Juvenile Chronic Arthritis is defined as a
group of Systemic Inflammatory Disorders affecting children below the age
of 16 years.
Three major subsets are described:-
1). Pauciarticular onset - with 4 or less than 4 joints involved.
2). Polyarticular onset - with more than 4 joints involved.
3). Systemic onset - with fever, rash and arthritis.
The condition of Juvenile Chronic Arthritis
was described in 1864, by Cornil who described 4 cases of arthritis in
children aged 12. Subsequently, other cases were described and the first
full overview was published in 1891. However, the first survey, was done
in 1896, by George Frederick Still. He noted 19 cases and also he categorised
these into sub-types. The condition subsequently was termed Stills disease.
Subsequently, these sub-types have been more clearly elucidated.
depends on the which side of the Atlantic Ocean one lives.
Juvenile Chronic Arthritis - JCA is
the terminology used in the United Kingdom, whilst in the United States,
the terminology Juvenile Rheumatoid Arthritis - JRA is more commonly used.
Under the European League Against Rheumatism (EULAR) criteria, Juvenile
Chronic Arthritis requires disease duration of at least 3 months. Whilst
under the American System - ACR Criteria disease duration should be at
least 6 weeks.
In order for diagnosis to be made, one requires
the patient to be under 16 years of age.
Other causes of Juvenile Arthritis require exclusion, before a diagnosis
can be made. In addition, the symptoms should have persisted for at least
6 weeks - 3 months. Before one can more clearly subtype the disease, one
should observe the disease after 6 months.
The different varieties include:-
1) Pauciarticular onset - 4 or fewer joints
- this is the commonest variety: - between 60 - 70%.
2) Polyarticular onset - 5 or more joints affected - comprises approximately
15 - 25%.
3) Systemic onset JCA - includes approximately 20% of the patients and
is closely associated with temperatures up to 39.5ºC for at least
2 weeks - with or without a typical rash.
The sub-types are identified after 6 months
of disease. In fact, an addition subset is noted under the European System
- Juvenile Spondyloarthropathy with Ankylosing
Spondylitis or Psoriatic Arthritis or enteropathic arthritis.
The incidence of
Juvenile Chronic Arthritis is approximately 9 - 25 out of 100 000 with
a prevalence of approximately 12 - 113 per 100 0000. The female to male
ratio is between 2 - 3 to 1. The disease is more frequent amongst Caucasian
patients and is rarer amongst the black population.
1) Pauciarticular onset JCA
These patients have involvement of up to 4
joints. A number of these may evolve into Juvenile Spondylo Arthropathy
or Psoriasis. The majority of these present between 1 and 3 years of age.
It occurs more frequently in females and usually present because the child
has a limp. They usually have no significant fevers or constitutional symptoms.
Commonest joints involved, are the knee - approximately 50%, but the ankles,
elbows or small joints of the hand can also be involved.
There is a large association with Anti-nuclear Antibodies - between 40
- 75% of these children, and they are frequently associated with a Chronic
eye disease - Uveitis - especially if the child is female and under 2 years
with positive Anti-nuclear Antibodies. Routine eye examinations therefore,
become essential and Iris irregularity may be seen on slit lamp microscopic
examination. The eye disease can be unilateral or bilateral - the eye disease
is not related to the pattern of the arthritis course.
With Pauciarticular Arthritis in males - there is a stronger association
with Sacroiliitis and Spondyloarthropathy with enthosopathy. There is an
association in these children, with HLA B27 gene subtype. Iritis is also
common in this group.
Another type of this Arthritis occurs with children with small joint involvement
in the hands and usually this occurs in girls - rather than the boys, and
these patients may subsequently develop psoriasis
2) Polyarticular onset JCA
This occurs in 20% of children with
of these are Rheumatoid Factor IgM positive and they can be similar in
pattern to the adult onset arthritis. Those patients are usually female
and present between 12 and 16 years of age with a symmetrical small joint
involvement, flexor tenosynovitis and frequently nodules and erosions.
Systemic features are less common in this group It is these patients who
frequently develop into active disease in adulthood. Systemic involvement
with extraarticular manifestations may occur- including lung, cardiac,
aortic and vascular disease.
