Juvenile Chronic Arthritis : JRA / JCA  by drdoc on-line
  1. Definition
2. History
3. Terminology
4. Epidemiology
5. The subtypes
6. Clinical picture
7. Prognosis
8. Differential diagnosis
9. Investigations
10. Aetiology
11. Pathology
12. General management
13. Medical therapy
14. Summary approach to therapy

 

 

Definition

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.

History

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 Still’s disease. Subsequently, these sub-types have been more clearly elucidated.

Terminology 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 39.5C 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.

The Sub-types:-

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 JCA. Some of these are Rheumatoid Factor IgM positive and they can be similar in pattern to the adult onset arthritis. Those patient’s 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 patient’s who frequently develop into active disease in adulthood. Systemic involvement with extraarticular manifestations may occur- including lung, cardiac, aortic and vascular disease.
In those patient’s 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 Arthritis

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 39.5C 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 of patient’s 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 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, before remitting.

Clinical

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.

Prognosis

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 limitations.

In those patient’s with Polyarticular Sero-negative 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.

Differential 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 Fever.
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, Behchet’s Vasculitis or Ankylosing Spondylitis.
6) Miscellaneous conditions such as Sarcoid and Familial Mediterranean Fever.
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.

Rheumatic Fever is usually seen with a migratory arthritis and fever - this is exquisitely painful.

Malignancy usually presents with painful joints, fever, thrombocytopenia and neutropenia.

The Collagen Vascular Disorders can present with Arthritis, but the associated features usually differentiate them.

Investigations.

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 disease.
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.

Aetiology and immune aspects.

The cause of the arthritis is largely unknown, but several predisposing factors are identified.
A possible infectious aetiology has been considered for a variety of arthritis conditions and clustering of patient’s, 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 Spondyloarthropathy’s, 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 and DPW2.
The Systemic onset JCA has an association with HLA DR4.

Pathology

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 and lymphocytes.
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 common.

Management

The main purpose of therapy is to
Relieve pain
Preserve function of the joint
Maintain normal growth and psycho-social development.

This usually requires a Multi-therapist approach - including :
Rheumatologists,
Paediatricians,
Physiotherapists,
Occupational Therapists,
Orthopoedists and
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.

Medical therapy:

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.
Mefenamic acid

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

Hydroxychloroquine 4mg/kg/day - 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 profile.
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 itch.
It is however, felt to be less effective than the other preparations with only approximately 20% remission at 5 years.

Penicillamine - 10mg/kg/day. This given on an empty stomach because it can bind the food. It is effective in between 10 - 75% of patient’s 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.

Sulphasalazine 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.

Methotrexate was 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 with arthritis.
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 in Children.

Systemic toxicity however, does include :
Bone marrow suppression.
Gastro-intestinal ulceration.
Diarrhoea.
Alopecia.
Dermatitis.
Hepatic cirrhosis.
Pulmonary toxicity with pneumonitis is also seen occasionally.

Cyclosporine A - this has been used in adults in the past.
Due to nephrotoxicity - (renal toxicity) it is therefore, used with caution in children.

Other immuno-suppressant drugs - include Azathioprine and Alkylating agents - Cyclophosphamide and Chlorambucil. 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 erosive arthritis.

Biologic drugs: The biggest 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 year.

Corticosteroids 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.

Corticosteroid eye-drops can be used for Uveitis, but this requires an ophthalmologist opinion where possible. Occasionally, oral steroids may be required to control the uveitis.

The overall 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 level, Corticosteroids may be used with reservation - aiming at low dose, unless there is severe systemic involvement.

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 child’s 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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Dedicated to Evelyn and Elena :-
who I havent met , but who never give up.
Article by drdoc on-line
Rheumatologist
Cape Town
July 1997

Revised 2011