The ACR on Systemic & Pauciarticular Juvenile Rheumatoid Arthritis

[Guest guest]

Very comprehensive article here, covering lots of aspects of treatment.

Many of us here wonder about the long-term prognosis of our kids. This

article states, regarding data on functional outcomes of systemic onset

JRA, between 25% and 50% of children have active disease after more than

10 years of follow-up.... And, about bone/joint effects, irreversible

changes in 45% of patients as early as 2 years after onset. Which is why

early, aggressive treatment is so important. So many doctors prescribe

just NSAIDs in the early stages when what may be most needed is DMARDs,

to try to prevent this kind of early, lasting damage.

~Georgina

Juvenile Rheumatoid Arthritis

Ilona S. Szer, MD

http://www.medscape.com/medscape/CNO/2000/ACR/ACR-04.html

Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis (JRA), also known as juvenile chronic

arthritis and juvenile idiopathic arthritis, is made up of a variety of

childhood disorders characterized by the development of chronic,

destructive arthritis. Each type of JRA has a different symptom complex,

genetic association, and course. Each represents a distinct entity and

much effort is currently devoted to the nomenclature of these illnesses.

Unfortunately, there is no current agreement on which term to use;

American pediatric rheumatologists continue to use the term " JRA, "

defined in 1977 and validated in 1986 by the American College of

Rheumatology. European pediatric rheumatologists prefer the term

" juvenile idiopathic arthritis " until pathophysiology and genetic

studies allow for more specific names to be used. Still others use the

term " juvenile chronic arthritis " because it best describes the natural

history of these illnesses.

The variety of terms is most confusing to students and physicians who

are not focused full time on childhood arthritis. " JRA " is used in this

review, but a number of the studies discussed may use the other terms

described above.

Pauciarticular Onset JRA

Pauciarticular onset subtype (pauJRA) is frequently complicated by

anterior uveitis. This complication may be as common as 40%, and the

hallmark of the uveitis is that it is asymptomatic until vision is

compromised. Often arthritis goes undiagnosed in children until they

present after having failed a screening vision test at school. Children

diagnosed with pauJRA must undergo frequent evaluations by an

ophthalmologist to document the presence of anterior uveitis and begin

treatment before synechiae and cataracts develop. Although this has been

a subject of intense investigations, to date no predicting factors have

been determined to identify those children at the greatest risk.

To identify children who carry the greatest risk of subsequent

development of iritis, investigators in Padua, Italy, conducted a study

that sought to recognize the cohort of children who may later develop

uveitis at the time of initial presentation with arthritis.[1]

The researchers evaluated 316 children with early onset pauJRA from 3

different centers using initial demographic, clinical, and laboratory

data in a retrospective review. Minimum follow-up was at least 2 years.

Patients were classified into 3 groups. Group 1 consisted of patients

with severe uveitis, which was defined as children with at least 1

episode of anterior uveitis per year or the presence of complications (n

= 66). Group 2 represented children with mild uveitis, who had less than

1 episode of uveitis per year (n = 64). Group 3, the control group,

included all children without uveitis (n = 186).

Two models were created. The predictive model was based on age of onset,

increased alpha 2-globulin, and human leukocyte androgen (HLA) A19 B22

DR9 (P = .001). The second model aimed at predicting severity of uveitis

was based on 2 variables: the time between the onset of arthritis and

uveitis and alpha 2-globulin level. The investigators subsequently

tested both models in a cohort of children from other centers.

The results document the first model's poor reliability of the

predictive value. However, the correlation between the severity of

uveitis and both variables used in the second model was excellent (P </=

..001; sensitivity, 89.5%; specificity, 75%; and efficiency, 85.2%). This

study provides the first reliable method for identifying children with

uveitis who carry a significant risk of severe course and subsequent

blindness, and it successfully predicts this course in 9 out of 10

children. Despite this correlation, children with pauJRA who are at risk

for uveitis should still undergo frequent ophthalmologic evaluations.

Nonetheless, these findings may allow the physician to focus more

efficiently on those children whose uveitis will run a prolonged course

and be associated with the greatest morbidity, and ideally will enable

the prevention of the more severe sequelae by identifying children at

risk early in the course of their uveitis.