In those patients of polyarticular JCA, who are Sero-negative for Rheumatoid
Factor - there is also an association with fever, hepatosplenomegaly, as
well as a symmetrical arthritis. However, the long-term prognosis is more
favourable. Hip, neck, hand and feet joints are commonly affected, as well
as the knee, wrists and ankles.
3) Systemic onset Juvenile Chronic
This is most serious type of Juvenile Chronic
Arthritis with significant morbidity and mortality. There is a strong association
with fever and this should rise to 39.5ºC for at least 2 weeks for
the diagnosis to be made. The fever, typically occurs late in the afternoon
or evening and returns to normal, or below normal, in the morning. The
child often is ill, and in 9 out of 10 patients, a salmon coloured rash
is seen on the trunk and thighs. The rash may sometimes be itchy. Up to
¾ of patients will have enlarged lymph nodes, liver and spleen.
Serositis may occur and cardiac involvement may also occur with Pericardial
and myocardial involvement. Pulmonary disease can occur with infiltrates,
pleurisy and pulmonary fibrosis.
The arthritis occurs in approximately ¾ of these children - usually
in the wrist, knees and ankles, but the temperomandibular joints, and hands
can also be affected. The condition usually lasts between 2 and 5 years,
Clinical examination in JCA children, often
finds an undersized infant or child with generalised growth abnormality,
compared to those children without arthritis. Growth hormone supplementation
to these children can increase growth patterns. The clinic picture is often
a child with a limp and who has swelling.
X-rays changes usually show soft tissue swelling,
but erosions can occur especially in the Polyarticular variety.
Systemic involvement is seen especially in
the Pauciarticular and Systemic disease subtypes.
The prognosis depends on the sub-type.
80% of those with Pauciarticular Juvenile
Chronic Arthritis are well after 15 years
15% of those with Pauciarticular Arthritis subsequently develop Polyarticular
Arthritis and severe joint involvement.
A major problem in these group of children, is the eye disease and 10%
will have blindness at 10 years.
50% will have a reduced visual acuity.
25% develop cataracts or glaucoma.
Of the group with Spondyloarthropathy, 10%
are limited at 15 years, but 33% will have had hip involvement and some
In those patients with Polyarticular
Rheumatoid Factor - only 10 - 15% have severe limitation at 15 years and
often go into remission with little erosive disease.
However, the Polyarticular Group which are
Rheumatoid Factor positive run a more severe course with only 33% independent
at 15 years with erosions and 20% require total hip replacements and approximately
10% require total knee replacements.
Of those children with Systemic onset Juvenile
Chronic Arthritis 50% remit without recurrence, but the remainder have
polyarticular arthritis with 33% having severe destruction. Those with
disease onset under 5 years do worst and especially those who have persistent
disease activity for the first 5 years. Approximately, 4% of the Systemic
onset - children die from infection and Amyloidosis.
diagnosis includes a variety of conditions including:-
1) Infection - Viral, bacterial, tuberculosis
or lyme disease.
2) Post-infectious - Post Streptococcal / Rheumatic Fever or Post Dysenteric
3) Non-inflammatory causes such as trauma, congenital disorders, slipped
epiphysis, osteochondrosis and hypermobility syndrome.
4) Haematological disorders - including malignancy such as leukaemia or
haemophilia with recurrent intraarticular bleeds. Other bleeding disorders
can also produce bleeding into the joints with joint damage.
5) Collagen Vascular Disorders - including Dermatomyositis, SLE, Mixed
Connective Tissue Disorder, Scleroderma, Psoriasis, Behchets Vasculitis
or Ankylosing Spondylitis.
6) Miscellaneous conditions such as Sarcoid and Familial Mediterranean
7) Malignancy including Leukaemia, Bone Tumours or Neuroblastoma.
It is only after the exclusion of these conditions
that Juvenile Chronic Arthritis can be made.
Exclusion of infection
may require aspiration and culture of the affected joint. But these cases,
usually, are ill with fever and are usually characterised by monoarthritis.
is usually seen with a migratory arthritis and fever - this is exquisitely
presents with painful joints, fever, thrombocytopenia and neutropenia.
The Collagen Vascular
Disorders can present with Arthritis, but
the associated features usually differentiate them.
Since the exclusion of other Arthropathies
are required, it is important to do :
Blood Count. Usually one sees an anaemia of Chronic disorders with elevated
Ferritin and a Leukocytosis (elevated White Cell Count). Thrombocytosis
may also be seen and thrombocytopenia is rare. Mild Proteinuria can be
identified and this is seen frequently in JCA (20 - 40%).
