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Editorial

Indian Pediatrics 2001; 38: 1083-1090  

Diagnosis and Management of Juvenile Idiopathic Arthritis: Current Status


Nomenclature and Classification

Juvenile idiopathic arthritis (JIA) is the umbrella term for a group of chronic childhood arthritides of unknown cause, in children below sixteen years of age, and persisting for at least six weeks. This is the new term proposed by the International League of Associations of Rheumatologists (ILAR) whose taskforce met twice to propose a unified classification in 1995 in Santiago, Chile and revised it in Durban in 1997(1,2).

This was necessary because the terms JCA (juvenile chronic arthritis) as defined by the European League Against Rheumatism - (EULAR) and JRA (juvenile rheumatoid arthritis as defined by the American College of Rheumatology) - (ACR) were not inter-changeable because the classification of subgroups and their definitions were different. Though the terms JCA and JRA represent different diseases they are often used interchangeably, making comparison of studies of the biological process and thera-peutic trials difficult. The primary goal of the ILAR classification has been to identify as far as possible, clinical and biologically homogenous groups of children with chronic arthritis. This is an essential first step towards further research to elucidate pathogenetic mechanisms of these conditions(1).

The Durban revision of the ILAR classification describes seven categories of patients with specific definitions, descrip-tors and exclusions for each type. The categories are listed in Table I, and the reader is referred to references 1 and 2 for a detailed review. The taskforce proposes to review this in the light of new data on clinical utility as well as new genetic/biological data, i.e., classification is of necessity a continuing process.

Incidence and Prevalence

The incidence of JIA is 10/100000, with a prevalence of probably 50/100000. This data is primarily from Northern European and White American populations, and illus-trates well the chronicity of the disease(3). There is paucity of epidemiological data on JIA from the Indian subcontinent.

Diagnosis

The diagnosis of JIA remains a clinical one, and is essentially one of exclusion in addition to pattern recognition (see below). There are no clinical, laboratory or radio-logic tests that are pathognomonic for this disease. This is primarily because the etio-pathogenesis is ill understood with some evidence that there is a genetic contribution, that Th 1 type T cells are involved in some but not all subgroups, and that pro inflam-matory cytokines are key players in both systemic and articular inflammation(4,5).

 

Table I - ILAR Classification


Systemic arthritis
Oligoarthritis

Persistent
Extended

Polyarthritis (Rf negative)*
Polyarthritis (Rf positive)*
Enthesitis related arthritis
Psoriatic arthritis

Other arthritis

Fits no category
Fits more than one category


* Positive test for Rheumatoid factor: At least two positive results 3 months apart during the first six months of observation.

 

The diagnosis of different subtypes of JIA is one of "clinical pattern recognition" with laboratory tests playing a supportive role. For example, a positive antinuclear antibody (ANA) is not diagnostic of any particular disease, and it is well documented that up to 45% of children with a positive ANA have no autoimmune disorder(6). A positive ANA in the context of chronic arthritis on the other hand, indicates a higher risk of silent anterior uveitis seen mainly in Northern European and American Whites.

Causes of chronic arthropathy that need to be excluded include three major groups of conditions: Firstly systemic diseases that can masquerade as JIA: infections including tuberculosis and reactive arthritides, neo-plastic disorders (especially acute leukemia, lymphomas, osteoid osteoma and neuro-blastoma), hematological disorders includ-ing bleeding diathesis, immunological disorders, cystic fibrosis and in India importantly, acute rheumatic fever. Secondly autoimmune disorders like juvenile dermato-myositis, systemic lupus erythematosus (SLE), systemic sclerosis and a variety of primary and reactive vasculitides may present with arthritis. Finally, noninflam-matory disorders such as chondromalacia patellae, anterior knee pain, reflex sympa-thetic dystrophy, and benign joint hyper-mobility often associated with chronic pain syndromes may be confused with JIA(3,7).

