Juvenile Rheumatoid Arthritis: A General Review and Report of 100 Patients Observed for 15 Years By John J. Calabro, William B. Holgerson, Girish M. Sonpal, and Majda I. Khoury

J

UVENILE RHEUMATOID ARTHRITIS (JRA) remains a capricious disease that continues to pose an unusual number of diagnostic and therapeutic challenges. This is not at all surprising in a disorder as protean as JRA, whose variable modes of onset and patterns of disease course are accompanied by a myriad of diverse signs, symptoms, and manifestations. Most of the literature since the disease was first described by Cornil’ in 1864 is directed at clinical descriptions and efforts to classify various “subgroups” of the disease. Even as early as 1890, Diamentberger,2 another French investigator, pointed out that rheumatoid arthritis (RA) in children could begin in an acute manner with high fever. He published observations on 35 patients, including three of his own, in what he termed a “new rheumatism of children” that began most often in large joints. Diamentberger was the first to note the frequency of growth disturbances and the flare-ups and remissions that are so typical of JRA. He also concluded that the prognosis for RA appeared to be more favorable in children than in adults. In a scholarly report in 1897, the English pediatrician George Frederick Still3 separated his 19 patients by the manner in which their disease began. In six patients, he described chronic polyarthritis, resembling that of adult RA, and in one, a chronic “post-rheumatic fever arthritis.” In 12 patients, he reported that joint disease was accompanied by high fever, lymphadenopathy, splenomegaly, hepatomegaly, and pericarditis. Thus, Still’s major contribution was to describe these distinctive systemic manifestations of JRA. Generally, Still’s disease is synonymous with JRA, although the popular eponym is sometimes used to describe an onset accompanied by prominent systemic manifestations. Clearly, this form of JRA remains the most difficult to diagnose and treat, even though it affects from only 5 to 26% of all JRA patients.4-6 This acute form of RA also occurs in adults, although less frequently. Known in the past as the Still-Chauffard syndrome,’ it has recently gained new attention as “Still’s disease in the adult”* and “adult onset JRA.“g

From the Division of Rheumatology, Department of Medicine, Worcester City Hospital, and the University of Massachusetts Medical School, Worcester, Mass. Supported in part by agrantfrom the Massachusetts Chapter of the Arthritis Foundation. John J. Calabro, M.D., F.A.C.P.: Chief of Medicine and Director of Rheumatology, Worcester City Hospital, and Professor of Medicine, University of Massachusetts Medical School, Woreester. Mass.; Consultant in Pediatric Rheumatology, New England Medical Center, and Professor of Pediatrics, Tufts University School of Medicine, Boston, Mass. William B. Holgerson: ElectiveSenior Student in Rheumatology, Worcester City Hospital and the University of Massachusetts Medical School. Worcester, Mass. Girish M. Sonpal, M.D.: Fellow in Rheumatology, Worcester City Hospital and the University of Massachusetts Medical School, Worcester, Mass. Majda I. Khoury, M.D.: Fellow in Rheumatology, Worcester City Hospital and the University of Massachusetts MediralSchool. Worcester, Mass. Requests for reprints should be addressed to: John J. Calabro, M.D., F.A.C.P., Worcester City Hospital, 26 Queen St.. Worcester. Mass. 01610. w1976 by Grune & Stratton, Inc. Seminars

in Arthritis

andRheumatism,

Vol. 5. No. 3 (February). 1976

257

258

CALABRO

ET AL.

A single disorder that has radically different kinds of onset presents difficulties in diagnosis. Unfortunately, diagnosis is too often delayed or incorrect. A 1965 survey lo suggests that errors in the diagnosis of JRA occur in about half of the children referred to specialists. Consequently, children are subjected to months or years of inconclusive and damaging diagnostic and therapeutic measures. In an effort to simplify the problem, a plethora of classifications have been suggested. 4-6*10-18Unfortunately, some of these have added confusion rather than clarification. Furthermore, the longer investigators work with JRA patients, the more subgroups they delineate. A case in point is Ansell, who initially in 195917 described only three types of patients. These included patients with involvement of at least four joints, those with swelling of a single joint, and a small inconclusive group designated as “probable” RA. In her most recent 1974 classification18 of 244 children observed for 15 yr, five subgroups had emerged: 19 patients, mostly boys, with ankylosing spondylitis, 12 with polyarthritis and sacroiliitis but without spinal involvement, 25 with seropositive, erosive arthritis, 12 with chronic iridocyclitis with relatively few joints involved, and 176 (7 1% of the entire group) with seronegative arthritis. The diagnostic criteria for adult RA,lg even when modified,16 are difficult to apply to JRA. Patients with single joint onset (35%) and half of those with acute febrile onset (10%) could never meet these criteria, as well as many with multiple joint involvement, because children, unlike adults with RA, are less apt to complain of early morning stiffness and infrequently have rheumatoid factor or subcutaneous nodules. Because of these inherent difficulties, a separate classification for JRA has recently been adopted by the American Rheumatism Association.15 No upper age limit is contained in this report, a serious shortcoming for future reporting. However, it stresses conditions which must be excluded, an important reminder of the many disorders that masquerade as JRA. This state of affairs is not due to the rarity of JRA. On the contrary, RA is the major chronic rheumatic disorder of childhood, affecting as many as 250,000 American children.20 Despite such prevalence, the etiology of JRA remains a mystery. THE ETIOLOGIC

PUZZLE

The cause of JRA remains unknown, in spite of numerous investigations into variable contributing or precipitating mechanisms, such as infection, trauma, psychologic factors, heredofamilial influence, and a host of immunologic phenomena.21 Currently, the two major theories being advanced are: (1) infection from an organism as yet to be identified, and (2) some form of immune process.22 It is very likely that both mechanisms may be operative. Infection and Trauma It was not so long ago that teeth or tonsils were removed because of the theory of “focus of infection” which, fortunately, has now been abandoned. Since then, a variety of microorganisms have been implicated, including bacteria, mycoplasma, and viruses, but none of these has been established.22 Elevated antistreptolysin-0 (ASO) titers have been noted in up to 30% of patients with JRA,23-25 suggesting a streptococcal etiology. These now appear to be nonspecific titers also observed in other childhood disorders, such as tuberculosis, hepatitis, and Henoch-Schiinlein purpura. 26-28These nonspecific titers can

JUVENILE

RHEUMATOID

ARTHRITIS

259

be inhibited by the addition of albumin to the test procedure, in contrast to specific AS0 titers that result from recent infection by Group A beta-hemolytic streptococcus.2S Our inability to suppress elevated AS0 titers in six patients with JRA following monthly intramuscular injections of benzathine penicillin over a 12-mo period seems at least to bear out the nonspecific nature of these titers.‘l In 1972, Ogra and Herdzg found rubella antibody levels to be higher in JRA than in controls, suggesting rubella might be involved in the pathogenesis of JRA. Subsequently, Phillips et a1.3oreported minimal to moderate elevations of multiple viral antibodies, including rubella. When these could be directly correlated with elevations of IgG, they concluded that high viral antibody titers were nonspecific features of hyperimmunoglobulinemia, and not necessarily features of pathogenesis. Upper respiratory infection31s32and trauma4p33 are often cited as precipitating factors that may trigger the disease or a subsequent flareup. However, these occur with such frequency in children that these observations are difficult to assess. Psychologic Factors

In 1954, Blom and Nicholls34 proposed a psychosomatic etiology for JRA, a view they were never able to support in subsequent studies.35 More recently, Grokoest et al.12 have suggested that children with JRA have a well-masked anxiety state. Also, it is generally believed that the more severe the disability, the more extensive are the underlying psychologic problems. As neither of these concepts has ever been substantiated, it would appear that there is no particular psychological profile in JRA. 35 Emotional conflicts that occur are more than likely the result of the severe restrictions imposed by JRA. Nevertheless, psychologic evaluations should be routine in these children so that impending problems may be promptly identified and corrected. Heredofamilial Influence

There are few reports pertaining to family or genetic studies, and none of racial or geographic factors. In the only family survey, reported by Ansell and colleagues in 1962,36a familial aggregation of ankylosing spondylitis (AS) greater than expected was found among the male relatives of patients with JRA. These results have to be critically reexamined, however, since by 1965 some of the 93 patients with JRA have gone on to develop AS.37 Twin studies give little support of any genetic influence because of the low concordance rate reported.38-40 In 1964, a possible genetic linkage was suggested when it was found that a higher percentage of serum haptoglobin l-l was noted in JRA than in controls.41 Subsequently, this observation could not be confirmed.42 The recent report 43of a high frequency of the HL-A antigen W27 in JRA also suggests some sort of genetic linkage. Of 26 patients, 42% had the antigen, in contrast to only 6% of 267 controls.* It would be interesting to observe with what frequency the W27 antigen occurs in the relatives of JRA patients,44 comparable to studies done in AS, where the antigen was found in 85% of patients and in up to half of the first-degree relatives.45 *This relationship, however, has not been confirmed in a subsequent survey, the most recent and largest reported; of 122 JRA patients, only 16% had the antigen as did 6% of 126 control children.4Ja This difference is not statistically significant.

260

immunologic

CALABRO

ET AL.

Phenomena

Immunologic parameters in JRA are deservedly attracting increasing attention. These include rheumatoid factor, antinuclear antibodies (ANA), and aberrations in serum immunoglobulin levels. 46 It is difficult to assign a pathogenetic role to rheumatoid factor because it is so infrequently observed in JRA.4R Recently, however, it has been shown that seronegative children with RA have IgG-anti-IgG rheumatoid factor (not detected by the usual agglutination tests), rather than the usual IgM--anti-IgG rheumatoid factor found in most adults and in a few children with RA.47 Whether IgG antibody has the same biologic activity of IgM rheumatoid factor is not yet known. The role of antinuclear antibodies (ANA), which occur in up to 30% of patients with JRA,4R*40also remains to be clarified. There is recent evidence to suggest that ANA help to perpetuate the chronic synovitis of RA.50 These antibodies comprise the major immunoglobulin classes, although the presence of IgG ANA seems to be linked to more severe and prolonged disease.‘” There is a high frequency of serum immunoglobulin abnormalities in JRA.‘“.“’ In a survey of 200 children,“’ patients with elevated immunoglobulin levels had a poorer functional status and an increased incidence of hip involvement. In a subsequent study of 148 children, 51 two groups of patients could be distinguished. One group with chronic active disease had elevated levels of IgG, IgA, and IgM antigammaglobulins and relative depressions of complement in sera and synovial fluid. Another group with self-limited active disease had elevated levels of IgG and IgA immunoglobulins and serum complement and negative latex fixation tests. The authors concluded that these findings suggest that IgG antigammaglobulins may activate the complement system in a different qualitative or quantitative manner than do IgM antigammaglobulins, and that presence of the former (and absence of the latter) is associated with a favorable, self-limiting course of disease. Selective IgA deficiency occurs with greater frequency in JRA patients (4%) than in controls (0.2%).52*53Consequently, it has been suggested that IgA deficiency may be related to pathogenesis as a reflection of a more profound but as yet unidentified immunologic disturbance involving the cellular immune system.““*54 Is it possible that infection plays a more direct role in JRA than that assigned to immune complexes, in keeping with the concept of “slow” and “latent” virus infections?“” And do “RA cells,” the result of complexing between rheumatoid factor and gamma globulin, 58 then set up a self-perpetuating cycle within synovial fluid and thus have a possible pathogenic role? And do lysosomal enzymes and prostaglandins next play a role in the continuing synovial inflammation?“7.“8 While answers to this and other vexing etiologic problems are still needed, one of the major advances in our understanding of JRA is the concept that certain clinical manifestations of RA are different in children than in adults. JUVENILE

VERSUS

ADULT

DISEASE

JRA is arbitrarily defined as RA beginning before the age of 16.5y While slightly more common in girls than in boys, it is rare before 6 mo of age. Generally, there are two peaks of onset, one at ages l-3, another from 8 to 12. Despite the inclination to link RA and JRA as identical diseases, one occurring in adults, the other in children, there are a number of striking differences between the two 5.2L.25.58~66

JUVENILE

RHEUMATOID

261

ARTHRITIS

Table 1. Major Differences

Between

100 Children

With Rheumatoid

and 100 Adults

Arthritis* Frequency Children

Manifestation High fever Rheumatoid

rash

Generalized

lymphadenopathy

Splenomegaly Chronic

Monarticular

onset

Rheumatoid *Consecutive

referrals

has been reported tLeukocytosis

20

3 2

43

21

33

7

9

0

32

6

8

20

56

23

19

76

nodules

Leukocytosist factor* to an arthritis

Adults

44

iridocyclitis

Subcutaneous

(%)

clinic. These 100 children

comprise

the same group that

in detail previously.s,6*-64 is not only more frequent

higher, usually from

15,000

$6~ the latex fixation

to 30,000,

in children,

occasionally

test, titer of 1:160

but the level of the white cell count is also

to 80,000.

or greater.

In a comparative survey (Table l), we found high fever and rheumatoid rash to be far more frequent in children than in adults with RA. This is difficult to explain, as is the greater frequency in children of generalized lymphadenopathy and splenomegaly. Another difference was the occurrence of chronic iridocyclitis in children (9%), but not in adults. The most susceptible children had the mildest form of JRA,g3 those with arthritis of only one to four joints, of whom 27% developed iridocyclitis. A monarticular onset appears more often in JRA than in adult RA. On the other hand, subcutaneous nodules are present in fewer children than in adults. However, they occur in the same areas in both groups. Nodules develop in areas of excessive pressure or friction and are thereby frequent at the olecranon process of the elbows or in back of the heels. Strangely, on histologic study, the nodules of JRA are more apt to resemble those of rheumatic fever than the nodules of adults with RA.65,66 A segmented neutrophilic leukocytosis was detected in children in about twice the frequency as in adults. And the total white cell count was generally higher: 15,000 to 30,000, sometimes as high as 80,000. Rheumatoid factor, as observed by either a positive sheep cell agglutination or latex fixation test, was present in only 19% of children, whereas in adults it was found in 76%. Failure to appreciate the relative infrequency of rheumatoid factor in JRA constitutes one of the major pitfalls in early diagnosis. MODES

OF ONSET

Early diagnosis of JRA rests on the recognition of 3 distinct modes of onset. These are acute febrile, polyarticular, and monarticular-pauciarticular.* Because of diverse and variable manifestations, each mode of onset will have its own *At the first international symposium sake of conformity in terminology the oligoarticular onset includes swelling designation monarticular-pauciarticular

on JRA held in Bristol, England (January 6-8, 1975), for the term oligoarticular was preferred to pauciarficular. Since of up to four joints and thus includes monarricular, the can be abandoned.

262

CALABRO

Table 2.