The ESR is usually elevated, but that does not correlate well with clinical
Rheumatoid Factors are present in 15 - 20% of the children - especially
those with late onset Polyarticular Juvenile Chronic Arthritis.
Anti-nuclear Antibodies are seen in 40 - 60% of the Pauciarticular variety.
Technetium bone scans may be helpful for early diagnosis where X-rays and
blood tests are normal.
and immune aspects.
The cause of the arthritis is largely
but several predisposing factors are identified.
A possible infectious aetiology has been considered for a variety of arthritis
conditions and clustering of patients, frequently following viral epidemics,
are identified episodically.
A wide range of viral infections are noted, including common illness such
as mumps, rubella, parvovirus, (especially that type causing Fifth Disease
- Parvovirus B19 - which causes erythema infectiousum.
However, overall, no virus has been isolated
from children with chronic arthritis and possible theories as to viral
onset, include cross immunity between the infectious agent, and a genetically
susceptible host. This is also seen in forms of Reactive Arthritis and
clear association has been identified following Streptococcal and Yersinia.
The Genetically susceptible host is identified
by the HLA Class Molecules.
For the Spondyloarthropathys, HLAB-27 is strongly identified.
For the Sero-positive Polyarticular Juvenile Chronic Arthritis - there
is an association with HLA DR 1 and DR4 - Class 2 Molecules.
For early onset Pauciartricular JCA with chronic uveitis - there is an
association with HLA DR5 and DR 8.
For early onset Pauciarticular JCA - there is an association with DQW1
The Systemic onset JCA has an association with HLA DR4.
The pathology of the tissues if one examines
the synovium, shows a vascular tissue with villous hypertrophy.
The synovium lining cells often contain engulfed material .
There is an increase in fibroblasts and an infiltration of plasma cells
The synovium is also rich in macrophages.
It is observed that the synoviocytes express Class 2 surface molecules
and may be the antigen presenting cells during the acute active process
- they release IL2, IL-6 and GM-CSF.
The lymphocytes that are located nearby are usually T-cells - CD4 variety
(helper cells), although CD 8 (Suppressor cells) may also been seen.
Cytokines are produced in particular, from macrophages - IL-1, IL-6, tumor
necrosis factor (Alpha), and GM-CSF. There are relatively low levels of
IL-2, IL-3, IL-4 and Interferon gamma, and tumour necrosis factor (beta).
IL1 is associated a fever and the acute phase response.
The Anti-nuclear factors that are produced are usually the speckled variety.
Homogeneous staining is also frequent.
SM Antibody, RNP Antibody, SSA / SSB Antibody and Anti double-stranded
DNA antibody are usually absent. Anti-histone antibodies are common.
Rheumatoid Factors are rarely specific and usually the IgM variety. In
the Polyarticular variety, IgA Rheumatoid Factor is seen in 60%.
Anti-cardiolipin antibodies have been found in patients in approximately
30% of JCA children, but clinical manifestations of Anti-cardiolipin antibodies
are rarely seen and their significance is not clear.
Immune complexes are frequently elevated and complement activation also
The main purpose of therapy is
Preserve function of the joint
Maintain normal growth and psycho-social development.
This usually requires a Multi-therapist approach
- including :
Ophthalmologists in the team.
The usual outcome is good to excellent in the
majority, but it is not possible at onset of disease to predict which child
will do better and an initial aggressive approach to control articular
inflammation and systemic disease, as well as to prevent deformity, and
maintain muscle strength, may be required.
This therapy depends on the sub-type of disease - Polyarthritis, pauciarticular
arthritis or Systemic Variety.
Adequate nutrition is also crucial. This reduces the growth retardation
and malnutrition aspects of the disease.
Physical and occupational therapy, maintain function and prevent deformities.
Initially, passive and subsequently active motion of involved joints is
performed, to encourage and maintain weight bearing and general activity.
However, whilst it is important to maintain activity as much as possible,
rest is also important - especially to that of swollen weight bearing joints.
Swimming is probably one of the best forms of exercise.
Counselling to the child and to the family is also important to try and
reduce the anxiety and help share management of the disease. Full education
of the disease is required. Such education can be performed by the doctor
or nurses, physical therapists and occupational therapists combined.
