis, frequently have hip girdle involvement early in disease and often have radiographie signs of sacroiliitis either at disease onset or at time of follow-up. 8 • 12 They are seronegative forboth rheumatoid factors and antinuclear antibodies but have a high prevalence of histocompatibility antigen HLA-B27. 8 • 12 Chronic iridocyclitis is not associated, but acute iridocyclitis of the type seen in ankylosing spondylitis and Reiter' s disease sometimes occurs during the childhood years.s• 16 At

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time of follow-up sorne of these patients are found to have classic ankylosing spondylitis. 8 •12 •17 Family histories are sometimes positive for either ankylosing spondylitis or acute iridocyclitis. This group of patients seems to include many individuals who have ankylosing spondylitis rather than JRA, although it may be years before findings in the sacroiliac joints and lumbodorsal spine permit an accurate clinical diagnosis of ankylosing spondylitis. It may be that sorne have a disease identical to ankylosing spondylitis but never develop fmdings which would, by present criteria, permit diagnosis of that disease. Dlagnoala The diagnosis of JRA is almost entirely clinical and rests on recognition of the disease patterns described above. Appreciation of the different types of JRA and their hallmarlcs is particularly important to accurate diagnosis. Other diseases mentioned in table 1 must be excluded. This is done largely by considering their possibility and making accurate clinical differentiation. No laboratory tests are diagnostic of JRA or any of the subgroups mentioned above. Leukocytosis and anemia are common, particularly in systemic-onset disease; however, the presence of bizarre leukocyte forms in the peripheral blood, profound anemia, leukopenia, or thrombocytopenia should always raise the question of malignancy. Acute-phase reactants, such as elevated sedimentation rates and C-reactive proteins, are commonly associated with active inflammatory disease but are not diagnostic. Furthermore, a number of children, often those with pauciarticular arthritis, have normal sedimentation rates in the face of obviously active arthritis. There is probably no virtue in obtaining more than one of the acute-phase reactants in a given patient; the sedimentation rate is generally the easiest to obtain. As noted above, rheumatoid factors are not found in the majority of children with chronic arthritis. Positive agglutination tests for rheumatoid factors do identify a group of children who have severe polyarthritis and rheumatoid nodules (see page 179).

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Figure 2. lndividual lesions of rheumatoid rash of systemic-onset juvenile rheumatoid arthritis. Lesions can occur anywhere on the body. Rash is recurrent and extremely evanescent. Reprinted from Schaller and Wedgwood, 2 wlth permission.

table 3. extra-articular manifestations of systemic-onset juvenile rheumatoid arthritls High intermittent fever

100%

Rheumatoid rash

95%

Hepatosplenomegaly or generalized lymphadenopathy

80%

Pleuritis or pericarditis

60%

Abdominal pain

30%

Leukocytosis

95%

Severe anemia

40%

Recently, lgG and lgA antibodies reactive with immunoglobulins have been identified by different techniques in sorne seemingly seronegative children with JRA; 18 the diagnostic and classification uses of these tests remain to be demonstrated. Antinuclear antibodies are commonly found in JRA, being associated with all subgroups of disease except pauciarticular arthritis of late childhood onset and systemic onset. Antinuclear antibodies appear to be useful in identifying children with pauciarticular arthritis who are at risk for chronic iridocyclitis. They are also commonly found in rheumatoid-factorpositive polyarthritis patients. Elevated serum immunoglobulins are commonly associated with active inflammatory disease, particularly if it is chronic; they have no diagnostic usefulness. A few children with

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Figure 3. Polyarthritis affecting wrist and finger joints. This pattern is characteristic of polyarticular juvenile rheumatoid arthritis.

chronic arthritis can be found to have IgA deficiency or hypogammaglobulinemia. Histocompatibility antigen HLA-B27 is associated significantly only with pauciarticular arthritis of late childhood onset and male predominance; there are no significant associations with other subgroups of JRA, 8 and the test bas no clear diagnostic value. 19 Radiographs in early JRA are not diagnostic, showing only osteoporosis, soft-tissue swelling, and perhaps accelerated epiphyseal growth or periostitis. Early radiographs may be useful in excluding other disease important in the differentiai diagnosis, however. Late radiographs showing changes of severe disease are diagnostic of JRA but rarely necessary for diagnosis. Loss of articular cartilage, erosions of juxta-articular bone, and varying destruction and fusion of joints are similar to changes seen in adult disease; fortunately such destructive changes occur in the minority of children with JRA. Therapy

The therapy of JRA should be geared to the type and extent of the disease in the individual