Differentiating

Features

of the Three Modes of Onset in Juvenile

Rheumatoid

ET AL.

Arthritis

As Observed in 100 Patients*

Acute Febrile

MonarticularPauciarticular

Polyarticular

No. children

20

48

32

Girls/boys

9/11

30118

2319

Mean age (yr) Onset peaks (yrj

4.6 l-3,11-13

2-4,

Systemic

features

Frequent

Fewer

findings

Variable,

Fever Articular

7.4

High only

arthralgia

l-3,11-13 lnfrequentt

Low

Low or none

Prominent,

Usually a knee,

to florid

more than four

arthritis Major hazards

7.3 IO-14

often painless

joints

Cardiac failure

Deformities

from myocarditis

from

Blindness from

progressive poly-

asymptomatic

arthritis;

iridocycl itis

secondary

amyloidosis

‘Part

of

a prospective

clinic, now followed earlier,5.62-64,67.68 tExcept

for

study of 100 children,

for

iridocyclitis

up to 15 yr. Various which

occurs

consecutive

in 22%

onset and in up to 27% in those who maintain

referrals

to a pediatric

rheumatology

aspects of this series have been reported of patients

with

in detail

a monarticular-pauciarticular

a disease course of pauciarthritis

(chronic

arthritis

of one to four joints).

differential diagnosis, and each its own potential hazards (Table 2). Consequently, each must be considered as if it were a separate entity and treated as such.5.6 It is, therefore, one matter to diagnose JRA and quite another to recognize the specific form and to treat it appropriately. The character, frequency, and severity of initial systemic and articular manifestations provide the best clues to the three types of onset.5 These, based on our prospective study of 100 patients now followed for 15 yr,5*62-64*67,68 are outlined in Table 2. The Patient Group

There were 62 girls and 38 boys, consecutive referrals to a pediatric rheumatology clinic in New Jersey. Prior to referral to our clinic, 45% of patients were incorrectly diagnosed for weeks, months, and in one instance for 4 yr. A careful work-up was done on each patient, together with exhaustive laboratory and clinical studies, placing special emphasis on how the disease began. All 100 patients have fulfilled the diagnostic criteria for JRA proposed by Ansell and Bywaters.11*38The mean age of onset was 6.8 yr; the youngest child was 6 wk and the oldest was 15 yr. Since their original visit, all patients have been followed regularly by the same group of physicians. Patients have had serial laboratory studies as well as yearly x-ray examinations. Ophthalmologic evaluations have been carried out at least every 6 mo, but more frequently in the more susceptible children. Our schedule of routine slit-lamp examinations will be outlined later. The current mean age of these patients is 20 yr; the youngest is 14, the oldest 32. The duration of disease from onset now averages 17 yr, or from 14 to 26 yr. Presently, 63 of our 100 children are in complete remission, while 34 continue to be active and three have died.

JUVENILE

RHEUMATOID

263

ARTHRITIS

Modes of Onset (Table 2)

An acute febrile onset is accompanied by prominent systemic manifestations, particularly high fever, rash, generalized lymphadenopathy, splenomegaly, and heart involvement. Joint manifestations are variable; occasionally, only arthralgia is present. In polyarticular onset, defined as synovitis of more than four joints, the arthritis predominates and is frequently generalized and symmetric, similar to adult RA. Systemic manifestations are less frequent than in acute febrile onset. Fever is invariably low grade. Monarticular-pauciarticular onset, with arthritis confined to a single joint (monarticular), usually a knee, or up to four joints (pauciarticular), is the mildest form. Systemic signs are minimal or absent, with the notable exception of iridocyclitis. ACUTE

FEBRILE

ONSET

Although first described as long ago as 1897 by the English pediatrician, George Frederick Still,3 acute febrile onset continues to remain a frequent, yet unfamiliar, presentation which deserves wider recognition. Characterized primarily by fever and other extra-articular manifestations, an acute febrile onset is also called systemic. 6 It is also designated by the term benign systemic disease,‘jg and by the eponyms Still’s type,5 Still’s disease,7o and among Europeans, as the Wissler-Fanconi syndrome.71

That acute febrile onset occurs frequently in JRA is shown in our series of 100 children (Table 2). Of this 100,20% had this mode of presentation. The mean age at onset was 4.6 yr; the youngest child was 6 wk and oldest 13 yr. There were two onset peaks, one at ages 1-3, another from 11 to 13. Boys slightly outnumbered girls; a predilection for boys is found only in this mode of onset.5*6 Perhaps the best way to highlight this mode of onset is to provide a typical case history taken from our current series. Case 1 A 2%-yr-old girl was hospitalized for high fever and arthritis. Seven wk previously, the child developed daily fever ranging from 103’ to 106” F. In spite of a IO-day course of penicillin, the fever persisted. The patient was anorectic and losing weight. One week prior to admission, the knees became painful and swollen. On physical examination, the child was listless and irritable; the rectal temperature was 102.4” F. She refused to walk; the right hip was tender and the right wrist and both knees were warm, red, and swollen. Minimal generalized lymphadenopathy and splenomegaly were present. The rheumatoid rash was absent, but was readily elicited by means of the Koebner phenomenon (Fig. I). The Westergren ESR was 82 mm at I hr. the WBC 37,000 with a moderate left shift, and the hematocrit 33%. Cultures of the throat, nasopharynx, urine, stool, spinal fluid, and blood yielded no pathogens. Pertinent tests that were normal included febrile agglutinins, AS0 titer, heterophile antibodies, LE prep, antinuclear antibodies, and latex fixation. Intermediate strength PPD was negative. X-rays of the chest and involved joints were normal. An ECG disclosed only tachycardia. Acute febrile JRA was suspected, but aspirin was withheld in order to ascertain the fever curve. It proved to be typical of acute febrile JRA (Fig. 2). An evanescent rash was now present, appearing briefly in conjunction with febrile spikes. Fever responded to aspirin, but only when a critical daily maintenance of 1 g/lb of body weight per day was attained (Fig. 2).

An acute febrile onset poses the greatest diagnostic difficulties, particularly when arthritis is absent initially. As is often the case, this child had unexplained fever for 6 wk before joint swelling appeared. Infection was originally suspected

264

CALABRO

ET AL.

Fig. 1. The physician has evoked the Koebner phenomenon by lightly scratching the child’s abdomen. Linear chains of maculopapules appear that often persist for several days. This sign has great diagnostic value in the child presenting with high fever without obvious arthritis.

because of high fever and a striking leukocytosis. The correct diagnosis only became apparent when typical JRA features emerged in the face of negative studies for infection. Recognition of acute febrile onset is easy when the young patient has obvious arthritis in addition to many of the characteristic systemic features (Fig. 3), as it was in 10 of our 20 acute febrile patients. However, in the other ten children, only arthralgia was present initially. The mean interval from the onset of high fever to the development of arthritis proved to be 1.2 yr (the median, 2.5 mo), with a range of 3 wk to a remarkable span of 9 yr, as shown in the following case history. Case 2 This girl was first seen at the age of 7, during the fourth year of FUO, and JRA was suspected. Between the ages of 3 and 12 yr, periodic fever with one or two daily peaks of 104”-105” F recurred

Patient Wt 30 LBS. 13.7 KG.

Fig. 2. The typical fever pattern of an acute febrile onset has one or two daily peaks and wide diurnal variations. Note fever suppression with critical salicylate dosage at 1 grain/lb par day.

1

98 97

1 I

DAYS

-

I

1



1

2

I

3

’ I

1

4

I

5

GRAINS 20

! 1 .

I

6

7

GRAINS 30

I

I

8

g

JUVENILE

RHEUMATOID

ARTHRITIS

265

Fig. 3. Acute febrile onset in a 5-yr-old girl with discrete macules on chest, axillary prominence due to lymphadenopathy, and symmetric swelling of hand and wrist joints. Note the apprehensive appearance. minimal periorbital edema, and abdominal distension. The patient was not receiving steroids.

regularly every 2 or 3 mo. These fevers lasted for 2 or 3 wk, usually accompanied by rash, generalized lymphadenopathy, and arthralgia. Fever responded to aspirin at a daily dose of 120 mg/kg of body weight. On repeated occasions, whenever the daily maintenance dose was empirically reduced by as little as 160 mg, the fever recurred. The 9-yr pattern of periodic fever ceased at the age of 12, when symmetric polyarthritis, including the joints of the hands, developed. The arthritis subsided completely when the patient was 16, and she has remained in remission for the past 8 yrs.

Appearance

Initially, when only arthalgia is present, the patient’s appearance may provide the first diagnostic clues. Younger children, generally those under 5 yr of age, usually appear toxic, listless, and irritable (Fig. 3); they are anorectic and are losing weight. Even with high fever, shaking chills are rare, but seizures are not unusual. Periorbital edema (unrelated to steroid therapy) may be present, as it was in 4 of our 20 youngsters. Paradoxically, older children usually appear healthy, even at the time of fever spikes. Generalized lymphadenopathy is frequent and may be so prominent, particularly in epitrochlear and axillary nodes (Fig. 3), as to suggest leukemia or lymphoma.5 Enlarged mesenteric lymph nodes may cause abdominal pain or distention that may suggest an acute surgical abdomen. In three of our patients, such misdiagnosis led to an inconclusive and needless exploratory laparotomy after other measures, such as courses of antibiotics, had failed. The presence of cerebral manifestations has received scant attention in the past 73,73They may be so striking as to suggest primary central nervous system disease.74 This occurred in 5 of our 20 children, all of whom had marked irritability. In addition, three of these five patients had drowsiness, one had seizures, and one had meningismus. The cerebrospinal fluid was normal in these patients, but their electroencephalographic tracings (unrelated to abnormalities

266

CALAERO

ET AL

A 4-yr-old boy with acute febrile onset who has Fig. 4. obvious polyarthritis facilitating early diagnosis. The patient assumes a typical position of generalized flexion in an effort to ease the discomfort of tender. swollen joints.

from aspirin therapy75) revealed transient, nonspecific focal and diffuse abnormalities. Joint Involvement This is variable, from only arthralgia to a generalized and florid arthritis. Synovitis should always be suspected when a child appears unusually inactive or refuses to walk for the examining physician. Also, children will attempt to protect tender joints without complaining of pain. When in bed, for instance, they will sit or lie in a position of generalized flexion in order to ease the discomfort of tender joints (Fig. 4). In patients with minimal or no objective arthritis, diagnosis then depends on the detection of characteristic systemic manifestations. Systemic Manifestations Of the many systemic manifestations, fever and rash are of the greatest diagnostic value. Both may be associated with generalized lymphadenopathy, splenomegaly, hepatomegaly, pericarditis, myocarditis, pneumonitis, and a striking neutrophilic leukocytosis (Table 3). Fever. Most often, the fever pattern is quotidian (intermittent) or double quotidi~n.B*~70~7s~77 One or two temperature peaks above 102°F (38.9”C) occur daily, while hyperpyrexia (fever to 105” F or 40.5” C) is observed only occasionally (Fig. 2). Diurnal ranges are wide, often as much as 8” or 9” F (4.4” -5” C), so that both hyperpyrexia and subnormal temperatures occur within the same day. Consequently, careful plotting of the fever pattern, with rectal temperatures taken every 4 hr around the clock, may suggest the diagnosis, especially since high fever may precede detectable arthritis by weeks or months, rarely even by years.ss Fever usually responds to aspirin, but relatively large amounts each day, as

JUVENILE

RHEUMATOID

Table 3.

267

ARTHRITIS

Initial Septemic

and Laboratory

Findings in 20 Patients With Acute

Febrile Onset

No. Patients

Findings Systemic High fever

20

Rash

18

Lymphadenopathy

17

Splenomegaly

15

Pericarditis

7

Pneumonitislpleuritis

6

Hepatomegaly

4

Myocarditis

2 1

Iridocyclitis” Subcutaneous

0

nodules

Laboratory Elevated

19

ES R

18

Leukocytosist

13

Anemia Latex titer 1 *Asymptomatic tWhite 20,000

and detected

cell counts to 30,000

were

2

160 or >

on routine slit-lamp examination.

under

in ten, 30,000

:

10,000

to 50,000

in two

patients

between

in five, and at 80,000

10,000

and 20,000

in two,

in one.

much as 130 mg/kg (1 grain/lb) of body weight, may be needed. When the critical amount is reduced (as in Case 2), the fever promptly recurs.6s.76 Rarely is the febrile pattern remittent. 68*77When fever is prolonged or recurs, the pattern may become relapsing or even periodic (as in Case 2). Remittent fever does not fall to normal, in spite of a minimal diurnal variation. Bouts of relapsing fever are interrupted in an irregular pattern by one or more days of normal temperature. Periodic fever recurs regularly, usually at intervals greater than 1 mo. Rash. A characteristic rash78,7g occurs in up to 90% of acute febrile patients6,78 (Fig. 3). It consists of discrete or confluent macules or maculopapules found on the trunk, face, or extremities, including the soles and palms. The eruption is usually nonpruritic, 78 but it may itch, sometimes intensely,80 in about 5% of patients.81 Occasionally constant, the rash is more often evanescent, appearing briefly in the late afternoon or early evening, and often in conjunction with fever spikes. Individual macules tend to migrate from day to day. The degree of erythema also varies; faint lesions may be intensified by massaging or by applying heat. The rash is most florid where the skin has been rubbed or subjected to mild trauma, such as the light pressure of underclothing. This manifestation is known as the Koebner phenomenon. It may be diagnostically useful when parents report a rash that is not present when the child is being examined. The typical rash may then be induced by rubbing or lightly scratching the skin at a susceptible site, an extremity or the lower abdomen 78 (Fig. 1). Within several minutes, blotches of macules will appear and often persist for a day or two. The Koebner phenomenon differs from dermatographia, in which the response is immediate and consists of pale, raised wheals bordered by erythema. We have never observed rheumatoid papules as described in one patient by Brewer.14 However, we have noted, although rarely, the nonspecific urticarial rashes and erythema multiforme that he mentions.14

268

CALAERO

ET AL.