The medical therapy, is designed to
reduce pain and the single most useful agent
is that of the non-steroidal anti-inflammatory drug.
Commonly used varieties include -
Aspirin 75 - 90mg/kg/day. Higher doses are tolerated in the younger. The
dose should be given 4 times a day, with meals. Elevated liver enzymes,
or Hepatitis, may develop in some children, but overt manifestation of
liver disease are extremely uncommon. A potential association between Aspirin
and Reyes Syndrome with Encephalopathy has been identified often with viral
illnesses. These children should be immunised for influenza and possibly
also to Varicella (chicken pox).
A number of anti-inflammatories
can be used instead of Aspirin - most commonly used are:-
Tolmetin 25mg/kg/day in 4 divided doses.
Naproxen 15mg/kg/day in 2 doses.
Ibuprofen 35mg/kg/day in 4 doses.
Diclofenac 2 - 3mg/kg/day in 2 doses.
Response should be seen by about 4 weeks.
Indomethacin can be used in the older child, but not in the younger child
and is especially used for Systemic Disease.
Toxic effects of the anti-inflammatories include
Renal toxicity with reduced renal output.
This is usually seen in immobilised or severely disabled children.
Analgesics including Paracetamol or Acetominophen
can be used for control of pain and fever.
Disease modifying drugs - DMARDs
- this is done as calculating a weekly dose and spreading this over the
week, in particularly small children. It is the least toxic DMARD.
Side affects include Retinopathy and Ophthalmological examination of the
red fields and colour vision should be done prior to therapy and then every
6 months afterwards. Clearly, this is difficult in children younger than
age 6 - 7 years. Corneal deposits are an indication for lowering the dose
of the drug. Response is seen only at 2 - 3 months up to 6 months. Improvement
occurs in 15 - 75% and remission up to 45%. Other toxicity includes GIT
irritation, dermatitis and bone marrow suppression.
Gold - this is
given as either intramuscular or oral gold.
Indication includes those children who have had unresponsive polyarthritis
for 3 - 6 months or where there is a rapid progression of arthritis. Doses
are 5mg IMI with weekly doses increasing to 0.75-1 mg/kg/week.
Objective improvement is seen within 6 months.
Maintenance therapy can then be started every 2 weeks for 3 months, every
3 weeks for 3 months and thereafter, monthly.
Toxicity includes bone marrow supression, renal toxicity and rashes and
skin reactions. 25% are unable to continue treatment because of toxicity
Improvement is seen between 29- 80% and remission up 60%.
Oral gold - Auranofin,
0.15 to 0.2mg/kg/day is given orally and appears safe for long-term management.
Toxicity is relatively mild with diarrhoea, abdominal pain or a rash and
It is however, felt to be less effective than the other preparations with
only approximately 20% remission at 5 years.
- 10mg/kg/day. This given on an empty stomach because it can bind the food.
It is effective in between 10 - 75% of patients with a remission in 20%.
However, there is a considerable side affect profile including renal toxicity,
gastrointestinal, and bone marrow toxicity.
Regular blood counts and renal function assessments are important.
Toxicity occurs between 10 - 55% and approximately 65% of the children
are taken off this drug because of adverse reaction.
tends to work over 6 weeks to 2 months. This is usually used for children
who have not responded to conservative therapy and the maintenance dose
is 40 - 60 mg/kg/day in 3 - 4 divided doses. One requires a slow increase
in the dose over 4 - 6 weeks - maximal dose is 2g/day. Side affects include
Gastro-intestinal Toxicity, mouth ulcers, skin rashes and bone marrow problems.
There is an association with significant leukopenia, thrombocytopenia and
acute pyrexia - this would required cessation of the therapy.
in the past used for management of severe polyarticular disease who had
failed to respond to other medications. Methotrexate is well established
in the treatment of adults with Rheumatoid Arthritis at low dose - the
drug is given as a weekly therapy with efficacy after approximately 2 months.
Dosage in children is that of 10 mg/m2/week and blood tests are usually
done prior to therapy at 2 weeks, 1 month and then every 2 - 3 months thereafter.
Monitoring of Liver Functions and Blood Counts are required.
Risk factors for this however, no longer require mandatory liver biopsies.
Studies have not shown evidence of Fibrosis in liver biopsies in children
at this time.
Preferably, Salicylates should not be used with Methotrexate.