Most children with uveitis respond well to local corticosteroids;

however, the rapid progression of some patients require more aggressive

therapies. Some children are threatened with blindness, despite the

addition of oral corticosteroids, methotrexate, and cyclosporine. Reiff

and colleagues[2] examined the efficacy of etanercept in the treatment

of refractory uveitis. Ten children with 18 affected eyes received

etanercept for 3.5-8 months at the recommended dose of 0.4 mg/kg twice a

week. Seven children had pauJRA and 3 had idiopathic uveitis. A total of

10 eyes improved (55%) despite increasing the dose of etanercept to 25

mg twice weekly in unimproved eyes after 3 months of follow-up. Five

eyes (28%) flared and 3 eyes (16%) went into remission. All children

tolerated etanercept well.

This study suggests that etanercept is rarely a remittive agent but may

be helpful in some children with resistant uveitis. Given its rapid

onset of action and low-toxicity profile, it should be used before other

more toxic and equally moderately efficacious agents are tried.

Systemic Onset JRA

Systemic onset JRA is one of the most difficult illnesses to treat. This

disease carries the highest risk of disability and may be associated

with high morbidity and even death. For this reason, the clinical

presentation, prognosis, and clues to the etiology of this highly

inflammatory disorder are of great interest. This onset subtype is

characterized by unremitting frequent fever, evanescent maculopapular

rash, and arthritis.

A highly inflammatory disease, systemic onset JRA presents with high

levels of all markers of inflammation, including white blood cell count,

platelets, and erythrocyte sedimentation rate (ESR) levels. If a child

does not have an elevated white blood cell or platelet count, but ESR is

higher than 120 mm/hr, leukemia should be suspected. The fever of

systemic JRA assumes a characteristic hectic pattern with regular spikes

once or twice daily and returns to normal temperature for many hours in

a 24-hour period.

The course of systemic JRA may be monocyclic, polycyclic, or persistent.

According to data published in 1976 by Calabro and colleagues,[3] only

15% of patients with systemic onset disease follow this more benign

course. About 35% of patients have a polycyclic course, and 50% have a

course that is persistent and unremitting.

Similar data were recently reported by Lomater and colleagues.[4] These

authors examined their experience and found that 11% of children had the

monocyclic course, while 34% had a polycyclic course and 55% developed

persistent disease, suggesting that the majority of patients are at high

risk for disability. Regarding data on functional outcomes of systemic

onset JRA, between 25% and 50% of children have active disease after

more than 10 years of follow-up.

Because systemic JRA is a disease that encompasses both systemic

symptoms and arthritis, outcome data on these 2 expressions of disease

are important. According to several studies,[5-7] systemic symptoms are

present in up to 15% of patients after 1 year of disease duration. In

addition, persistent arthritis is documented in more than 50% of

patients and, in most, assumes the polyarticular evolution. Most

commonly, wrists, hips, ankles, the cervical spine, and the knees are

affected; the prognosis for hip disability is very high and occurs in

almost half of the affected patients. Radiologic studies further confirm

irreversible changes in 45% of patients as early as 2 years after onset,

according to a report by Wallace and colleagues.[8]

Functional tools support the poor outcome data presented above. Using

the Steinbrocker Classification, up to 40% of patients reach class III

and IV, both of which reflect a high level of disability. Newer methods,

particularly the Child Health Assessment Questionnaire, which examines a

variety of functional abilities, document a moderate to severe

disability index in 15% to 28% of patients.

Identifying the patients who are at the highest risk for severe

disability is extremely difficult. Young age of onset (< 5 years) and

female sex are poor prognostic factors. Statistically significant

predictors of severe arthritis are persistent systemic symptoms and high

platelet count; less significant is the presence of leukocytosis,

polyarthritis at onset, and anemia. Using the classifications of

monocyclic, polycyclic, and persistent disease, the functional outcome

of the monocyclic group is associated with 100% remission and normal

function, which is not surprising.