Carditis. While fever may be misinterpreted and the rash overlooked, cardiac involvement of an untreated child may have serious, if not fatal, consequences. Myocarditis is the most serious because it may rapidly induce cardiac enlargement and subsequent heart failure. It should always be suspected in the presence of tachypnea, tachycardia disproportionate to the degree of fever, pericarditis, or pneumonitis. Endocarditis does not seem to occur; cardiac murmurs that suggest its presence are believed to be functional,s2 but they may be related to involvement of the mitral valve.Qa4 Pericarditis, which is more frequent than myocarditis, is usually a benign manifestation that tends to recur. 85 Its early detection is important because it may herald impending myocarditis. Precordial pain or dyspnea are rarely present; most attacks remain asymptomatic and undetected, perhaps overshadowed by other systemic manifestations. Pericarditis should be suspected in all patients, and the child monitored regularly for evanescent friction rub, for cardiomegaly, or for elevated S-T segments and T waves on ECG .s6 Recently, echocardiography has been hailed as the most sensitive indicator of underlying pericarditis.83*84.87 Other systemic manifestations. Pneumonitis or pleuritis may frequently accompany carditis, but they also occur independently. Pleuritis is apt to be asymptomatic and detected as an incidental finding on chest x-ray. Chronic pulmonary fibrosis is rarely observed. Splenomegaly occurs frequently, hepatomegaly less SO.~,~~*” Massive hepatomegaly may be accompanied by abdominal pain and distention (Fig. 3), as well as abnormalities of liver function and nonspecific histologic changes.88 In addition to direct hepatic involvement from JRA, abnormalities of liver function may also result from therapy with aspirin. 8Q*Qo Progressive hepatomegaly should arouse suspicion of secondary amyloidosis, but this complication of JRA is rarely encountered during the first year of disease. Encephalitis and vasculitis are rare manifestations of JRA. Their presence should alert the physician to consider other diagnostic possibilities, particularly polyarteritis or hypersensitivity angiitis. Serous peritonitis is rare, but it constitutes another cause of abdominal pain and distention. Laboratory Findings The most constant abnormality is a striking neutrophilic leukocytosis, usually between 20,000 and 30,000 cells, rarely as high as 80,000 (Table 3). Anemia is usually mild, but sometimes the hematocrit level drops below 30% during an exceedingly florid bout of acute febrile disease. The ESR is usually elevated, as are other acute phase reactants. While these abnormalities are not diagnostic, they may be helpful in following the course in individual patients. Routine urinalysis reveals little except for febrile proteinuria. Serum protein electrophoresis, although frequently normal, may disclose a low concentration of albumin and elevation of gamma and alpha-2 globulins. Serologic abnormalities are infrequent in acute febrile onset; rarely are rheumatoid or antinuclear factors present (Table 3). Differential Diagnosis When arthritis is absent, the early diagnosis of acute febrile JRA rests on frequent examinations for detection of the evanescent rash, the characteristic fever

JUVENILE

RHEUMATOID

pattern, and the physician must always illustrated in

ARTHRITIS

269

other typical systemic features. Despite the presence of such clues, must always eliminate other causes of high spiking fever. Infection be considered first, even in the presence of prominent arthritis, as the following patient.

Case 3 A 16-mo-old girl was hospitalized elsewhere because of fever and vomiting for 1 wk. She was listless and cried when her extremities were moved. On examination, swelling of hands, ankles, and feet and stiffness of the neck were noted. She was thought to have acute febrile JRA and treated with aspirin, 100 mg/kg of body weight daily. After 5 days, because fever and arthritis persisted, she was transferred to us for further evaluation. On admission, the child appeared toxic, had fever of 102” F, and generalized swelling of metacarpophalangeal and metatarsophalangeal joints. There was a striking meningismus. Laboratory studies revealed a white blood cell count of 10,800 and a shift to the left, hematocrit of 23%, Westergren ESR of 80 mm at I hr, and a platelet count of only 56,000. Lumbar puncture disclosed purulent fluid with abundant neutrophils and gram-negative bacilli which on culture yielded Hemophdus influenzae. Despite prompt treatment with antibiotics, the child suffered permanent neurologic damage.

Initially, nuchal rigidity in this girl was believed to be due to cervical arthritis. When we evaluated her, it was the combination of neck rigidity and low platelet count that led us to the correct diagnosis. Clearly, while meningismus may occur in JRA, albeit rarely, thrombocytopenia does not. In addition to infection, other causes of high fever,, rash, and joint pain must be considered. Prominent among these are systemic lupus erythematosus (SLE), polyarteritis, hypersensitivity angiitis, Henoch-Schiinlein (anaphylactoid) purpura, and leukemia. When periodic fever is present, then etiocholanolone fever, familial Mediterranean fever, or “periodic fever” must also be excluded. SLE About 15% of SLE occurs in childhood, although it is rare under 5 yr. Nevertheless, SLE must always be suspected because of its striking resemblance to JRA. In fact, children with SLE, in contrast to adults, are more apt to have generalized lymphadenopathy, hepatosplenomegaly, and high fevergl-features that are also typical of JRA. Like the arthritis, the early rash of SLE may be similar to that found in JRA. To confuse the problem further, a moderate leukocytosis (up to 20,000 cells) may occur in childhood SLE, but white counts rarely soar to the high levels observed in JRA. However, the presence of oral mucosal lesions, renal involvement, and a positive Coomb’s test support a diagnosis of SLE. Further clues to the diagnosis of SLE include the presence of thrombocytopenia, low serum complement, leukopenia, and LE cells, although the latter two findings occasionally occur in JRA.22 On the other hand, the absence of ANA virtually excludes SLE. Actually, ANA may be detected in both JRA and SLE. However, in JRA, the titers are low; in SLE, they are high. Polyarteritis and Hypersensitivity Angiitis It is often difficult to distinguish JRA from these disorders, both of which are rare in children, particularly when their manifestations are atypica1.25*g2 Unlike JRA15 and SLE,g3 criteria for the classification (diagnosis) of these disorders have not been established. Striking cutaneous involvement suggests hypersensitivity

270

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angiitis, which is often caused by drugs, notably sulfonamides and penicillin.g4 The toxic appearance of children with either polyarteritis or hypersensitivity angiitis reflects the variable and widespread organ involvement that results from diffuse vascular occlusion. Case 4 A lCyr-old hoy was admitted to the hospital because of fever, abdominal pain, vomiting, and loss of appetite for 4 days. On physical examination, the patient appeared acutely ill and slightly emaciated. The temperature was 101” F, the pulse 112, and the respirations 20. The blood pressure was I IO/70 mm Hg. There was slight tenderness in the right lower quadrant of the abdomen. The initial laboratory results were Hb 14.8 g/l00 ml, Hct 44%, WBC count 13,400 with 71% segs, 18% lymphs, 7% eos, 3% monos, and 1% basopbils, a Westergren ESR of 63 mm at I hr, and hypergammaglobulinemia. An exhaustive battery of other studies, including chemistry, serology, bacterial and viral tests, were normal. During the initial month of hospitalization, the patient continued to have anorexia, abdominal pain, low-grade fever, progressive anemia, and lost 20 lb. An exploratory laparotomy was then performed. An inflamed appendix was removed, which showed pinworms in the lumen. The patient now complained of arthralgia, numbness of the toes, and weakness of the lower extremities. There was no joint swelling or deformity. Neurologic examination showed mononeuritis multiplex affecting the distal portions of the lower extremities. The Westergren ESR had now risen to 130 mm at I hr; the WBC was 20,000, with a continuing shift to the left and minimal eosinophilia. There was slight elevation of the MOT, SGPT, and LDH. A liver biopsy was performed and disclosed ballooning of hepatocytes with areas of liver cell necrosis. The portal areas showed infiltration of polymorphonuclear leucocytes and perivascular inflammation with fibrinoid necrosis of the arterial wall and destruction of some arteries, compatible with polyarteritis. Retrospectively, additional sections of the appendix removed 2 wk earlier were reexamined and showed similar changes in the appendiceal and mesenteric vessels. The patient responded slowly to 60 mg of prednisone daily. He was well at 6 mo, following which he was sucessfully weaned from steroid therapy without recurrence of disease for 3 yr.

A diagnosis of polyarteritis in children is based primarily on clinical suspicion and confirmed only by biopsy. It was the occurrence of peripheral neuropathy that provided the diagnostic clue in our patient. Additional early clues include hypertension, renal involvement, and purpura. Infantile Polyarteritis

This is an extremely rare form of childhood polyarteritis that is seldom diagnosed prior to death. The onset is acute, often resembling a florid viral infection, and the course is brief and fatal .g6 Diagnosis can only be established by arterial biopsy, but should be suspected in the presence of high fever, evanescent rash, conjunctivitis, abnormal urinary sediment, hypertension, cardiomegaly, and heart failure.g5 Henoch-Schiinlein

(Anaphylactoid) Purpura

Unlike polyarteritis, this disease is usually benign. It may begin with joint pain and swelling, severe colicky abdominal pain, skin rash which is variable and not always purpuric, or any combination of these. Occasionally, a macular erythema of the trunk and face simulating the rash of JRA may be the initial finding. However, purpuric and ecchymotic blotches may soon occur, as well as renal manifestations, both common to this and other forms of necrotizing angiitis.

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271

ARTHRITIS

Leukemia In leukemia and other forms of childhood malignancy, which share many JRA features including high fever and arthritis, profound anemia occurs early.g7*s8 Other signs that suggest malignancy are purpura, leukopenia, or osteolytic lesions on x-ray examination of joints.98 “Periodic Fever”

If the pattern of high fever is periodic, etiocholanolone fever,gg periodic perior even “periodic fever” as a specific tonitis (familial Mediterranean fever), 1oo-102 disorder102 should be considered. These disorders first appear in childhood or adolescence, and recur intermittently throughout life. Attacks of abdominal pain and/or arthritis usually last less than a week; rarely is there fever above 103” F or a striking leukocytosis. POLYARTICULAR

ONSET

This mode of onset, characterized by arthritis of more than four joints, occurred in almost half of our JRA patients (Table 2). There are almost twice as many girls as boys (30:18). Their mean age is 7.4 yr. But polyarticular onset occurs both early and late in childhood; 17 of our 48 children were between the age of 2 and 4, and 17 between 10 and 14. Polyarticular onset in children bears a close resemblance to adult RA, particularly when arthritis is symmetrical and involves the small joints of the hands and feet (Fig. 5). However, when only large joints are involved and antistreptolysin-0 (ASO) titers are elevated, there may be confusion with rheumatic fever as shown in the following case. Case 5 A girl, age 6 yr, experienced popliteal swelling (Baker’s cyst) of the right knee without antecedent trauma. Shortly after surgical excision, florid swelling of both knees and ankles developed. Within the next 2 mo, when additional joints became swollen and tender, she was rehospitalized. On physical examination, the child appeared acutely ill and was irritable, preferring to lie in a position of generalized flexion. Vital signs were normal except for daily afternoon low-grade fever. There was generalized lymphadenopathy, most prominent in the epitrochlear nodes. There was no rash, hepatosplenomegaly, or subcutaneous nodules. Moderate effusions were present in knees, ankles, and wrists. Both elbows were held in 10” of flexion. Laboratory survey disclosed a Westergren ESR of 49 mm at 1 hr, hematocrit 35%, and WBC 13,400 with a slight shift to the left. The AS0 titer was elevated at 1000 Todd units. LE preparations, antinuclear antibody, and latex fixation tests were normal. X-rays of involved joints confirmed soft

Fig. 5. Polystticular onset in a 7-y-old girl: characteristic rheumatoid changes include symmetrical swelling of proximal interphalangeal. metacarpophalangeal, and wrist joints. Swelling between interphalangeal and metacarpophalangeal joints is present, a finding more frequent in children under 5 yr of age.

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tissue swelling; demineralization or erosions were not present. A slit-lamp examination was normal. Aspiration of the right knee yielded 20 ml of amber-colored synovial fluid. The mucin clot was poor, white cell count 24,500 with 81% polymorphonuclear leukocytes, and glucose level 95 mg/ 100 ml (blood sugar: 105 mg/lOO ml). Smear and culture yielded no organisms. The knee was injected with 100 mg of hydrocortisone sodium succinate (Solu-Cortef, Upjohn). The clinical and laboratory findings were all compatible with a diagnosis of polyarticular JRA. On 30 grains of aspirin daily (patient’s weight was 45 lb), the fever and irritability promptly subsided. Within 2 mo, all joint swelling had cleared except for a large effusion of the left knee. This responded to arthrocentesis and intra-articular injection of 20 mg of triamcinolone hexacetonide (Aristospan, Lederle). The patient was then free of joint swelling for 6 mo, after which aspirin was discontinued without recurrence after 2 yr of followup.

The presence of typical systemic manifestations, particularly daily low-grade fever and generalized lymphadenopathy, coupled with striking polyarthritis and characteristic synovial fluid findings are all compatible with JRA. Even the elevated AS0 titer conforms, since it is known to occur in up to 30% of patients with JRA. It is found particularly in patients with a polyarticular onset. In addition to rheumatic fever, there are other childhood rheumatic disorders that may be confused with a polyarticular onset, such as serum sickness or drug reaction. Correct diagnosis, therefore, depends on careful and repeated observations for typical JRA features, beginning with the appearance of the patient. Appearance

Most children appear ill. They are usually listless, febrile, anorectic, and losing weight. The child’s appearance will also depend on whether the onset is abrupt or insidious. When abrupt, there is painful swelling of several joints, which the child will guard by assuming a position of generalized flexion. When insidious, there may be minimal or no complaints of joint discomfort; even early morning stiffness is absent. Nevertheless, these children will wince on movement, limp on walking, or be reluctant to walk or play. Articular Findings

The large joints, the knees, wrists, ankles, and elbows, are the most frequent sites of initial involvement. Affected joints are usually swollen, tender, and restricted in motion. while warmth and redness may or may not be present. Elbow

Fig. 6. Polyarticular onset in a lo-y-old boy with symmetrical swelling of ankle, matatarsophalangeal. and toe joints. The “sausage” shaped second toes ara infrequent findings in juvenile rheumatoid arthritis and ara more characteristic of psoriatic arthritis and Reiter’s syndrome.

JUVENILE

RHEUMATOID

ARTHRITIS

273

involvement is frequently asymptomatic (as in our case above); disclosure of minimal flexion deformities may provide an additional diagnostic clue. The pattern of arthritis varies. It may be generalized, like adult RA, with symmetrical involvement of the hands and feet (Fig. 5,6). In children under 5, however, a fusiform swelling between the joints of the fingers often replaces the more typical swelling at the joints (Fig. 5). The rheumatoid foot. Although much has been written concerning the hand in JRA, relatively little attention has been focused on the foot.‘03 Eventually, the feet become affected in almost half of all JRA patients, often constituting the major source of disability. lo4 The metatarsophalangeal joints are usually the first to become swollen and tender (Fig. 6). Metatarsophalangeal tenderness is best detected by applying light pressure to each of the joints. Swelling of interphalangeal joints is less frequent. Heel pain may also occur, occasionally as the initial complaint.103-105 In the back of the heel, it results from inflammation of the retrocalcaneal bursa (achillobursitis) and/or Achilles tendon (achillotendinitis). At the bottom of the heel, pain is most often caused by plantar fasciitis, or rarely, by a subcutaneous nodule in the plantar fat pad. Whatever the initial site, continuing metatarsophalangeal inflammation promotes contractures of ligaments and supporting structures. These contractures, in turn, lead to progressive hallux valgus, retracted or cocked-toes, and depression (subluxation) of metatarsal heads. Secondary discomfort may be induced by microtrauma from shoes producing callus, corns, and bunions. The cervical spine. Affliction of the cervical spine is frequent. It causes tenderness and restriction of flexion, extension, rotation, or lateral bending. The earliest x-ray changes include demineralization of vertebral bodies and apophyseal narrowing, primarily at C-2 and C-3 (Fig. 7).lo6 Asymptomatic

Fig. 7. Early x-ray changes due to cervical involvement include diffuse deminaralization of vertebral bodies and minimal zygapophyseal fusion at C-2 and C-3.