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patient. Generally speaking, several aspects of disease need treatment: the arthritis per se (synovitis), the extra-articular manifestations, and the whole child. Synovitis - For active synovitis itself, various anti-inflammatory agents are employed in treatment. Of these, salicylates are the safest and best at this time and, ifused in sufficient dosages and for sufficient periods of time, will provide satisfactory control of disease in the vast majority of children. An adequate course of salicylate therapy might be defined as enough salicylate to main tain blood levels at between 20 and 30 mg/100 ml for several months. To achieve these blood levels, 100 mg/kg/day of aspirin in four divided doses is generally sufficient for children weighing 25 kg or less; for children beavier than 25 kg, doses ofbetween 40 and 60 grains daily are generally suffident. Hazards of salicylate therapy include salicylism, which should always be avoided, and gastric irritation. If an adequate trial of salicylates does not control synovitis, gold is generally the second drug of choice. Gold therapy bas similar side effects in children and adults, and appears to be relatively safe if carefully given. The appropriate dosage is 1 mg/kg/wk, again up to a weight of 25 kg. The course of therapy is similar to that in adults, with injections of maintenance dosage being given weekly for 20 weeks and then spaced out to every two, three, or four weeks to maintain remission. Chloroquine is a useful antirheumatic drug in a few children but must be given extremely carefully because of possible eye toxicity and also because it is a poison with no antidote if taken in overdosage. Nonsteroidal antiinflammatory agents, such as indomethacin, phenylbutazone, ibuprofen, and tolmetin, are not yet available for use in children in the United States. These drugs appear to be relatively rarely associated with complete disease remissions in rheumatoid arthritis. Corticosteroids should be used as rarely as possible to control articular manifestations of JRA and, if absolutely necessary for symptomatic control of disease, should be given in the lowest possible dosages. Ample evidence bas accumulated that corticosteroids

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do not prevent the occurrence of joint destruction in severe JRA and, indeed, may even hasten it. There is little rationale for the use of various anticancer drugs in the treatment of rheumatoid arthritis in children at the present time. Extra-articular manifestations -The systemic manifestations of systemic-onset JRA are usually controlled by salicylates in a regimen as described above. If a trial of salicylate therapy does not work, a short course of treatment with corticosteroids is indicated to bring symptomatic relief to the patient. lt must be remembered, however, that since systemic manifestations of JRA rarely last more than six months, the corticosteroid therapy should never be prolonged. Patients can be maintained on salicylates as corticosteroids are being withdrawn and discontinued. ln managing patients with systemic-onset JRA, it is important to define what it is that needs treatment at the moment, whether joint disease or systemic manifestations. The iridocyclitis of JRA should be managed in collaboration with an ophthalmologist. Topical steroids and dilating agents are appropriate initial therapy and will adequately control the eye disease in many patients. If active ocular inflammation persists, however, either loc ally injected steroids or systemically administered steroids should be used in an effort to preserve vision. The dose of steroids can be regulated by observing the degree of inflammation by slit-lamp examinations; the lowest possible doses to achieve suppression of the process should always be used. Whole child - Concerning treatment of the whole child, great care should be taken to avoid the image of chronic invalidism in affected patients. Patients need to be managed by a physician who is comfortable with the disease and is able to work closely with the patient and the family. Children should not be restricted from activities needlessly but should be encouraged to do as much as possible. Bed rest is generally contraindicated, and ali but the most severely handicapped children should attend regular schools.

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Jane Schaller Dr. Schaller is professer of pediatries, University of Washington School of Medicine, Seattle.

Prognosls and Morbldlty

It bas been recognized increasingly in recent years that the prognosis for children with JRA or other chronic childhood arthritis is much better than bad been previously supposed. Taking patients together as a whole, it appears that 75% of them, or perhaps more, will eventually enter long remissions without having incurred any permanent joint damage. The types of morbidity are dependent on the type of disease and differ somewhat from group to group. Severe, unremitting, destructive arthritis occurs in the majority of children with rheumatoid-factor-positive polyarthritis and in about 20% of children with systemiconset disease. Severe destructive arthritis is much less common in children with rheumatoid-factor-negative polyarthritis and rarely occurs in children with pauciarticular JRA. A certain, as-yet-unidentified percentage of children with pauciarticular arthritis of late onset (predominantly male) will have ankylosing spondylitis at follow-up and may incur disability from this disease. The ocular damage of chronic iridocyclitis is virtually confined to children with pauciarticular arthritis of early onset (predominantly girls); this is the major cause of morbidity in this group. The systemic manifestations of systemiconset JRA are dramatic and troublesome but are generally self-limited and rarely fatal; occasionally, severe pericarditis, myocarditis, or severe anemia may demand heroic treatment. lt should be remembered, however, that patients with systemic-onset JRA are at risk of ultimate morbidity from chronic arthritis, not generally from their systemic manifestations. ..,.