There is no definite association with oncogenicity, other than very isolated
reports of haematological malignancies and no production of sterility.
Overall, there appears to be a low toxicity
as measured and reported in a number of studies on Methotrexate in children
One usually sees a reduction in the systemic features and, reduction in
the joint counts and a reduction in the requirements for corticosteroids.
Monitoring of efficacy can be performed with
joint counts as well as the ESR and CRP.
The world experience and literature seems to have established that Methotrexate
is perhaps the most effective agent for use in Chronic Juvenile Arthritis
Systemic toxicity however, does include :
Bone marrow suppression.
Pulmonary toxicity with pneumonitis is also seen occasionally.
- this has been used in adults in the past.
Due to nephrotoxicity - (renal toxicity) it is therefore, used with caution
Other immuno-suppressant drugs
- include Azathioprine
and Alkylating agents - Cyclophosphamide
These however, are associated with sterility and amenorrhoea and they are
used as an adjunctive therapy in steroid toxic children and for systemic
disease with life threatening complications and for severe progressive
recent change is now the availability of biologic drugs where first line
drugs such as methotrexate fail. Results have been astounding. Disease
control is better and the greater the degree of swelling stiffness and the
greater the degree of inflammation, the better the results. Trials today
suggest that the anti TNF drugs such as Enbrel, Humira and Remicade /
Revellex and anti IL6 drugs such as RoActemra . Tocilizumab are the best
for JRA. These do have a more
profound suppression of the immune system, so we still tend to hold them
as a second line. However the more aggressive the disease the greater the
urgency to use them.
Intravenous Gamma globulin
- has been used in a number of autoimmune diseases, especially in Systemic
Juvenile Chronic Arthritis with Vasculitic Diseases and Idiopathic Thrombocytopenic
purpura, and dermatomyositis. The dose is 2g monthly intravenous for one
are indicated for those children with life threatening complications and
also topically for the eye involvement. They are extremely effective, but
are major cause of growth retardation and
bone demineralization. The dose for systemic
complications is 0.5 to 1mg/kg/day and in general, the use of the drugs
to suppress joint inflammation is not generally advisable, although low
dose may be of benefit for those children with severe polyarthritis who
are unresponsive to other therapeutic modalities.
They are also useful as an interval therapy pending the action of disease
modifying drugs - DMARDs. Withdrawals should be attempted slowly against
the benefit of these DMARDs.
Severe Systemic manifestation are also treatable
by intravenous pulse therapy
- using Medrol
10 - 30mg/kg/pulse, using up to 3 pulses on alternative days.
Intraarticular injections, using in particular
Triamcinolone 5 - 30mg depending on the size of the joint are useful for
joints that are out of phase with the general picture. However, this is
difficult in children because of the difficulty in giving injections. Sometimes
injections can be given with a light anaesthetic.
can be used for Uveitis, but this requires an ophthalmologist opinion where
possible. Occasionally, oral steroids may be required to control the uveitis.
therapeutic intervention therefore,
is a multiple disciplinary approach bringing the parents and family into
the management team and educating them. Basic therapy with non-steroidal
anti-inflammatories are required to control of pain together with analgesics.
Occupational and Physical therapy
and exercises are essential and adequate nutrition is essential. Where
the joint manifestations are poorly controlled or in the polyarticular
variety. An addition of a disease modifying drug is probably advisable
using in particular, Hydroxychloroquine or
Sulphasalazine or Gold initially, but in resistant disease Methotrexate
or combined therapy.
More recently, it is current practice that
the more efficacious drug such as Methotrexate are employed earlier in
the concept of inverting the pyramid. Where therapy fails at symptomatic
may be used with reservation - aiming at low dose, unless there is severe
Immunosuppressive therapy is used for life
threatening systemic disease.
Long-term outcome may require surgical
management where necessary.
This includes modality such as joint replacement
or synovectomy. Total joint replacement in
a growing skeleton is reserved only for those cases where there is severe
limitation of the childs physical capacity. The implant must be small
enough to fit the skeleton and in most cases, the joint is usually subluxed
or destroyed prior to replacement. Long-term follow-up shows loosening
of the prosthesis and later infections, could be a potential problem. Cementless
hip prosthesis are now available and the inevitable redo operations are
more easily performed.
Rehabilitation is a vital component and hydrotherapy
in particular is very useful and beneficial.
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