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sacroiliitis is another early roentgenographic finding that appears to correlate with hip involvement, rheumatoid factor, and with disease onset in patients 10 yr or older.‘O’ Axial articulations other than the cervical and sacroiliiac are rarely involved. Systemic Manifestations

The joint manifestations are the most prominent component of a polyarticular onset. This is in contrast to acute febrile onset, in which systemic features predominate. Nevertheless, rash, lymphadenopathy, splenomegaly, and pericarditis do occur, but are far less frequent (Table 4). Fever is invariably low-grade, with one or two daily peaks less than 102” F. Occasionally, a tachycardia out of proportion to the fever may also be observed. Subcutaneous nodules were present in eight children. Laboratory Findings

The ESR is elevated in the majority of patients, levels being generally lower than those observed in acute febrile onset. White cell counts are moderately elevated, rarely exceeding 20,000 cells (Table 4). Occasionally, the white cell count is normal or minimal leukopenia is noted. A moderate degree of anemia is present in at least half of the patients; it is usually normocytic and normochromic, occasionally hypochromic. The latex fixation test was positive in 12 children, while low titers of antinuclear antibody were present in five. About a third of the patients had elevated levels of immunoglobulins IgG, IgA, and IgM. Selective IgA deficiency was found in two patients. Elevation of AS0 titers, sometimes persistent for years, were present in 20 of the 48 patients. Early roentgenographic changes are nonspecific. These include juxta-articular demineralization, radiodensities from soft tissue swelling and effusion, and, occasionally, premature closure of epiphyses. Periosteal proliferation may also be Table 4.

Initial Systemic

and Laboratory

Findings in 48 Patients With Polyarticular No. Patients

Findings Systemic Low-grade

fever

38

Rash

19

Lymphadenopathy

20

Splenomegaly

11

Pericarditis

3

Pneumonitis/pleuritis

2

Hepatomegaly

2

Myocarditis

0

I ridocyclitis Subcutaneous

1 8

nodules

Laboratory ESR

40

Leukocytosis”

30

Anemia Latex titer 1 : 160 or >

28 12

Elevated

*White

cell counts were usually under 20,000,

the highest was 32,000.

Onset

JUVENILE

RHEUMATOID

ARTHRITIS

275

noted as an early and transient x-ray manifestation that recedes rather promptly in spite of persistence of active synovitis of the affected joint.lo6 Erosions of cartilage and bone are only late features. This is because the cartilage of children is much thicker than that of adults. Therefore, the early presence of erosions must signal a search for some other disorder, particularly leukemia or other forms of malignancy. Differential

Diagnosis

The list of disorders that must be excluded are many, but the most important are rheumatic fever, serum sickness, and drug reactions. Rheumatic

Fever

There are certain similarities that make it difficult to distinguish the early phase of polyarticular JRA from acute rheumatic fever.‘O*The initial arthritis of both disorders may be asymmetric and migratory, involving large joints, and responsive to aspirin or other antirheumatic drugs. Both disorders may manifest low-grade fever, rash, pericarditis, abdominal pain, and elevation of the AS0 titer.5*23 Observation of the fever pattern may provide the first diagnostic clue. Remittent or sustained (continuous) fevers, in which the daily temperature does not fall to normal or subnormal levels, should suggest rheumatic fever, while quotidian or double-quotidian fevers characterize JRA. The erythema marginatum of rheumatic fever may be confused with the rash of JRA, particularly the larger macules with pale centers. However, the rheumatoid rash may be found on the face, soles, or palms, which is rarely the site of erythema marginatum. The individual macules of rheumatic fever generally appear as open rings with distinct outer edges, and only a few discrete rings with pale centers will be present. Erythema marginatum extends centrifugally, while the proximal skin returns to normal, and it rarely lasts for more than a week or two. On the other hand, the rheumatoid rash, while migratory and evanescent, does not spread centrifugally, and it usually recurs for many weeks or months. Several other JRA features help to rule out rheumatic fever. These are onset under 4 yr (when rheumatic fever is rare), nonmigratory symmetric polyarthritis (particularly of the hands and feet), cervical involvement, little or no joint discomfort in the presence of obvious joint inflammation, generalized lymphadenopathy, and hepatosplenomegaly in the absence of cardiac failure. The most important differentiating points in favor of JRA are (1) presence of a poor mucin clot on synovial fluid analysis, and (2) persistence of polyarthritis beyond the second month. The arthritis of an initial attack of rheumatic fever lasts only a few weeks; joint deformities and roentgenographic changes do not occur. Serum Sickness

and Drug Reaction

While polyarthritis and fever are usually prominent, the presence of urticaria and remittent or sustained fevers will favor these disorders, rather than JRA. In both serum sickness and drug reaction, the joints become painful and stiff 2 or 3 days after the skin manifestations appear. Large joints, such as knees, ankles, and wrists, are most frequently afflicted. There may be considerable

276

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swelling and effusion, but heat and erythema are usually absent and deformities do not occur. The joint fluid may contain as many as 20,000 leukocytes/cu mm, predominantly polymorphonuclear cells. However, the ESR is often normal, and there is rarely a significant leukocytosis, as occurs in JRA. Serum complement levels are diminished, the result of binding by immune complexes. This finding constitutes the most important laboratory clue to a diagnosis of serum sickness or drug reaction. Arthritis of Viral Hepatitis Strangely, the arthropathy of hepatitis has not been widely appreciated in the differential diagnosis of acute polyarthritis. logThe small joints of the hands and the large joints of both the upper and lower extremities are most frequently affected,‘1° thereby simulating the arthritis of JRA. Diagnosis is especially difficult when arthritis occurs in the anicteric prodrome of hepatitis. Arthritis and urticaria gradually disappear with the onset of clinical jaundice. Suspected patients, particularly drug addicts, should be checked for total serum hemolytic complement levels, which are severely depressed during the acute phase of their joint symptoms,1og as well as for hepatitis associated antigen (HAA) and liver function tests. The typical features of this serum-sickness-like syndromelOg are best illustrated by the following case. Case 6 A boy, age 14 yr, was hospitalized for low grade fever and a generalized, pruritic, urticarial rash present for 3 days. The patient also complained of swelling of the ankles and knees, as well as arthralgia of the wrists, shoulders, and metacarpophalangeal joints. He recalled one episode of dark urine a few days before admission. The patient initially denied abuse of drugs, but he later admitted to their parenteral use. Initial examination revealed a temperature of 100” F, generalized lymphadenopathy, and an urticarial rash over the extremities and abdomen. The liver edge was palpable 2 cm below the right costal margin; it was firm and nontender. There was no splenomegaly or jaundice. Effusion of the ankles and knees were present. The white cell count was 11,650, the differential count was normal except for 8% atypical lymphocytes. The Westergren ESR was 5 mm at 1 hr. Liver function tests were normal except for slight elevation of the SGOT and SGPT. HAA was positive on two determinations, and the total serum hemolytic complement level was markedly depressed. Jaundice was first noted on the seventh hospital day. It became most florid on the 17th hospital day, at which time the total serum bilirubin was 6.6 mg/lOO ml, along with an SCOT of 630, SGPT 212, and LDH 700. By this time, the rash and joint symptoms had completely subsided.

Rubella Synovitis The arthritis that follows rubella may resemble JRA.“’ A rising or falling hemagglutination-inhibition antibody titer in acute and convalescent sera, as well as the paucity of neutrophils in synovial fluid, serve to differentiate rubella synovitis from JRA.“’ Arthritis as a complication of rubella vaccination occurs in up to 3% of children.‘12 It involves primarily the knees or wrists. Arthritis appears 2-8 wk following vaccination and usually lasts for a few days to several weeks. A normal ESR and changing rubella hemagglutination-inhibition antibody titers constitute the major laboratory clues.

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277

ARTHRITIS

Arthritis of Hypogammaglobulinemia About a third of young patients with hypogammaglobulinemia have arthritis, or, rarely, connective tissue disorders, such as SLE.l13 The arthritis may be transient, but sometimes persists for years with effusions and slight tenderness, particularly of the knees. The tendency to asymmetric involvement, a normal ESR, and the lack of osteoporosis on x-ray are features that help to distinguish this form of arthritis from JRA. Dermatomyositis All of the connective tissue disorders should be considered in the differential diagnosis of polyarthritis. SLE leads the list in terms of frequency; the salient features of this disorder have already been cited. Another misdiagnosis is childhood dermatomyositis, primarily because the arthritis is so similar to that of JRA. Initially, loss of muscle strength is minimal and serum muscle enzymes may be normal, while only arthritis predominates. Clues to an early diagnosis of dermatomyositis include a violaceous periorbital edema (heliotrope facies) and the presence of scaly, atrophic erythema of the skin over extensor surfaces of the joints, particularly knees, elbows, ankles, and metacarpophalangeal joints. MONARTICULAR-PAUCIARTICULAR

ONSET

This mode of onset manifest by arthritis of a single joint (monarticular) or to four joints (pauciarticular) occurred in 32% of our 100 patients (Table Three times as many girls as boys are affected. The mean age at onset was 7.3 with two peaks-one between the ages of 1 and 3 yr, another between 11 and The following is a representative case from our files.

up 2). yr, 13.

Case 7 A 3-yr-old girl, who had been previously healthy, fell on her right knee. That very same day, the parents noticed redness and swelling of the knee, accompanied by a painless limp. The redness promptly subsided as the swelling persisted and the knee was held in constant flexion. After 6 mo of continuous knee swelling, the child was hospitalized with a provisional diagnosis of JRA. Physical examination was normal except for moderate effusion and a 35” flexion contracture of the right knee. Laboratory studies were normal, including a CBC, AS0 titer, C-reactive protein, Westergren ESR, and a latex fixation test. X-rays of the knees showed only soft tissue radiodensity on the right. Arthrocentesis yielded 10 ml of cloudy synovial fluid; smear and culture yielded no organisms, but no other studies were performed. The patient was immobilized in a full-leg cast for 1 mo, but did not improve. Intra-articular steroids were next given on 2 successive months without benefit. A synovectomy was then performed, following which the patient had right knee pain and stiffness for the first time. She also developed intermittent pain of the left knee and right elbow. It was at this time that she was referred to us for evaluation and therapy. Examination disclosed a healthy child except for a 15” flexion deformity of the right knee and slight swelling of the left knee. Aspirin was started, 30 grains daily, based on the usual recommendation of f grains/lb/day (the patient’s weight was 46 lb). She was seen by our ophthalmologist and found to have asymptomatic bilateral iridocyclitis. The visual acuity was 20/30 bilaterally. The patient has required topical mydriatic and corticosteroid therapy since, and she is being evaluated monthly by the ophthalmologist. Her most recentjoint examination was entirely normal.

There are several aspects of this case that deserve comment. Painless swelling is common in a monarticular onset, and it did not detract from a proper diagnosis in spite of a positive history of injury and inadequate studies of the synovial

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fluid. However, management of this patient was clearly inappropriate. Most children with monarticular or pauciarticular disease respond favorably to aspirin, provided appropriate quantities are given, and synovectomy is rarely, if ever, needed. Similarly, prolonged full-leg casting is unwarranted; it only predisposes to muscle atrophy, which requires months to correct. The most serious pitfall was the delay in iridocyclitis detection. Although present in 5510% of all JRA patients, iridocyclitis occurs at an alarming rate of 20% in patients with a monartitular or pauciarticular disease.6*63~64Ophthalmologic screening was delayed until the second year in this child. She may still lose vision because of this unfortunate delay. Appearance

Children 5 yr of age or less are often listless and irritable, have low-grade fever, and fail to grow at a normal rate. On the other hand, older children do not appear ill; constitutional manifestations are notably absent. If the lower extremity is involved, an antalgic (pain-relieving) limp may be noted.l15 Articular

Findings

The onset of arthritis is usually insidious, with swelling and stiffness. Joint pain is usually mild and is sometimes completely absent, even in the presence of marked swelling and effusion. When the hip is involved, pain may be exquisite.‘16 The initial joint most often involved is the knee.6~s4~115~117~118 It proved to be the initial site in 14 of our 32 patients. 64Next in order of frequency were the hip (five patients), ankle (four), and elbow (three). In two children, a single metatarsophalangeal joint was affected, and in one child, a proximal interphalangeal joint of the hand. Painful tendinitis or bursitis of the heel was the initial manifestation in three children. Systemic

Manifestations

Comparatively few systemic manifestations occur in this form of JRA (Table 5). Low-grade quotidian fever was present in only half of the group, while rash, lymphadenopathy, and splenomegaly were only occasionally found. Rash. While relatively infrequent, rash has been a useful diagnostic aid, also cited by Bywaters and Ansell.“’ There are several reports,6~115~118 however, in which rash was not disclosed in this mode of onset. The histologic changes of the skin rash are variable, although the preponderance of perivascular mononuclear cells, rather than neutrophils, may be helpful in differentiating rheumatoid rash from the exanthem of rheumatic fever.‘* Pericarditis, myocarditis, pneumonitis, and pleuritis were notably absent, as were subcutaneous nodules. The most important and potentially serious systemic manifestation was chronic iridocyclitis. It occurred in one of every five patients, a frequency comparable to that reported by others.6~117*118*11g What makes this ocular manifestation so particularly treachIridocyclitis. erous is that it so often is asymptomatic in its evolution, smoldering quietly for weeks or months until failing vision alone compels attention.63*11gIt has even been observed from 6 mo up to 4 yr before the development of arthritis.11g-123 The course of iridocyclitis is usually chronic, with long periods of active ocular inflammation, remission, and subsequent recurrence. Initially, ocular pain and

JUVENILE

RHEUMATOID

Table 5.