By contrast, 59% of children with polycyclic course and 48% with

persistent course were classified into Steinbrocker class III and IV.

Mortality in systemic JRA varies from 3% to 14%, with an overall

mortality rate of 0.29% (33 deaths among 11,287 patients).[8] Causes of

death are related to either the disease or its treatment.

Disease-related causes include cardiac, macrophage activation syndrome

(MAS), amyloidosis, and neurologic events, often associated with MAS.

Treatment-related causes include infection, MAS, and malignancy.

MAS is a dreaded complication of systemic JRA that carries a mortality

rate of 15% to 30%. It may be a fulminant syndrome at disease onset or

may occur suddenly many years later. Mortality risk increases with

multisystem involvement, especially neurologic and renal, and delayed

diagnosis. It is critical to differentiate MAS from a flare of

underlying disease. Children with MAS have persistent and not

intermittent fever; they are initially weak and quickly become drowsy

and lethargic before becoming comatose. Arthritis is not as prominent a

feature as it is in disease flare, and laboratory studies show

normalization of the usually highly inflammatory parameters, including

ESR. Unless treated aggressively with high-dose corticosteroids and

cyclosporin A, children with MAS progress quickly to death.

Pathophysiology. Systemic onset JRA is a heterogeneous disease with many

differences in disease manifestation, duration, and severity, which may

indicate genetic variability in responses to an environmental agent.

Seasonality of onset has been observed in one part of North America but

has not been supported by others. Infection as a triggering agent is

frequently observed in clinical practice and examples of this have been

well documented.

A genetic predisposition has been proposed for all types of juvenile

arthritis. However, very few sibling pairs with systemic onset arthritis

have been reported, and no family pedigrees have been described in the

Western white populations studied so far. This observation would suggest

that there might be a number of susceptibility genes with weak effects

that are of no consequence in themselves, but when present in a certain

combination (and may require the addition of environmental factors)

would result in this disease. Some of these genes may determine the

severity of disease rather than have a significant effect on

susceptibility.

Association studies of candidate genes have been performed for genes of

the major histocompatibility complex (MHC) and the cytokine network so

far. Genome scans for shared alleles in sib pairs are in progress. HLA

studies have been conflicting and reinforce the impression that systemic

onset JRA is a genetically heterogeneous group. DR4 association has been

found in some populations and not others.[9] No HLA associations have

been found in a recent HLA workshop study of a large cohort of European

children, or in an analysis of a large cohort of UK patients.[10]

Short-term cytokine network imbalance in acute inflammation is normal,

but prolonged imbalance is seen in chronic idiopathic inflammatory

disease such as JRA. A case for the pathogenic nature of interleukin-6

(IL-6) in systemic disease has been well argued in a review by de

Benedetti and i.[11] Serum IL-6 is particularly high compared with

other types of JRA and adult RA. IL-6 in systemic JRA is also

characterized by hypergammaglobulinemia, thrombosis, osteoporosis, and

growth retardation. All of these observations suggest an overproduction

of IL-6. This overproduction is likely to be a genetic trait. Previous

work in Dr. Woo's laboratory[12] has shown a polymorphism in the

promoter of the IL-6 gene that regulates the level of IL-6 expression.

Furthermore, the investigators have shown a significant absence of the

low responder genotype (protective genotype) in systemically ill

children younger than 6 years.[12] Family studies are in progress to see

if this can be confirmed.

Association with a tumor necrosis factor (TNF)-alpha promoter single

nucleotide polymorphism as well as HLA DR4 has been reported in a

Japanese cohort.[13] This may suggest linked markers of the MHC region

to a susceptibility gene, or alternatively, the TNF functional

polymorphism variant could be implicated in the pathogenesis of systemic

arthritis. The authors postulated a difference in environmental and/or

genetic factors between Asian and Western white patients because the

frequency of systemic arthritis was reputed to be much higher in the

Asian patients than in the white patients. Complete haplotype analysis

of the TNF promoter variants will need to be performed in that

population as well as in Western white patients.

Treatment. Systemic JRA is the most difficult onset subtype to treat,

and it takes a serious toll on the well-being of the child and the

family. It interferes with school attendance and work, and is associated

with a high frequency of divorce and decreased functioning by siblings

of affected patients.