Fifty per cent of patients with JIA in the northern European and American populations fall in the oligoarticular category. The peak age of onset is between 1-4 years, with a female predominance. Seventy per cent have a positive ANA, and 20% have anterior uveitis, with no redness or discomfort. The knee joint is most commonly involved, followed by the ankle, and small joints of the hand. Many children complain of little pain, and are brought to the physician because the parent notes joint swelling. A young child, usually less than four years of age may have associated failure of appetite and/or personality change, as they are not able to articulate the concept of pain. A modest elevation of ESR can occur, but usually this is not raised(3,8-10). Thus a young child with severe pain in the knee joint, fever, and a strikingly high ESR does not fit the pattern of oligo JIA, instead warrants exclusion of infection with a degree of urgency. There is some evidence from India, and South America to suggest that ANA positive oligoarticular disease in the preschool age is rare in these ethnic groups(11,12).

Polyarticular disease is defined as involvement of five or more joints in the first six months of disease. The common age of onset in this category is one to five years. Older teenage girls with polyarticular disease often have a positive Rheumatoid factor, present with symmetric involvement of the small joints of the hands with a tendency to progress to multiple joint destruction with time. Up to a third of children may have systemic features such as malaise, or low-grade fever. The ESR is usually raised(3).

Systemic onset JIA affects 20% of children with JIA and perhaps this group of children have the worst long-term prognosis, at least in the European and American series. The fever is quotodian, with an evanescent 

rash and often associated with lymphadeno-pathy, hepatosplenomegaly and serositis. The onset of arthritis is variable. Perhaps the most important clue to diagnosis in these patients is the striking variation in the clinical signs and symptoms that can occur in a 24 hour period: the child can look very well throughout the day only to look toxic at the time of a fever spike(3,8).

Enthesitis (inflammation of the enthesis, i.e., insertion of tendon sites) related arthritis (includes probable and definite juvenile Ankylosing Spondylitis as defined in the EULAR criteria) is five times more frequent in boys than in girls with a mean age of onset of 12 years. Back pain is not a feature of this disease in childhood, and is usually seen in the late teens or twenties. There is relative sparing of the upper limbs with predominant lower limb, asymmetric large joint involvement. HLA-B 27 is often positive in this subgroup of patients(7).

The incidence of inflammatory arthritis in childhood psoriasis is uncertain. The pattern of arthritis in children may be quite variable: asymmetric large joint involvement, distal interphalangeal joint disease, and arthritis mutilans have all been described. Asymmetric involvement of small joints especially the DIP joint, and dactylitis is characteristic of psoriatic arthritis. Signifi-cant nail pitting often precedes arthritis. The skin and joint disease may not always follow the same course(13).

Management

The aims of good management of JIA are to prevent joint destruction, and promote growth and development(14). Effective management of JIA needs a multidisciplinary team approach with inputs from a pediatric rheumatologist, who will liaise with the local general pediatrician or general physician ophthalmologist, nurse specialist, physio-therapist, occupational therapist, orthopedic surgeon, podiatrist, clinical psychologist and social worker.

Each member of the team has defined roles, and depending upon the clinical situation a member adopts the key role. For instance a four-year-old child with oligo articular disease effecting one knee joint who has been treated with intra-articular steroids and has a flexion contracture of 30 degrees needs sustained physiotherapy to regain lost range of movement. On the other hand a 10-year-old boy with a flare of systemic onset JIA presenting with an ESR of 100 mm needs skilled medical management from a pediatric rheumatologist. The main pathways of managing various types of JIA are detailed in Table II.

In recent years three modalities of medical treatment have contributed to improving daily life of children with JIA: intraarticular injections of triamcinalone hexacetonide, weekly methotrexate and the use of twice weekly etanercept(8).

Detailed below are salient features of some of the key therapeutic tools used in children with JIA.

NSAIDs

The choice of NSAIDs is largely empirical, often dictated by the availability of liquid preparations or by individual response. Children tolerate NSAIDs very well. It is important to use the right dose for at least two months before attempting to change the drug because of an inadequate response (Table III). Proton pump inhibitors are useful to prevent and treat gastrointestinal symptoms. The newer or cox-2 NSAIDs are now available and clinical studies are ongoing in children(3).