279

ARTHRITIS

Initial Systemic

and Laboratory

Findings in 32 Patients With

Monarticular-Pauciarticular

Onset* No. Patients

Findings Systemic Low-grade

16

fever

Rash

7

Lymphadenopathy

6

Splenomegaly

7

Pericarditis

0

Pneumonitis/pleuritis

0

Hepatomegaly

4

Myocarditis

0 7

lridocyclitis Subcutaneous

0

nodules

Laboratory Elevated

21

ESR

8

Leukocytosist

15

Anemia

5

Latex titer 1 : 160 or > “All

32 of our patients

initial month include

had a monarticular

of disease. Nevertheless,

monarticufar.6

onset,

pauciarticular

If we had arbitrarily

probably

(involvement

because onset

included

only

the

of one to four joints) would also

chosen 6 mo of initial

disease as the onset period,

many of our patients would be classified pauciarticular. tWhite

cell

counts

were

usually

under

15,000,

the

highest

was 20,000;

two

patients

had

leukopenia.

redness may be absent, and the process goes undetected until sight is impaired, first from synechiae (adhesions between the iris and ciliary body) or glaucoma, and later by cataract or band keratopathy (Fig. 8). Periodic slit-lamp examinations are the best means of early iridocyclitis detection, when early therapy can still avert major complications. Since we first instituted this approach 12 yr ago, five treatable patients with early asymptomatic iridocyclitis, including two with recurrence, have been detected by routine ophthalmologic screening. In three of these patients, the underlying arthritis had been quiescent for periods as long as 4 yr.

Fig. 8. Undetected iridocyclitis may lead to band keratopathy (as shown above) with calcific deposits extending horizontally across the cornea.

280

Laboratory

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ET AL.

Findings

The routine CBC is especially unrewarding in this group of patients, since the ESR, WBC, and hematocrit are so frequently normal (Table 5). Rheumatoid factor was disclosed in only five patients, a frequency comparable to that reported by Cassidy et al.lls Recently, Schaller et a1.12*have found positive tests for ANA in 51 of ANA. 58 (88%) JRA patients with chronic iridocyclitis. ANA were predominantly of the IgG class of immunoglobulins. In our initial screening for ANA, performed at UCLA,46*63 none of our iridocyclitis patients were positive. Subsequently, ANA was found in four of these patients. We are at a loss to explain this discrepancy. In eight of Schaller’s patients tested early in disease, ANA were found prior to the onset of iridocyclitis. The presence of ANA should prove useful in identifying JRA patients at risk for iridocyclitis, as shown in the following example. Case 8 A girl, 20 yr of age, developed monarticular JRA at the age of 10. The course of disease was characterized by recurrent synovitis of the knees, ankles, and shoulders, readily controlled with aspirin. The patient had been seen by us regularly at 3-mo intervals, although she preferred to have slit-lamp examination done by her own ophthalmologist. The latex and ANA tests had always been negative. On one of her visits, earlier this year, routine serologic studies disclosed ANA for the first time. Slit-lamp examination was normal. When she was seen 3 mo later, she had no ocular complaints, but the titer had risen further. At this time, ophthalmologic examination showed clumps of cells and protein in the anterior chamber of the right eye, so minimal that her ophthalmologist decided to withold therapy. Within a week, the right eye became red and painful, and iridocyclitis treatment was begun. Three months later, minimal synechiae were present in spite of standard local therapy.

Two points of this case deserve comment. The ophthalmologist should have begun iridocyclitis therapy immediately in spite of the minimal findings. The patient developed symptoms from the ocular inflammation, as is often the case when initial or recurrent iridocyclitis develops in young adult life. X-ray examination. X-ray findings here may be more informative than those found in other modes of onset. Nevertheless, they are still nonspecific. Juxtaarticular osteoporosis, accelerated epiphyseal maturation, and metaphyseal overgrowth may occur. Longitudinal overgrowth of long bones adjacent to the affected joint may also occur. 11*This is particularly striking with knee involvement. When the heel is involved, calcaneal erosions, loss of the normal trabecular pattern, and early apophyseal closure may be observed (Fig. 9). Differential

Diagnosis

In this mode of onset, observation of low-grade quotidian fever and evanescent rash is of only occasional diagnostic value. Diagnosis usually requires arthrocentesis and synovianalysis, or synovial biopsy, primarily to rule out infection or traumatic synovitis. Infectious

and Traumatic

Arthritis

Clearly, nothing short of careful analysis of the synovial fluid can help to distinThe gross examination of guish between these two disorders and JRA. 64*118*125

JUVENILE

RHEUMATOID

281

ARTHRITIS

Fig. 9. Progressive left heel involvement from monarticular onset has resulted in premature formation and early closure of apophysis. Note minimal erosions and loss of the fine trabecular pattern of the affected calcaneus.

synovial fluid in JRA shows a yellow fluid that is clear to opalescent. Results of the mucin clot will range from good to poor. The synovial complement level ranges from 20 to 60 hemolytic units. I25The average white cell count is 10,000 cells, but the range is wide, from only 150 to as high as 50,000 cells.1’s There appears to be no correlation of synovial white cell counts and the degree of joint inflammation present clinically. I18 Paired determinations of the serum and synovial sugar values shows only minimal disparity, or no more than lo-15 mg/ 100 ml. Infectious arthritis, whether septic or tuberculous, will disclose cloudy or turbid synovial fluid on gross examination, with a poor mucin clot and a white cell count of 50,000-100,000 cells, sometimes even higher. Microorganisms can often be demonstrated in the synovial smear, while bacterial cultures may or may not yield a specific organism. The difference between the serum and synovial sugar values is marked in infectious synovitis, the disparity being greater than 50 mg/ 100 ml. A negative skin test usually rules out active tuberculous arthritis. If this diagnosis is suspected, synovial biopsy will reveal caseating granulomata. The synovial fluid of traumatic arthritis is noninflammatory in character, with a good mucin clot, white cell count of less than 5000 cells, and no difference in serum and synovial fluid sugar values. The gross appearance of synovial fluid is clear to blood-tinged; the latter finding will often provide the first clue to diagnosis. Case 9 We recently saw a 15-yr-old girl because of an acute onset of pain, swelling, and warmth of the right knee. There was no definite history of trauma, although she had engaged in 4 hr of cheerleading 3 days earlier. Her pediatrician suspected infectious arthritis and referred the patient to us. The right knee was warm, tender, and swollen. Aspiration yielded 20 cc of hemorrhagic fluid; smear and culture were negative. There was no laboratory evidence of an underlying bleeding disorder. With supportive measures, the swelling completely subsided in 1 wk.

Gonococcal Arthritis

The most common

systemic manifestation

of genitourinary

infection with

Neisseria gonorrhea is arthritis. 126In 1968, two different syndromes of gonococ-

282

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ET AL.

cal arthritis were described.lz7 The first is a bacteremic one in which fever, shaking chills, and skin lesions are frequent; multiple joints are involved, but synovial effusion is unusual. The second is a septic joint syndrome which is manifest by monarticular arthritis without fever, chills, and skin lesions. The two clinical forms are believed to represent extremes in the evolution of the disease, from a bacteremic polyarticular stage to subsequent localization in one or a few joints. In a recent reportlzs of 31 adults with gonococcal arthritis by Brandt, Cathgart, and Cohen, every patient showed features of both syndromes, casting doubt on the concept of two clear-cut clinical syndromes. A recent editorial by Sharplz8 supports the Brandt view, as does our own personal experience of children and newborns with gonococcal arthritis.12Q*130 That children can develop gonococcal arthritis is not appreciated.‘2Q-131 We reported five cases found during a 5-yr period (1963-1968); their ages ranged from 5 to 14. In the children reported by Fink, 131the youngest was also 5 yr of age. Our youngest patient, an example of gonococcal arthritis of the newborn, was a 2-wk-old infant. This must be extremely rare, since we have not seen a single case since our report of this infant in 1961.130 Gonococcal arthritis is frequently overlooked, we suspect, because physicians today simply do not believe that a child may have the disease. We cannot urge sufficiently the overriding importance of prompt arthrocentesis in every child who presents with arthritis of a single or only a few joints. Transient Synovitis

of the Hip (Observation

Hip)

This disorder is the commonest cause of painful hip in children.‘32 It is characterized by pain and limp of acute onset that is generally self-limited and unassociated with changes on x-ray examination. Laboratory studies, including the ESR, are distinctively normal. Juvenile Ankylosing

Spondylitis

That pauciarticular arthritis of childhood may precede by years and herald the development of back complaints and ankylosing spondylitis has not been appreciated. 5*37*133-136 Boys are primarily affected, with arthritis principally of the hips, knees, or heels that may antedate back complaints by l-10 yr.136 Other clues to an early diagnosis of ankylosing spondylitis (rather than JRA) include the presence of an acute, not chronic, iridocyclitis,135 restriction of the chest cage (less than 2 cm) because of asymptomatic costovertebral involvement, and asymptomatic sacroiliitis detected on x-ray examination.136 Reiter’s Syndrome

This symptom complex consists of urethritis, conjunctivitis, arthritis, diarrhea, and mucocutaneous lesions. 137It is rare in children and affects primarily boys; the youngest patient ever reported was only 2 yr of age.‘% Weight-bearing joints are most commonly involved, often asymmetrically. A striking manifestation, occasionally the only articular involvement, is an acute synovitis of both the distal and proximal interphalangeal joints of a single digit. Combined with local tenosynovitis, this creates the appearance of a sausage digit, a highly characteristic, but not necessarily diagnostic, sign of Reiter’s syndrome.137

JUVENILE

RHEUMATOID

ARTHRITIS

283

Psoriatic Arthritis There are few reports of psoriatic arthritis in children. We have now observed 11 patients, eight of whom have recently been reported.‘3g The initial arthritis may be monarticular, as it was in five of our patients, and “sausage” digits are frequent. The skin and articular manifestations usually begin simultaneously, but, in four of our children, psoriasis developed l-4 yr after the onset of arthritis. Therefore, in children with pauciarticular arthritis, check for nail pitting, occasionally the earliest clue to impending psoriasis. Other Disorders Be sure to rule out osteochondritis, epiphysitis, or meniscus tear, each of which are characterized by distinctive physical and x-ray findings. In familial osteolysis, a rare syndrome recently described, I41 there is acute arthritis of the wrists and ankles beginning about the age of 5 yr, which is then followed by gradual painless dissolution of the carpal and tarsal bones. Remember, too, that pauciarticular arthritis may be the initial manifestation of such diverse disorders as sarcoidosis, hemophilia, sickle cell anemia, ulcerative colitis, and regional enteritis.15v140 Additional possibilities continue to arise, as in the following patient with lymphedema praecox. Case 10 A 12-yr-old girl was incorrectly diagnosed as having monarticular JRA for almost a year. She came to us because of painless swelling of the left ankle, minimal in the morning and worse at night. No fluid could be obtained on joint aspiration. Laboratory and x-ray studies were entirely normal, The patient was treated with aspirin and the ankle swelling gradually subsided within 2 mos. One month later, she returned with the same findings, and aspirin was resumed. Within 3 mo, the swelling had disappeared, but aspirin therapy was continued. Five months later, the patient again developed painless swelling, this time of the entire foot, ankle, and lower leg.

Lymphedema praecox affects girls predominantly, most often beginning at the time of puberty. It usually begins with puffiness about the ankle or foot. The edema is more pronounced after long periods of activity and disappears with rest. The disorder is usually progressive, so that the entire limb becomes edematous in a period of months to years. Sometimes, however, the swelling remains limited to an ankle or foot, and then diagnosis is obscure, as in our patient. We felt compelled to present this case, not only to point out our obvious error, but also in the hope that others will profit by our experience and avoid this pitfall. Lymphedema praecox should be added to the list of causes to be considered in the child presenting with swelling of an ankle or foot. COURSE OF DISEASE AND OUTCOME

At this time, 15 yr after we first observed them, 63 of our patients are in complete remission. They have no evidence of articular or systemic disease and are not taking any medication. Of the remaining 37 patients, 34 continue to have active disease and three have died (Table 6). Spontaneous remissions occurred most often among children with the most severe systemic involvement initially (75% of those with an acute febrile onset). This surprised us, as did the disclosure that one of the most serious manifesta-

284

CALABRO

Table 6.

Onset, Disease Course, and Outcome Arthritis

Onset

Disease

ET AL.

of 100 Patients With Juvenile Rheumatoid

Observed for 15 Years

Course

Status

After

15

Years

FU”C. Pattern

Modes of

No.

20

onset

Acute

NO.

Febrile

(Systemic)

of

Course

3

Monocyclic

7

Polycyclic

Active

1

0

0

0

0

19

10

1

2

0

0

0

0

22 a

Polyarthritis Monocyclic Pauciarthritis

6

0

6

6

Polyarthritis

4

0

1

0

F$

3

100

t34 *Of

the

zt

Functional

Class II:

Classification.

Adequate

of one or more joints.

for

13 patients

sively downhill

normal

iz$

142 Class I: Ability activities

Class I I I : Limited

or self care. Class IV: Bedridden

patients continue

0

Monocyclic

Pauciarticular

occupation

0

0

13 2

handicaps.

1

0

0

35

motion

0

2

3

Monarticular-

limited

0 AcFeb

3

32

without

Died

Polyarthritis

Polyarticular

Rheumatism

lridocvclitis

10 48

*American

Classes III-IV’

or confined

despite

to carry on all usual duties handicap

of discomfort

or

only to little or none of duties of usual to wheelchair;

little or no self care.

to have active disease, 3 died, 63 are in remission. in functional

course of polyarthritis

classes III and IV, ten have had an unremitting ranging from 4 to 22 yr. Eighty-seven

patients

and progresare in func-

tional classes I and I I. §Of

these nine patients,

only two have lost vision in one eye which

occurred

before referral to

us.

tions, chronic iridocyclitis, developed most often in children who had the mildest form of disease. There is no way to predict the subsequent course of disease for the individual patient. Nevertheless, our observations suggest four major patterns (Table 6). These are: (1) a monocyclic course (18 patients) manifest by active disease terminating within 2 yr from onset without sequelae and without recurrence; (2) a polycyclic acute febrile course (seven patients), in which periods of inactive disease are interspersed with a few weeks or months of acute febrile flareups; (3) polyarthritis (53 patients), or chronic arthritis of more than four joints; and (4) pauciarthritis (22 patients), designated as oligoarthritis in previous reports,5,21 or chronic arthritis of one to four joints. The course of disease is largely determined by the mode of onset. Acute Febrile Onset Of these 20 patients, three have had a monocyclic course. They have been in remission for 15 yr, but their ultimate outcome remains unpredictable. Seven patients have had recurrent flareups of systemic features, primarily high fever and rash, and little or no arthritis-a disease course designated as polycyclic acute febrile. The number of acute febrile attacks has varied from only one to as many as ten in a single year. None of these seven patients has ever developed chronic arthritis, and all but two are presently in remission. One youth, now living in San Diego, had a recurrence recently after being in remission for as long as 12 yr. The other, with recurrent disease for 17 yr (the longest ever recorded), is described below.

JUVENILE

RHEUMATOID

ARTHRITIS

Fig. 10. This youth of 17 yr is over 6 ft tall in spite of over 50 recurrences of fever since the age of 6 wk. There is minimal swelling of the knees.