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Considerable morbidity in JRA results from residua of disease which exceed the period of active disease. With current methods of treatment, it is not always possible to prevent severe destructive arthritis or even to control it while it is going on. However, appropriate therapy can lessen musculoskeletal residua, such as joint contractures and muscle wasting. Care must be taken to avoid iatrogenic harm to patients, unnecessary ocular scarring, and psychosocial invalidism. Ali of these factors cancontribute to the long-term morbidity of this disease. JRA occasionally recurs in adulthood after many years of apparently complete remission. It is safe to say to an individual patient, however, that most children do get over this disease without any serious lasting disability. Recognition of the disease subgroups described above appears to be helpful in predicting the problems of individual patients and, in a sense, in predicting the ir outcome as weil.

set, polyarticular, and pauciarticular types. Appreciation of the different types and their hallmarks is particularly important to accurate diagnosis, which is determined by exclusion of other known disease entities in children with chronic arthritis (more than three months' duration). Therapy should be directed at the arthritis per se (synovitis), at the extra-articular manifestations, and at the whole child. Salicylates provide the most satisfactory control of the arthritis per se and of the systemic manifestations in most cases. Iridocyclitis should be managed in consultation with an ophthalmologist. Patients should not be regarded as invalids or restricted needlessly. The prognosis for children with juvenile rheumatoid arthritis is good. In most patients, the disease remits without causing permanent joint damage. •

Summary

ReadySource on rheumatoid variants appears on page 190.

Juvenile rheumatoid arthritis is a diverse group of diseases that includes systemic-on-

CME Credit quiz on rheumatoid variants be gins on page 195.

Address reprint requests to Jane Schaller, MD, Department of Pediatries, University of Washington School of Medicine, Seattle, WA 98195.

References 1. American Rheumatism Association, Juvenile Rheumatoid Arthritis Criteria Committee: Revision of JRA Criteria. Symposium on the Rheumatic Disease of Childhood. (Suppl) Arthritis Rheum (in press) 2. Schaller J, Wedgwood RJ: Juvenile rlteumatoid arthritis: A review. Pediatries 50:940, 1972 3. Bywaters EG: Heberden oration, 1966: Categorization in medicine-A survey of Still's disease. Ann Rheum Dis 26:185, 1967 4. Calabro JJ, Marchesano JM: The carly natural hi stol)' of juvenile rheumatoid arthritis: A 10-year follow-up study of 100 cases. Med Clin North Am 52:567, 1968 S. Symposium on the Rheumatic Disease of Childhood. (Suppl) Arthritis Rheum (in press) 6. Schaller J, Bitnum S, Wedgwood RJ: Ankylosing spondylitis with childhood onset. J Pediatr 74:505, 1969 7. Ladd JR, Cassidy JT, Martel W: Juvenile ankylosing spondylitis. Arthritis Rheum 14:579, 1971 8. Schaller JG, Ochs HO, Thomas ED, et al: Histocompatibility antigens in childhood-onset arthritis. J Pediatr 88:926, 1976 9. McMinn FJ, Bywaters EG: Differences between the fever of Still's disease and that ofrlteumatic fever. Ann Rheum Dis 18:293, 1959 10. Isdale IC, Bywaters EG: The rash of rlteumatoid arthritis and Still's disease. QJ Med 25:377, 1956

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II. Lietman PS, Bywaters EG: Pericarditis in juvenile rheumatoid arthritis. Pediatries 32:855, 1963 12. Schaller JG, Wedgwood RJ: Pauciarticular childhood arthritis: Identification of two distinct subgroups. Arthritis Rheum (in press) 13. Smiley WK, MayE, Bywaters EG: Ocularpresentations of Still's disease and their treatment. Ann Rheum Dis 16:371, 1957 14. Schaller J, Kupfer C, Wedgwood RJ: Iridocyclitis in juvenile rheumatoid arthritis. Pediatries 44:92, 1969 15. Chylack LT Jr, Bienfang OC, Bellows AR, et al: Ocular manifestations of juvenile rlteumatoid arthritis. Am J Ophthalmol 79: 1026, 1975 16. Schaller JG, Johnson GD, Holborow EJ, et al: The association of antinuc1ear antibodies with the chronic iridocyclitis of juvenile rlteumatoid arthritis (Still's disease). Arthritis Rheum 17:409, 1974 17. Edmonds J, Morris RI, Metzger AL, et al: Follow-up study of juvenile chronic polyarthritis with particular reference to histocompatibility antigen W.27. Ann Rheum Dis 33:289, 1974 18. Torrigiani G, Ansell BM, Chown EE, et al: Raised IgG antiglobulin factors in Still' s disease. Ann Rheum Dis 28:424, 1969 19. Schaller JG, Omenn GS: The histocompatibility system and human disease. J Pediatr 88:913, 1976

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Juvenile rheumatoid arthritis.

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