Table II - Pathways for Management of JIA


Juvenile idiopathic Key Management.

arthritis

All subtypes  Multi disciplinary team approach with regular physiotherapy programme.
Oligo articular 

Intra-articular steroids+NSAID+uveitis screen.

Polyarticular  NSAID+DMARD (methotrexate-first line agent) + Vitamin D and calcium prophylaxis + uveitis screen. IV Methylprednisolone for flares +/– oral steroids.
Systemic onset NSAID (indomethacin/naproxen/ibuprofen) + DMARD (methotrexate - first line agent) + Vitamin D and calcium prophylaxis + uveitis screen. IV Methylprednisolone for flares +/– oral steroids.
Enthesitis related arthritis

 NSAID + DMARD (? preferred salphasalazine) + Vitamin D and calcium prophylaxis.

Psoriatic arthritis NSAID + DMARD + Vitamin D and calcium prophylaxis + skin treatment.

DMARD: Disease modifying anti-rheumatic drugs
NSAID: Nonsteroidal anti-inflammatory drugs.

 

Intra-articular Steriods

Intra-articular steroids are the mainstay of treatment for children with oligoarticular JIA, where they are proven to be safe and prevent long-term morbidity(15,16). In a background of general disease control in other types of JIA, one or two remaining active joints can be treated this way with good effect. Triam-cinalone hexacetonide is the preparation preferred due to the long-term and pre-dominantly local effects, with a reported median duration of improvement for a period of 74 weeks, as seen in a recent retrospective review of 1439 injections(17). This particular formulation is currently not available in India, though triamcinalone acetonide is.

Table III - Non Steroidal Anti-inflammatory Drugs Used in JIA(3)

NSAID Total daily dose (mg/kg/day) Maximum daily doses (mg)  No. of doses/day 
Asprin 80-100 5200 3 or 4
Naproxen 10-20 1000 2
Ibuprofen 40-60  3200  3 or 4
Diclofenac 2.5 225 2
Indomethacin 1.5 - 3  200 2
Piroxicam 0.25 - 0 20 4

Methotrexate

This is currently the drug of choice among the disease modifying agents for a number of subgroups of JIA. It may be given orally, or subcutaneously, usually in a dose of 15 mg/m2/week increasing as needed up to 1 mg/kg or 20mg/m2 and is continued for at least six months after the patient has achieved remission. The absorption of methotrexate is 20% better if given as a subcutaneous (SC) injection. Follow-up studies have shown that it is a safe drug, with no significant risk of hepatotoxicity or malignancies. It does need regular monitoring of hematological para-meters and liver function tests. While on methotrexate the patient should avoid live vaccination, and being a powerful teratogen, pregnancy should be avoided. Almost 60 to 70% of patients benefit significantly from methotrexate therapy in standard doses(18,19).

Osteoporosis and Growth Retardation

Patients with JIA are at a risk of osteoporosis for a number of reasons. The disease itself has an osteopenic effect, the treatment with corticosteroids, and lack of physical activity contribute to a lowered bone mass as well(20). Though there is a paucity of supportive data, most pediatric rheumato-logists give a supplement of Vitamin D and calcium to patients with JIA, in addition to early use of DMARD’s, using minimal steroids and encouraging daily physical therapy. Bisphosphonates have been used with encouraging success in a number of small series, and growth hormone also improves the growth retardation and osteo-porosis, particularly where the disease is stable but not in remission(21-24).

The issue of delayed adolescence both physically and emotionally is being recog-nized more widely and adolescent centered services to aid transition to adulthood have a major role to play in the long term care of the patient(25).

Uveitis

As clinicians looking after children with JIA use early and effective DMARD’s, the incidence of uveitis is likely to fall, as has been recently demonstrated(26). This should however not induce complacency and it is reemphasized that uveitis in JIA is silent and painless except in children with enthesitis related arthritis that have acute painful anterior uveitis. Thus, it is mandatory that patients with JIA be electively screened for uveitis at regular intervals, as untreated uveitis is known to cause visual loss and morbidity. Standard treatment of uveitis is the use of topical methyl prednisolone and mydriatics to prevent synechiae. While methotrexate and other DMARDS have been tried, there is no clear evidence that they are especially useful in uveitis resistant to steroid treatment (3,27).