Case I1 Acute febrile JRA commenced in this patient at the early age of 6 wk. It was manifest by hyperpyrexia, rash, and generalized lymphadenopathy. We first saw him at the age of 4, during his fifteenth acute febrile attack. At that time, he had high fever, rash, lymphadenopathy, splenomegaly, and minimal swelling of the knees. Since then, he has had over 50 recurrences of fever, averaging four a yr, each lasting from 2 to 6 wk. He is now I7 yr of age, and appeared well when this photo (Fig. 10) was taken during his most recent recurrence, in spite of fever of 105.4’ F. His growth and development have not been impaired; he is over 6 ft tall and weighs I50 lb. Fever responded to aspirin, but only when the daily intake was pushed to 9 g (145 grains). Aspirin was discontinued I mo later without recurrence of fever. He has been instructed to take the same amount of aspirin should a subsequent febrile attack occur.

The other ten patients have developed polyarthritis, three after having a polycyclic acute febrile course lasting 4-9 yr (the girl with the 9-yr course has already been described; case 2). Three of these ten patients have had unremitting polyarthritis with a progressively downhill course lasting 5-20 yr. One of these patients, an Syr-old girl, died of nephrosis from renal amyloidosis. Her course was marked by severe polyarthritis and secondary amyloidosis which developed I yr following an acute febrile onset at the age of 3 (Fig. 11). Polyarticular

Onset

Of these 48 patients, the course was monocyclic in 13 and polyarthritic in 35 (Table 6). The course of polyarthritis was intermittent, characterized by

286

CALABRO

ET AL

Fig. 11. Progressive and florid polyarthritis led to the detection of amyloidosis in this girl only 01>e year after an acute febrile onset at age 3. She died of renal failure at the age of 8.

exacerbations and remissions, in 25 children and unremitting in ten. Of these latter ten, all in functional classes III or IV, 142two have died. A 19-yr-old boy died of staphylococcal bacteremia a month after knee synovectomy; the other at age 25, within the past year, of suicide. Monarticular-Pauciarticular

Onset

Of these 32 patients, the course was monocyclic in two, polyarthritic in eight, and pauciarthritic in 22 (Table 6). A course of pauciarthritis is characterized by involvement of relatively few joints, usually four or less, and also by frequent periods of remission and exacerbation .5 All but 6 of the 22 patients with pauciarthritis are in remission, and all 22 are in the more favorable functional classes I and I1.142 On the other hand, 6 of these 22 patients have developed chronic iridocyclitis (27’S), including one already blind in one eye when first referred to us. Another patient has impaired vision of one eye because of chronic iridocyclitis that occurred during active polyarthritis, also when first referred to us. Iridocyclitis has recurred in three of these seven patients with eye involvement, including the two with unilateral blindness, in whom the underlying arthritis had been quiescent for periods of up to 4 yr. We were able to disclose each silent recurrence in the good eye early enough for successful treatment. One of these patients, however, required 4 yr of continuous therapy for protracted iridocyclitis.

JUVENILE

RHEUMATOID

287

ARTHRITIS

Fig. 12. Marked micrognathia in a young man wi th prolonged polyarthritis and PIrogl.essive cervical involvement.

After 15 yr, only 13 patients are in the unfavorable functional classes III and IV,142 or capable of little or no self care (Table 6). Each has had a course of polyarthritis which has been unremitting and deforming. Of these 13, three died, ten had progressive hip involvement, and four had subcutaneous nodules. Also, of these 13, seven had serious problems of growth and development, six of whom also had pronounced micrognathia (Fig. 12). Micrognathia occurred primarily in patients with progressive cervical spine involvement, which suggests that the hyperemia of adjacent cervical inflammation may be causative. Contrary to popular belief, micrognathia did not correlate with temporomandibular involvement. Of our 100 children, 88 have been maintained during the past 15 yr only on aspirin. The remaining 12 patients also received aspirin, but four also needed oral steroids for more than 1 yr (three because of protracted iridocyclitis) and eight required gold therapy. Although we are greatly encouraged by the generally favorable prognosis for this conservative program of management, we do not wish to give the impression that JRA is anything but a difficult and capricious disease requiring vigorous and continuous care of the many articular, systemic, ocular, and psychosocial problems as they arise. MANAGEMENT

In recent years, the fulfilled promise of conservative treatment for the child with RA has changed the entire approach to this potentially dangerous disorder.e*38.143*144 Prolonged corticosteroid administration has proven unnecessary, if not destructive,143.144 and is being used less and less. In a recent world survey of JRA treatment, American rheumatologists used steroids as the

288

CALABRO

ET AL.

sole agent in only 0.3% of cases and in combination with other drugs in 5%. Steroid use was higher in other p&s of the world; it was used alone in 1.5% of patients and in combination with other agents in 27%.145 Effective management begins with early diagnosis, rests on appropriate antirheumatic measures, but depends in large measure on parental cooperation, home care, and adequate followup. 143Generally, what the physician seeks to preserve for his young patient is a childhood as close to normal as possible. The specific and principal goals of treatment are to prevent crippling from progressive polyarthritis and to avert blindness due to chronic iridocyclitis. The physician must acknowledge from the very beginning that he can only initiate and supervise therapy. The core of treatment will be carried out in the home by the parents and patient, and the results will depend on establishing a working relationship with them. Consequently, the physician must educate and motivate the parents. They must be taught all about their child’s disease; what they must do, and what to expect. This is clearly the best way to reassure the parents and to allay their anxieties. The most important components of home care are physical measures. These, however, can be implemented only after active disease has been quelled by one or more of the antirheumatic drugs (Table 7). Drug Therapy

The list of available drugs is limited; many new preparations are on the horizon. Unfortunately, most of these are not being tested in children, so that they will not be recommended for children under 15 yr of age. A recent example is ibuprofen (Motrin, Upjohn), just released in October 1974. Fortunately, the time-honored aspirin is a highly effective drug in JRA. Aspirin

For all modes of disease onset, and for active disease generally, aspirin continues to be the drug of choice. Active disease can be suppressed in the majority of children by four to six daily doses that total 90-130 mg/kg ( 8 -1 grain/ lb) of body weight (Table 7). The more frequent and higher dosage may be required by children with prominent systemic manifestations, as, for example, in an initial or recurrent attack of acute febrile disease.es We usually begin with 90 mg/ kg daily, and increase the dosage slowly to a maximum of 130 mg/kg daily. Experience has taught us that above this dosage we do little more than run the risk of acute salicylate intoxication. With this approach, approximately 10% of patients fail to respond to aspirin. E8When aspirin fails, steroids or other drugs should be used. Only rarely is drug therapy unsuccessful, as illustrated in the following patient. Case 12 When first seen by us, a ICyr-old boy reported recurrent high fever, abdominal pain, and generalized lymphadenopathy for 2 yr. Initially, because of hyperpyrexia and epigastric pain, an abdominal exploration was performed. Diffuse enlargement of mesenteric lymph nodes was found. He subsequently had four additional hospital admissions, with an array of studies and various modalities of therapy, but the symptoms persisted. Examination disclosed the typical rheumatoid rash, generalized lymphadenopathy, and minimal swelling of the proximal interphalangeal and wrist joints. A diagnosis of JRA was established.

JUVENILE

RHEUMATOID

289

ARTHRITIS

Table 7.

Drug Therapy

in Juvenile Rheumatoid

Dosage Range

Drug

90-130

Aspirin

Therapeutic

mg/kg daily

Arthritis Side Effects Unique to Children

Value

Acute toxicity:

Drug of choice

metabolic

acidosis

and hyperpyrexia

in

infants; respiratory alkalosis in older children Chronic toxicity: lethargy

or episodic

hyperpnea

in children

too young to complain of tinnitus Adrenocorticosteroids

0.5-I

Limited*

mglkg

prednisone

Retarded

growth,

pseudotumor

(or

cerebri

equivalent) daily 0.8-l

I M gold

mg/kg weekly

For polyarthritis unresponsive

Reactions are more frequent

to

aspirint Chloroquine

For polyarthritis

4-7 mg/kg daily

or

unresponsive

hydroxychloroquine

in children

under 6 yr Rapid cardiorespiratory arrest on a single

to

dose of 1 g

aspirint

(chloroquine) 50-200

Phenylbutazone

Not recommendeds

mg daily

Hepatitis,

thrombo-

cytopenia,

and

agranulocytosis more often

are

in

younger children lndomethacin

Unknown

Not recommendedz

Unknown

Ibuprofen *Recommended

for

myocarditis,

Not recommendedt pericarditis,

febrile disease, or in patients who do not tolerate tTo

be used only by physicians familiar

SContraindicated arthritis

in children

chronic

iridocyclitis,

Unknown Unknown life-threatening

or acute

or fail to respond to aspirin.

with method of administration

14 years of age or less until

and potential

data on use in juvenile

side effects. rheumatoid

become available.

Hectic fever up to 106” F recurred daily, usually at midday or in the early evening, and was accompanied by evanescent rash and only mild fatigue. Fever continued despite separate trials for 2 mo of 7.2 g of aspirin daily (beyond the point of tinnitus), of 60 mg of prednisone daily, of 400 mg of phenylbutazone daily, and of a combination of 7.2 g of aspirin and 60 mg of prednisone daily. In his fourth year of illness, while the patient was receiving subtinnitus amounts of aspirin, fever became relapsing, both high and low grade, for several months, and then stopped. Fever has not recurred for the past 9 yr. Presently, he is healthy; thejoint examination is entirely normal.

With high fever, the amount of aspirin that is needed is critical: fever may escape established control by reduction of the daily salicylate intake by as little as 150-400 mg.6s*76 One cannot rely on serum salicylate levels because of their poor correlation with a therapeutic response.14*68,146 In using prolonged, high doses of aspirin, the physician must be constantly on the alert for the earliest signs of toxicity (Table 7). In infants and younger children, acute toxicity manifests itself by intense ketosis, acidosis, and, paradoxically, hyperpyrexia. In older children, however, respiratory alkalosis is

290

CALABRO

ET AL.

usually observed.6S Chronic salicylate intoxication is easily overlooked because children rarely complain of tinnitus. The earliest signs are lethargy and episodic hyperpnea; should these occur, aspirin should be stopped for 24 hr, then resumed at a slightly lower dosage. In patients maintained on both salicylates and adrenocorticosteroids, caution must be exercised when steroids are tapered and withdrawn. Steroids increase the renal clearance of aspirin, and consequently their abrupt reduction may precipitate acute salicylate toxicity.147 Only occasionally does aspirin cause gastric upset in children. Control can usually be achieved by changing to buffered, enteric-coated, or choline salicylate. Recent attention has been focused on hepatotoxicity from salicylates.8s~s0 The implications of these observations are not understood. We have also observed abnormal liver function tests in many of our patients. However, we have never encountered a single instance of permanent hepatic damage from our long-term use of this drug, and continue to use aspirin as the drug of first choice. The question always arises as to when to stop aspirin after active disease is suppressed. Initial or recurrent acute febrile attacks that are associated with minimal or no arthritis generally last only 6 wk. Consequently, we gradually withdraw aspirin at this time, but if fever recurs, resume the critical salicylate dose and then try subsequent withdrawals at 3-mo intervals. When high fever and other systemic manifestations subside but arthritis persists, then we reduce the daily aspirin intake to 90 mg/kg (2/3 grain/lb). For initial, recurrent, or persistent arthritis, we usually give aspirin for at least 6 mo after all articular signs and symptoms have subsided, and then begin gradual withdrawal over several weeks. If arthritis recurs, we reinstitute aspirin at the original dose which is again maintained for 6 mo until all signs of arthritis have subsided, and then attempt withdrawal again. Adrenocorticosteroids

These drugs fail to alter the basic underlying disease.‘** Nevertheless, they may be essential for the seriously ill child or when the disease threatens life or sight (Table 7). Quite realistically, steroids have limited therapeutic value in long-term treatment because of marked adverse reactions,143 and an appreciably increased mortality rate.38 Also, they may seriously impair growth.148,14s Alternate-day steroid therapy is attended by less suppression of growth than daily usage.14s However, the maximum dosage that can be safely administered without inhibiting growth has not yet been established. Steroids should not be used for progressive hip involvement. They only predispose the child to the additional hazards of aseptic necrosis of the femoral head and vertebral collapse. A rare adverse reaction to steroids is pseudotumor cerebri, a form of intracranial hypertension causing headache, nausea, vomiting, and papilledema.150 It is due either to an abrupt decrease in maintenance dosage or to a change from one steroid compound to another. To correct this disorder, one must return to the previous maintenance dosage or resume treatment with the original drug. The use of intra-articular steroids may facilitate exercise and rehabilitation. They may benefit patients with pauciarticular arthritis and even those with polyarthritis, when only one or two joints are more severely inflamed than others. As

JUVENILE

RHEUMATOID

ARTHRITIS

291

a rule, we never inject the same joint more often than three times during a 12-mo period-for fear of impairing protective sensory mechanisms. There is also recent evidence that the systemic effects of intra-articular steroids are greater and more prolonged than were previously realized.15’ Gold

In children with polyarthritis who fail to respond to aspirin, gold therapy may be added. The dosage should be calculated on the basis of the child’s weight, being certain to first check for hypersensitivity with an initial intramuscular injection of only 1 mg (Table 7). A weekly dose of 0.8-1.0 mg/kg is administered for approximately 20 wk and then gradually tapered to monthly injections. The buttock is the preferred site, since it assures deep intramuscular deposition and injections here are relatively painless. Side effects are more frequent in children under 6 yr of age15z and during the early months of administration. Renal and hematopoietic toxicity, although uncommon, are the most serious and potentially fatal. It is therefore important to evaluate blood and urine tests before each gold injection. A favorable effect from gold may appear any time from the third to the sixth month of therapy. Clearly, success can only be measured by months of trial and error; this constitutes the major drawback of this form of therapy. Whether to check periodically for serum gold levels is a matter of current dispute.153*154 An timalarials

We have limited experience with these drugs in JRA. They are reserved for patients with polyarthritis who respond poorly to aspirin, and particularly when gold therapy has failed. Laaksonen155 on the basis of toxicity studies, recommends that with chloroquine the daily dosage should not exceed 4 mg/kg per day of body weight, with hydroxychloroquine 5-7 mg (Table 7). Retinal toxicity continues to be the major hazard of long-term treatment, since visual deterioration can continue long after antimalarial therapy has been stopped.156 In children, there is an additional hazard, since the accidental ingestion of as little as 1 g (four tablets) may rapidly produce cardiorespiratory arrest.15’ Because no antidote exists, survival depends on prompt endotracheal intubation and repeated gastric 1avage.158 Other Drugs