Treatment principles are the same as for any chronic childhood

arthritis: to promote normal growth and development and to prevent

disability.

For children with monocyclic course, the combination of nonsteroidal

anti-inflammatory drugs (NSAIDs) and intra-articular steroids is often

adequate. If desired response is not achieved with an NSAID alone,

methotrexate (MTX) is indicated. Although the response to MTX is not as

high for systemic onset JRA as it is for polyarticular JRA, nonetheless,

50% of children achieve good control when MTX is added to the NSAID

therapy (and 89% of children with polyarticular JRA achieve good

control).

Unfortunately, most children with polycyclic and persistent course

require steroids for control of cardiac manifestations, severe anemia,

and poor quality of life. Because of the prolonged nature of this

disease and young age at onset, morbidity related to steroid use is

extremely high, especially short stature, avascular necrosis of bone,

and cataracts. Whenever possible, steroids should be administered using

a once-daily regimen.

1. TNF inhibitors. Etanercept, an anti-TNF receptor protein recently

labeled for use in children with JRA, appears to provide some hope. In a

study by Kimura and colleagues,[14] after 6 months of treatment with

etanercept, 64% of patients improved and up to 53% of responders

improved during the first 2 months of treatment. There was no response

in 33% of the patients.

Infliximab was compared with etanercept in a pilot trial of 15 children

with polyarticular arthritis, as reported by Lahdenne and colleagues.

[15] All patients responded, and both treatment groups did well

regarding efficacy and response to either agent. After 6 months of

treatment, 1 child who had received etanercept had a flare and another

was unable to lower the dose of sulfasalazine. Two children stopped

infliximab therapy because of adverse effects; fever and pancytopenia

developed in a child with systemic JRA, and alopecia developed in a

9-year-old girl with polyarticular JRA along with new onset of

anti-double-stranded DNA antibodies. Although only several children have

received infliximab thus far, this preliminary study suggests that

infliximab is as efficacious as etanercept in the treatment of

refractory childhood arthritis.

2. Cyclosporin A. Cyclosporin A appears to provide some help, but only

6% of patients achieve remission and it is steroid-sparing in up to 42%

of patients.

3. Intravenous immunoglobulin. In small pilot trials, intravenous

immunoglobulin (IVIG) is sometimes associated with improvement, but a

placebo-controlled trial[16] failed to demonstrate a significant

difference in outcome. However, the area under the response curve was a

trend toward improvement. In anecdotal reports, IVIG seems to be

associated with both improvement, decreased need for steroids, and,

rarely, remission.

4. Stem cell transplantation. Autologous stem cell transplantation has

been used as the last possible intervention after failure of 1 or more

of the above conventional therapies. To date, 11 children with severe

systemic onset JRA have been transplanted in Utrecht, The Netherlands.

[17] Two children died posttransplant at 12 days and 5 months. Both

patients had evidence of infection and hemophagocytosis compatible with

MAS. Both children also had evidence of active systemic symptoms prior

to transplant. Of the surviving patients, all are doing well, with only

mild flares of arthritis requiring NSAID treatment. Of interest, most

flares are preceded by intercurrent infections. It appears, therefore,

that autologous stem cell transplantation in these severely ill patients

induces a prolonged drug-free remission but carries a significant risk

of serious infection.

(info on juvenile Sjögren syndrome snipped, for space)

Summary

Recent reports confirm the disabling nature of childhood rheumatic

diseases and underscore the need for physicians to ensure that children

with these conditions have access to appropriate specialists. Pediatric

rheumatologists who are skilled in the evaluation and management of

chronic and potentially disabling conditions should be involved in the

care of these children if at all possible. Children with rheumatic

disease often need difficult, complex treatments over long periods of

time, requiring careful monitoring while at the same time ensuring

optimal growth and function.

References

(snipped. available at websitre, listed above)

The materials presented here were prepared by independent authors under

the editorial supervision of Medscape, Inc., and do not represent a

publication of the American College of Rheumatology.