Physiotherapy and Occupational Therapy

The therapists are critical to restore function and strength of affected joints and musculature. They plan a treatment program that incorporates exercises, stretches for the joints, and activities of daily living. The occupational therapist provides custom made splints to maintain joint position, and assist children whose disability requires modifica-tion of the environment. Physiotherapy provides pain relief, in addition to improving joint range and muscle strength. Finally the therapist is usually the key person to educate the parents, and school personnel to ensure integration of therapy goals into the child’s daily routine(28).

Treatment of "Severe" JIA

For difficult to control patients who have failed treatment with high dose weekly subcutaneous methotrexate there are various strategies that can be employed before stem cell transplant, currently an experimental form of treatment(14,29,30). Important amongst these are: (i) Methotrexate in combination with corticosteroids either as weekly pulses of IV methylprednisolone, or daily oral prednisolone. Steroids are ideally used as a "bridge" to control the disease initially while waiting for the DMARD to be effective; (ii) Methotrexate in combination with cyclosporin, or sulphasalazine, or hydroxychloroquine; (iii) Use of cyclophos-phamide; and (iv) Use of newer agents such as anti TNF drugs (etanercept and infliximab), and leflunamide either alone or in combination with methotrexate. This group of patients is best managed in specialist units.

Outcome Measures

These are critical objective parameters both for therapeutic trials and for day-to-day office practice to judge whether or not the patient has improved. An international consensus conference proposed "The defini-tion of improvement" to assess disease response. This definition employs a core set of six response variables: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or parent, number of "active" joints (joints with swelling not due to deformity or joints with limitation of motion and with pain, tenderness, or both), number of joints with limitation of motion, functional ability by a validated test, and erythrocyte sedimentation rate. To meet the definition of improvement at a scheduled visit, patients should have a 30% improvement from baseline in at least three of the six response variables, and worsening of 30% or more in no more than one of the six response variables(31,32).

Prognosis

It is important to appreciate that JIA is a chronic disease with perhaps 50% of patients with active arthritis in adult years(33). JIA impacts upon the life style of not only the child, but also the whole family. There is still very little published data to predict which patients will have a prolonged disease course, and which medications are likely to be effective in which type of patients(14). In general those with involvement of few joints do better than those with systemic disease or Rf factor positive JIA(34). Specific criteria are suggested only for systemic onset JIA where patients are classified as "high risk" if they meet the following criteria at 6 months from disease onset : active systemic disease or the need to use corticosteroids, and a platelet count of >600 ´ 109/litre. This group of patients have a poor long-term prognosis as defined by a childhood health assessment score (CHAQ) score of ³0.75, or disease associated death(35).

Concluding Comments

JIA is the most common group of rheumatic diseases in childhood, and effect-ive treatment demands a multidisciplinary team approach. Awareness amongst general pediatricians, early recognition, appropriate referral to specialist units, and institution of specific therapy as soon as possible are measures that will improve outcome and quality of life for these children.

Funding: None.
Competing interests: None declared.

Sujata Sawhney,
Consultant Pediatric Rheumatologist,
Sir Ganga Ram Hospital, New Delhi, India
E-mail: [email protected]

Patrica Woo,
Professor of Pediatric Rheumatology,
Windeyer Institute Of Medical Sciences,
UCLMS, London, U.K.
Email: [email protected]

Key Messages

  • JIA is a clincial diagnosis and essentially one of exclusion.

  • Appropriate management demands a multidisciplinary team approach.

  • Early, appropriate and aggressive therapy continued for at least six months after drug induced remission would perhaps improve the long-term outcome for these children.

  • The accompanying uveitis is painless, variable in onset, but can blind the child; hence regular slit lamp screening is mandatory.

 


 References


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