Strict analgesics (acetaminophen, codeine, etc.) are unsatisfactory alternates to aspirin because they lack the necessary anti-inflammatory effect. Phenylbutazone, indomethacin, and ibuprofen are not recommended for children 14 yr of age or less. The therapeutic value of these agents in JRA has not been determined. The most serious toxic effects of phenylbutazone (and oxyphenbutazone) are hepatitis, thrombocytopenia, and agranulocytosis. These reactions occur more often in young children and may be fata1.38 We have no experience with the experimental immunosuppressive or cytotoxic agents. There is a report of a single case of JRA with severe disease that responded dramatically to cyclophosphamide. 159We were about to use this drug recently in one of our patients with progressive disease. There was a fortunate delay of 3 mo while the parents pondered the issue. Just about this time, the patient responded

292

CALAERO

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to gold therapy, and therapy with cyclophosphamide was not needed. It is important to stress again that JRA will most often respond to conventional therapy. There is currently only a rare indication, therefore, for these experimental drugs. Home Care

Physical measures are the most important part of the patient’s daily care. Extra rest at night and a nap during the day facilitate resolution of synovial inflammation. Complete bed rest must be avoided, however, since this may lead to flexion contractures because children tend to flex inflamed joints in order to ease pain and spasm (Fig. 4). Another complication of prolonged bed rest is muscle atrophy, which may be appreciable in the short span of only 2 wk.161 Lightweight bivalved splints, made of plaster of Paris or of plastic, may be easily fitted to the individual patient. One use is to rest inflamed joints, another to correct deformities.‘60 When a joint is acutely inflamed, resting splints are generally needed for no more than 3 or 4 wk; sometimes they are only required at night. Sandbags, traction, or other methods of keeping joints in proper alignment are alternatives to resting splints. With hip involvement, traction is preferred to splinting. If a joint deformity has already been sustained, a flexion contracture of a knee for example, serial splinting may prove useful. A new bivalved splint is applied about every 2 wk as the range of motion improves. Splints may be removed to permit daily exercise and then replaced. Two types of casts should be avoided, the cylindrical plaster cast and the wedging circular cast.12 The former predisposes to fibrous ankylosis and marked muscular atrophy, while the latter may lead to fracture by over-vigorous wedging. A physiatrist or physical therapist must teach the patient or parents a program of regular daily exercises that can be performed readily in the home. Daily activities, in addition to prescribed exercises, should be geared to maintain strength and move joints primarily through motions of extension. Recreation and sports can help to achieve these goals. However, those that involve sharp impact (basketball, football, volleyball, etc.) must be avoided. Swimming is an ideal sport; it promotes primarily extension exercises and has the added advantage of the positive buoyancy of water. Keeping the child in school also assures that mental activities are maintained. Sometimes, special provisions must be made to allow the patient more freedom than other children. Special Measures

Basic approaches to proper eye care and corrective joint surgery are currently areas of major interest. Eye cure. The recognition and therapy of iridocyclitis should only be entrusted to an ophthalmologist. One cannot detect early iridocyclitis with an ophthalmoscope. Periodic slit-lamp examinations are therefore the only means of early iridocyclitis detection. These should be carried out at 6-mo intervals in all patients. Children with involvement of only one to four joints (the most susceptible group) require examination every 3 mo, even if the arthritis is quiescent. Children with previous iridocyclitis should have this examination on a monthly basis because of the high recurrence rate. Ophthalmologic screening should be

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routine until patients reach adulthood, when attacks tend to become acute and routine screening for silent iridocyclitis is no longer urgent. One must also observe on routine ophthalmologic screening for the evolution of Sjogren’s syndrome. Unlike iridocyclitis, which occurs in children with minimal arthritis, Sjogren’s syndrome develops in patients with severe polyarthritis. The occurrence of keratoconjunctivitis is also correlated with high titers of rheumatoid factor and the presence of subcutaneous nodules.‘G” Surgery. Particular interest is now centered around early synovectomy. The object is to remove granulation tissue (pannus) soon enough to prevent erosion of cartilage and bone. When to perform this type of surgery is the issue at the moment.lG3 Patients 6 yr or younger are more apt to do poorly because of their inability to cooperate fully with important postoperative measures.164 Early results seemed promising, L66but long-term experience is needed since regeneration of synovium may be followed by subsequent joint inflammation. Future evaluation of this approach will depend upon accumulated experience, including the final results of British and American controlled trials now in progress.166 At 3-yr followup, results of the American multicenter trial revealed no difference between synovectomized joints and control joints. 16’ This study will be continued for a total of 5 yr; the final results should prove interesting. While the status of early synovectomy remains uncertain, established deformities can be successfully corrected by a variety of procedures,163 including the rarely performed soft tissue releases. Epiphyseal stapling may be useful in correction of a valgus deformity of the knee. 16*When hip replacement or other arthroplasty is required, it is usually delayed until the patient is fully grown. Patients may also need orthodontic care or plastic reconstruction of mandibular recession.‘6g Above all, it should be stressed that most children with RA will never require corrective surgery as part of their life-long care. PROGNOSIS

The probable outcome of this disease is mitigated only by early diagnosis and availability of a multidisciplinary approach to management.143 With early diagnosis, a patient’s functional status is appreciably better.*,” Couple this with the care of specialists and consistent home treatment from steadily supportive parents and the outlook is optimal.143 Long-term studies report a mortality in 2%-5% of patients.5~6~12,3s.170,171 Fatalities are rare in acute febrile disease, where they are usually due to myocarditis or profound toxicity. Patients with pauciarthritis rarely die from causes related to their disease. Most deaths occur in children with prolonged active polyarthritis and is primarily due to secondary amyloidosis.‘71 Complete remission occurs in at least 50% of patients followed for up to 10 yr. During this same period, at least 70% will regain normal joint function.“,6,12,3X. 17o-‘72Occasionally, however, a patient in remission for as long as 20 yr will have a severe exacerbation as an adult, resulting in joint destruction and severe disability for the first time.173 ACKNOWLEDGMENT We would like to thank Drs. Joseph Marchesano and G. Richard Parrino for retrieval of information on our current series of patients. We are also grateful to Drs. Michael M. Repice, Shankar

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L. Garg, Elise Jacques, Lawrence G. Kidd, and Robert E. Wagner for their assistance presentations, and to Phil Kaplan, our medical illustrator for visual aids.

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with case

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Is juvenile chronic polyarthritis more than one disease? J Rheum (Suppl) 1:79, 1974 19. Ropes MW, Bennett GA, Cobb S, et al: 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958 20. Calabro JJ: Juvenile rheumatoid arthritis. GP 11:78-88, 1969 21. Calabro JJ, Marchesano JM: Medical intelligence. Current concepts. Juvenile rheumatoid arthritis. N Engl J Med 277:696-699, 746-749, 1967 22. Schaller JG: Rheumatic disorders, in Steim ER, Fulginiti VA (eds): Immunologic Disorders in Infants and Children. Philadelphia, Saunders 1973, pp 403-405 23. Roy SB, Sturgis GP, Masse11 BF: Application of anti-streptolysin-0 titer in evaluation of joint pain and in diagnosis of rheumatic fever. N Engl J Med 254:95-102, 1956 24. Sievers K, Ahvonen P, Aho K, et al: Serological patterns in juvenile rheumatoid arthritis. Rheumatism 19:88-93, 1963 25. Calabro JJ: Juvenile rheumatoid arthritis, in Hollander JL, McCarty DJ Jr (eds): Arthritis and Allied Conditions. Philadelphia, Lea & Febiger, 1972, pp 3877402 26. Bywaters EGL, Isdale I, Kempton JJ: Schiinlein-Henoch purpura. Evidence for a group A B-haemolytic streptococcal etiology. Quart J Med 26:161-175, 1957 27. Sitzmann FC: Der Antistreptolysintiter (ASL) bei der Hepatitis epidemica des Kindes. Arch Kinderheilk 171:260-266, 1964 28. Slomska-Schmitt J, Kozlowska E, Baczynska K, et al: Badania nad surowicami o nieswoiscie wysokim mianie antystreptolizyny 0. Rheumatologia 2:133-135, 1964 29. Ogra PL, Herd JK: Serologic association of rubella virus infection and juvenile rheumatoid arthritis. Arthritis Rheum 15:121, 1972 30. Phillips P, Lim W, Parkman P, et al: Virus antibody and IgG levels in juvenile rheumatoid arthritis. Arthritis Rheum 16:126, 1973 31. Kelley VC: Rheumatoid disease in children. Pediatr Clin North Am 7:4355456, 1960 32. Norcross BM, Lockie LM, Macleod CC: Juvenile rheumatoid arthritis, in Talbott JH, Lockie LM (eds): Progress In Arthritis. New York, Grune & Stratton, 1958

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33. Schlesinger BE, Forsyth CC, White RHR, et al: Observations on the clinical course and treatment of one-hundred cases of Still’s disease. Arch Dis Child 36:65-76, 1961 34. Blom PS, Nicholls G: Emotional factors in children with rheumatoid arthritis. Am J Orthopsychiatry 24:588-601, 1954 35. McAnarney ER, Pless IB, Satterwhite B, et al: Psychological problems of children with chronic juvenile arthritis. Pediatrics 53:5233528, 1974 36. Ansell BM, Bywaters EGL, Lawrence JS: A family study in Still’s disease. Ann Rheum Dis 2 I :243-252, 1962 37. Bywaters EGL, Ansell BM: Sacroiliitis in juvenile chronic polyarthritis. Z Rheumaforsch 24:122-125, 1962 38. Ansell BM: Still’s disease, in Dixon A St J (ed): Progress in Clinical Rheumatology. Boston, Little, Brown, 1965, pp 955113 39. Meyerowitz S, Jacox RF, Hess DW: Monozygotic twins discordant for rheumatoid arthritis: A genetic, clinical and psychological study of eight sets. Arthritis Rheum I l:l-21, 1968 40. Baum J, Fink C: Juvenile rheumatoid arthritis in monozygotic twins: A case report and review of the literature. Arthritis Rheum 11:3336, 1968 41. Howard A, Ansell BM: Vertical starchgel electrophoresis in some rheumatic diseases. Ann Rheum Dis 23:232-235, 1964 42. Peacock AC, Alepa FP: Haptoglobin types in patients with juvenile rheumatoid arthritis. Ann Rheum Dis 25:567-569, 1966 43. Rachelefsky GS, Terasaki PI, Katz R, et al: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 290:892893, 1974 44. Calabro JJ, Repice MM: Letter: W27 antigen and juvenile rheumatoid arthritis. N Engl J Med291:1033104, 1974 45. Brewerton DA, Hart FD, Nicholls A, et al: Ankylosing spondylitis and HL-A 27. Lancet 1:904-907, 1973 45a. Gibson D, Schur PH, Carpenter CB, et al: Distribution of HL-A antigens in patients with juvenile rheumatoid arthritis. Arthritis Rheum 18:285, 1975 46. Bluestone R, Goldberg LS, Katz RM, et al: Juvenile rheumatoid arthritis: A serologic survey of 200 consecutive patients. J Pediatr 77:988102, 1970 47. Torrigiani G, Roitt IM, Lloyd KN, et al: Elevated IgG antiglobulins in patients with seronegative rheumatoid arthritis. Lancet 1:1416, 1970

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48. Barnett EV, North AF Jr, Condemi JJ, et al: Antinuclear factors in systemic lupus erythematosus and rheumatoid arthritis. Ann Intern Med 63:100-108, 1965 49. Miller JJ, Henrich VL, Brandstrup NE: Sex differences in incidence of antinuclear factors in juvenile rheumatoid arthritis. Pediatrics 38:916-918, 1966 50. Zvaifler NJ, Martinez MM: Antinuclear factors and chronic articular inflammation. Clin Exp Immunol8:271~278, 1971 5 I Bianco NE, Panush RS, Stillman JS, et al: Immunologic studies of juvenile rheumatoid arthritis. Arthritis Rheum 14:6855696, 1971 52. Strober W, Blaese RM, Waldmann TA: Immunologic deficiency diseases. Bull Rheum Dis 22:686-69 I, 1972 53. Cassidy JT, Petty RE, Sullivan DB: Abnormalities in the distribution of serum immunoglobulin concentrations in juvenile rheumatoid arthritis. J Clin Invest 52:1931 1936, 1973 54. Panush RS, Bianco NE, Schur PH. et al: Juvenile rheumatoid arthritis. Cellular hypersensitivity and selective IgA deficiency. Clin Exp Immunol 10:1033115, 1972 55. Miller JJ III, Robertson WVB: Mechanisms of arthritis in children, in Schulman I (ed): Advances in Pediatrics, Vol 18. Chicago, Year Book, 1971 pp 151-179 56. Hollander JL, McCarty DJ Jr, Astorga G. et al: Studies on patbogenesis of rheumatoid joint inflammation. I. The “R. A. cell” and working hypothesis. Ann Intern Med 62:271280, 1965 57. Weissmann G: Lysosomes and joint diseases. Arthritis Rheum 9:834840, 1966 58. Zurier RB: Prostaglandins, inflammation, and asthma. Arch Intern Med 133:101Il10, 1974 59. Calabro JJ: Juvenile rheumatoid arthritis. Arthritis Rheum 9:82-87, 1966 60. Calabro JJ: Juvenile and adult rheumatoid arthritis: A comparison. Southwest Medicine 51:193~197,1970 61. Levinson JE: Juvenile rheumatoid arthritis Postgrad Med 51:62-68, 1972 62. Calabro JJ, Parrino GR, Marchesano JM: Prognosis in juvenile rheumatoid arthritis: A tenyear follow-up. Arthritis Rheum 13:310-31 I, 1970 (Abst) 63. Calabro JJ, Parrino GR, Atchoo PD, et al: Chronic iridocyclitis in juvenile rheumatoid arthritis. Arthritis Rheum 13:406-413, 1970 64. Calabro JJ, Parrino GR, Marchesano JM: Monarticular-onset juvenile rheumatoid arthritis. Bull Rheum Dis 21:613-616, 1970 65. Bywaters EGL, Glynn LE, Zeldis A:

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Subcutaneous nodules of Still’s disease. Ann Rheum Dis 17:278-285, 1958 66. Calabro JJ: Discussion, arthritis rounds, rheumatoid-like nodules presenting as “pump bumps” in a patient without arthritis. Arthritis Rheum 13:178-179,197O 67. Calabro JJ, Marchesano JM: Medical management of juvenile rheumatoid arthritis. Bull Rheum Dis 15:378-38 1, 1965 68. Calabro JJ, Marchesano JM: Fever associated with juvenile rheumatoid arthritis. N Engl J Med 276:l l-18, 1967 69. Ansell BM, Bywaters EGL: Diagnosis of “probable” Still’s disease and its outcome. Ann Rheumat Dis 21:253-262, 1962 70. Editorial: Fever in Still’s disease. Lancet 1:1145, 1967 71. Bourel M, Gouffault J, Lenoir P, et al: Fievre, exantheme et polyarthrite rebelle. La maladie de Wissler-Fanconi. Ann Pediatr (Paris) 37:1295-1296, 1961 72. Jan JE, Hill RH, Low MD: Cerebral complications in juvenile rheumatoid arthritis. Can Med Assoc J 107:623-625, 1972 73. Editorial: Cerebral involvement in juvenile rheumatoid arthritis. JAMA 222:1555, 1972 74. Calabro JJ, Garg SL, Parrino CR, et al: Acute febrile juvenile rheumatoid arthritis. Arthritis Rheum 16:536, 1973 75. Brown CL, Wilson WP: Salicylate intoxication and the CNS with special reference to EEG findings. Dis Nerv Syst 32: 135- 140, 197 1 76. McMinn FJ, Bywaters EGL: Differences between the fever of Still’s disease and that of rheumatic fever. Ann Rheum Dis 18:293-297, 1959 77. Schlesinger B: Rheumatoid arthritis in the young. Br Med J 2: 197-201, 1949 78. Calabro JJ, Marchesano JM: Rash associated with juvenile rheumatoid arthritis. J Pediat 72:61 I-619, 1968 79. Isdale IC, Bywaters EGL: The rash of rheumatoid arthritis and Still’s disease. Quart J Med 25:377-387, 1956 80. Schaller J, Wedgwood RJ: Pruritis associated with the rash of juvenile rheumatoid arthritis. Pediatrics 45:296-298, 1970 81. Calabro JJ, Katz RM, Marchesano JM, et al: Pruritus in juvenile rheumatoid arthritis. Pediatrics 46:322-323, 1970 82. Vanace PW, Tuncali M: The incidence and types of heart disease associated with juvenile rheumatoid arthritis. Arthritis Rheum 5~326-327, 1962 83. Nomeir A-M, Turner R, Watts E, et al: Cardiac involvement in rheumatoid arthritis. Ann Intern Med 79:800-806, 1973

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84. Prakash R, Atassi A, Poske R, et al: Prevalence of pericardial effusion and mitralvalve involvement in patients with rheumatoid arthritis without cardiac symptoms. An echocardiographic evaluation. N Engl J Med 289:597600, 1973 85. Lietman PS, Bywaters EGL: Pericarditis in juvenile rheumatoid arthritis. Pediatrics 32:855-860, 1963 86. Laine V, Borkowska K: Electrocardiographic findings in juvenile rheumatoid arthritis. A study of 116 cases. Acta Rheum Stand 12:197-203, 1966 87. Bernstein B, Takahashi M, Hanson V: Noninvasive techniques in the study of cardiac involvement in juvenile rheumatoid arthritis. Arthritis Rheum 16:535-536, 1973 88. Schaller J, Beckwith B, Wedgwood RJ: Hepatic involvement in juvenile rheumatoid arthritis. J Pediatr 77:203-210, 1970 89. Rich RR, Johnson JS: Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis. Arthritis Rheum 16:1-9, 1973 90. Athreya BH, Gorski AL, Myers AR: Aspirin-induced abnormalities of liver function. Am J Dis Child 126:6388641, 1973 91. Meislin AC, Rothfield N: Systemic lupus erythematosus in childhood. Analysis of 42 cases, with comparative data on 200 adult cases followed concurrently. Pediatrics 42:37-49, 1968 92. Hanson V, Kornreich H: Systemic Rheumatic disorders (“collagen disease”) in childhood: Lupus erythematosus, anaphylactoid purpura, dermatomyositis, and scleroderma. Bull Rheum Dis 17:435-440.44-446, 1967 93. Cohen AS, Canoso JJ: Criteria for the classification of systemic lupus erythematosusstatus 1972. Arthritis Rheum 15:54&543, 1972 94. Calabro JJ: Diseases of connective tissue. In Gellis SS, Kagan BM (eds): Current Pediatric Therapy 6. Philadelphia, Saunders, 1973 pp 377381 95. Gillespie DN, Burke EC, Holley KE: Polyarteritis nodosa in infancy: A diagnostic enigma. Mayo Clin Proc 48:773-775, 1973 96. Roberts FB, Fetterman GH: Polyarteritis nodosa in infancy. J Pediatr 63:5 19-529, 1963 97. Calabro JJ: Cancer and arthritis. Arthritis Rheum 10:553-567, 1967 98. Calabro JJ, Castleman B: Case Records of the Massachusetts General Hospital: Multiple osteolytic lesions in a 16-year-old boy with joint pains. N Engl J Med 286:2055212, 1972 99. Bondy PK, Cohn CL, Gregory PB: Etiocholanolone fever. Medicine 44:2499262, 1965 100. Loop JW, Clawson DK: Unusual ar-

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periodic peritonitis. JAMA thropathy in 192:1162-l 164, 1965 101. Sohar E, Gafni J, Pras M, et al: Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227-253, 1967 102. Reimann HA: Periodic fever and periodic peritonitis (periodic polyserositis): Unsettled problems. Am J Med Sci 252:137-145, 1966 103. Calabro JJ: A critical evaluation of the diagnostic features of the feet in rheumatoid arthritis. Arthritis Rheum 5:19-29, 1962 104. Vainio S: The rheumatoid foot: A clinical study with pathological and roentgenological comments. Ann Chir Gynaecol Fenn (Suppl) 45:ll107, 1956 105. Bywaters EGL: Heel lesions of rheumatoid arthritis. Ann Rheum Dis 13:42-5 1, 1954 106. Martel W, Holt JF, Cassidy JT: Roentgenologic manifestations of juvenile rheumatoid arthritis. Am J Roentgen01 88:40&423, 1962 107. Carter ME: Sacro-iliitis in Still’s disease. Ann Rheum Dis21:1055120, 1962 108. Calabro JJ, critical reappraisal arthritis. Clin Orthop

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A, Brackett rubella vacci1971

113. Good RA, Venters H, Page AR, et al: Diffuse connective tissue diseases in childhood: With a special comment on connective tissue diseases in patients with agammaglobulinemia. Lancet 81:192 204, 1961 114. Calabro JJ, Parrino CR, JM: Monarticular-onset juvenile arthritis. Bull Rheum Dis21:613-616, 115. Griffin PP, Tachdjian Pauciarticular arthritis in 184:23328, 1963

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MO, Green WT: children. JAMA

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JT, Brody

CL, and Martel

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Monarticular juvenile rheumatoid arthritis. J Pediatr 70:867-875, 1967 119. Schaller J, Kupfer C, Wedgwood RJ: Iridocyclitis in juvenile rheumatoid arthritis. Pediatrics 44:92-100, 1969 120. Smiley WK, May E, Bywaters EGL: Ocular presentations of Still’s disease and their treatment. Iridocyclitis in Still’s disease. Ann Rheum Dis 16:371l383, 1957 121. Smiley WK: Iridocyclitis in Still’s disease. Trans Ophthal Sot 85:351-356, 1965 122. Kimura SJ, Hogan MJ, O’Connor GR, et al: Uveitis and joint diseases: A review of 191 cases. Trans Am Ophthal Sot 64:291-310, 1966 123. Sury B: Rheumatoid Arthritis in Children, A Clinical Study. Copenhagen, Munksgaard, 1952, pp 6468 124. Schaller JG, Johnson CD, Holborow EJ, et al: The association of antinuclear antibodies with the chronic iridocyclitis of juvenile rheumatoid arthritis (Still’s disease). Arthritis Rheum 17:40!-416, 1974 125. Hedberg H: The depressed synovial complement activity in adult and juvenile rheumatoid arthritis. Acta Rheum Stand 10:109127, 1964 126. Brandt KD, Cathcart ES, Cohen AS: Gonococcal arthritis. Clinical features correlated with blood, synovial fluid and genitourinary cultures. Arthritis Rheum 17:5033510, 1974 127. Keiser HL, Ruben FL, Wolinsky E, et al: Clinical forms of gonococcal arthritis. N Engl J Med 279:234240, 1968 128. Sharp JT: Editorial: Gonococcal infections and arthritis. Arthritis Rheum 17:5 I l-5 12, 1974 129. Calabro JJ: Gonococcal arthritis in the young. N Engl J Med 279: 1002, 1968 130. Sponzilli EE, Calabro JJ: Gonococcal arthritis in the newborn. Report of a case and review of the literature. JAMA 177:919-921, 1961 131. Fink CW: Gonococcal arthritis in children. JAMA 194:237-238, 1965 132. Jacobs BW: Synovitis of the hip in children and its significance. Pediatrics 47:558566,197 1 133. Ellefsen F: Juvenile ankylosing spondylitis. Acta Rheum Stand 13:14-19, 1967 134. Jacobs F: Ankylosing spondylitis in children and adolescents. Arch Dis Child 38:492499, 1963 135. Schaller J, Bitnum S, Wedgwood RJ: Ankylosing spondylitis with childhood onset. J Pediatr 74:505-516, 1969 136. Calabro JJ, Katz RM, Maltz BA: Ankylosing spondylitis. J Pediatr 75:912, 1969 137. Calabro JJ, Garg SL, Khoury MI, et al:

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Reiter’s syndrome. Am Fam Physician 9:80-94, 1974 138. Lockie GN, Hunder GG: Reiter’s syndrome in children: A case report and review. Arthritis Rheum 14:767-772, 1971 139. Calabro JJ, Garg SL: Psoriatic arthritis in children. Arthritis Rheum 16:117, 1973 140. Jacobs JC, Downey JA: Juvenile rheumatoid arthritis, in Downey JA, Low LL (eds): The Child With Disabling Illness: Principles of Rehabilitation. Philadelphia, Saunders, 1974, pp 5-24 141. Gluck J, Miller JJ III: Familial osteolysis of the carpal and tarsal bones. J Pediatr 8 1:506-510,1972 142. Steinbrocker 0, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662, 1949 143. Calabro JJ: Management of juvenile rheumatoid arthritis. J Pediatr 77:355-365, 1970 144. Schaller JG: Editorial: Corticosteroids in juvenile rheumatoid arthritis (Still’s disease). J Rheum 1:137-139, 1974 145. Orozco-Alcala JJ, Baum J: Treatment of juvenile rheumatoid arthritis-A world survey. J Rheum 1:187-189, 1974 146. Paulus HE, Siegel M, Mongan E, et al: Variations of serum concentrations and half-life of salicylate in patients with rheumatoid arthritis. Arthritis Rheum 14:527-532, 1971 147. Kline&erg JR, Miller F: Effect of cortocosteroids on blood salicylate concentration. JAMA 194:131-134, 1965 148. Blodgett FM, Burgin L, Lezzoni D, et al: Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children. N Engl J Med 254:636641, 1956 149. Ansell BM, Bywaters EGL: Alternateday corticosteroid therapy in juvenile chronic polyarthritis. J Rheum 1:176-186, 1974 150. Walker AE, Adamkiewicz JJ: Pseudotumor cerebri associated with prolonged corticosteroid therapy: Reports of four cases. JAMA 188:779-784, 1964 151. Koehler BE, Urowitz MB, Killinger DW: The systemic effects of intra-articular corticosteroid. J Rheum I:1 17-125, 1974 152. Sairanen E, Laaksonen A-L: The toxicity of gold therapy in children suffering from rheumatoid arthritis. Ann Paediat Fenn 8:1055 109, 1962 153. Lorber A, Chang CC, Friou GJ, et al: Application of serum gold determinations for chrysotherapy. Arthritis Rheum 12:312, 1969 154. Gerber RC, Paulus HE, Bluestone R, et al: Clinical response and serum gold levels in chrysotherapy. Lack of correlation. Ann Rheum Dis 31:308-310,1972

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155. Laaksonen A-L, Koskiahde V, Juva J: Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. Stand J Rheumatol 3:103-108, 1974 156. Carr RE, Henkind P, Rothfield N, et al: Ocular toxicity of antimalarial drugs. Long-term follow-up. Am J Ophthalmol66:738-744, 1968 157. Cann HM, Verhulst HL: Fatal acute chloroquine poisoning in children. Pediatrics 27:95-102, 1961 158. Markowitz HA, McGinley JM: Chloroquine poisoning in a child. JAMA 189:950-951, 1964 159. Skoglund RR, Schanberger JE, Kaplan JM: Cyclophosphamide therapy for severe juvenile rheumatoid arthritis. Am J Dis Child 121:531~533,1971 160. Calabro JJ: Rheumatoid arthritis: A potentially crippling disease that may attack at any age. CIBA Clin Symp 23:1-32, 1971 161. Editorial: Bed rest: A two-edged sword. Postgrad Med 46:221, 1969 162. Jackson J, Anderson L, Schur PH, et al: Sjogren’s syndrome in juvenile rheumatoid arthritis. Arthritis Rheum 16:122, 1973 163. Eyring MJ: Report of the Seminar on the Role of the Orthopaedist in the Management of Juvenile Rheumatoid Arthritis. Washington, D.C., Dept. Health, Education, and Welfare, 1972 164. Fink CW, Baum J, Paradies LH, et al: Synovectomy in juvenile rheumatoid arthritis. Ann Rheum Dis28:612-616, 1969 165. Eyring EJ: The therapeutic potential of synovectomy in juvenile rheumatoid arthritis. Arthritis Rheum 11:688-692, 1968 166. Editorial: Synovectomy of the knee in rheumatoid arthritis. Br Med J 2:757, 1969 167. McEwen C, O’Brian WM: Multicenter evaluation of early synovectomy in the treatment of rheumatoid arthritis. J Rheum Suppl 1:107, 1974 168. Laine H, Mikkelson OA: Epiphyseal stapling in juvenile rheumatoid gonarthritis. Acta Rheum Stand 14:317-322, 1968 169. Erich JB: Plastic repair for the receding chin. Mayo Clin Proc 34:419-422, 1959 170. Laaksonen A-L: A prognostic study of juvenile rheumatoid arthritis. Acta Paediatr Stand (Suppl) 166:1-163, 1966 171. Bywaters EGL, Ansell BM: Cause of death in juvenile chronic polyarthritis. J Rheum (Suppl) 1:78, 1974 172. Lindbjerg IF: Juvenile rheumatoid arthritis. A follow-up of 75 cases. Arch Dis Child 39:576-583, 1964 173. Jeremy R, Schaller J, Arkless R, et al: Juvenile rheumatoid arthritis persisting into adulthood. Am J Med 45:419-434, 1968

Juvenile rheumatoid arthritis: a general review and report of 100 patients observed for 15 years.

Juvenile Rheumatoid Arthritis: A General Review and Report of 100 Patients Observed for 15 Years By John J. Calabro, William B. Holgerson, Girish M. S...
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