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Critial Investigation of the etiology of juvenile idiopathic arthritis

| December 15, 2012

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Juvenile idiopathic arthritis is an umbrella term which includes all forms of arthritis that begin before the age of sixteen, of over six week’s duration, and of unknown cause. (Petty el al 2004)  With various contributing environmental and genetic factors, arthritis is an autoimmune disease.

Ongoing research, into the etiology of juvenile idiopathic arthritis, has identified the most common risk factor as infection in combination with genetic susceptibility.  An autoimmune reaction occurs as a result of an infection or trauma, this causes synovial hypertrophy and chronic joint inflammation in genetically susceptible individuals.  (Rabinovich 2010).

Juvenile idiopathic arthritis is a genetically complicated characteristic in which many genes are important as indications at the onset of the disease. Both the IL2RA/CD25 and the VTCN1 genes have recently been identified as juvenile idiopathic arthritis susceptibility loci (Hinks et al 2009) .Pathogenesis has many other contributing factors such as stress and maternal smoking. (Prince et al 2010)

The International League of Associations for Rheumatology (2004) classification of Juvenile idiopathic arthritis, JIA, includes seven subtypes: Systemic onset JIA, oligoarticular, polyarticular RF-positive and RF-negative, Enthesitis-related arthritis, Juvenile ankylosing spondylitis, and ‘‘other.’’

The most common type of JIA is Oligoarticular.   60% of children, mainly girls under 5, with JIA have this type. During the first 6 months Oligoarticular affects between one and four joints.  The knees, ankles and wrists are the most affected. After 6 months it can spread to more than four joints and is known as ‘Extended oligoarthritis’ affecting 2 in 5 children. Affected children are moody and difficult as a result of their symptoms, which include joint stiffness in the morning and joint pain.  Walking may be delayed in very young children. 1 in 5 children also have inflammation of the eye, Uveitis.  Children who carry antinuclear antibodies in their blood are most at risk of uveitis. (Arthristis Research UK, 2010)

Polyarticular arthritis, which again is more common in girls, affects 20% of children with JIA.  (Arthristis Research UK, 2010) Polyarthritis mainly affects the joints of the hands and feet, which become painful, swollen and stiff. This type can often affect more than one joint, usually over 4, at a time. The child can often become unwell and pain may be accompanied by a fever. About 10% of children will have the rheumatoid factor (RF), meaning that their blood contains an antibody similar to that often found in adult rheumatoid arthritis. Most RF-positive children are girls, typically aged 10 or over. RF-positive children can have a more severe form of the disease which, without early intervention, can result in long-term joint damage. It is unlikely that RF-positive children will be free from Polyarthritis with symptoms continuing into adult life. Permanent remission is more often seen in children who are RF-negative.  (David and Lloyd 1999, pg 207)

About 10% of cases of arthritis in children are systemic. This type of arthritis affects girls and boys equally but is more often seen in under fives. (Arthritis Research UK, 2010). This severe and potentially fatal form of JIA includes children who have arthritis associated with marked systemic features. Systemic  arthritis can be identified by a fever  which persists daily for at least two weeks either at the onset or prior to the arthritis. One or more of the subsequent systemic features must also occur,  these are a rash, generalised lymphadenopathy, liver or spleen enlargement and  serositis (inflammation of the serous tissue, which lines the major organs including the heart and lungs.)  Every child is different. Some children will fully recover after one bout of systemic arthritis. Others could have symptoms that come and go for several years and a number of children go on to develop polyarthritis but have no further fever attacks.  (Arthritis Research UK, 2010)

Psoriatic arthritis affects less than 10% and is most commonly found in girls aged 8 to 9 years. Psoriasis, a skin condition causing  a widespread flaky skin rash is prevalent.   The rarer form, Enthesitis-related arthritis usually affects boys aged eight and over. The main symptoms are arthritis in several joints at once, often located at the sacroiliac joint. Enthesitis-related arthritis has a genetic risk factor with children carrying, the HLA-B27 gene. This gene is an indicator common with some adult forms of arthritis. However affected children don’t always go on to suffer in adult hood. (Arthritis Research UK 2010)

Although Munro et al (2009)  reported that there are no specific tests for the diagnosis of JIA. Diagnosis is made on both clinical findings and investigations. A literature review, by Munro et al (2009), reports that past research recommends documenting the range of motion in all joints, the extent of joint swelling, the presence of bony overgrowth and whether affected joints are affected by muscle atrophy and weakness. Significant trauma, fever, in particular if it is persistent for 10 days or without clear cause or coupled with a rash also need to be evident..  Rheumatoid factor and antinuclear antigen screening tests should be conducted although children with an infection or current pathology may have positive findings, and the tests should not be used as a definite diagnosis of JIA. Inflammation, identified with a raised white cell or platelet count,   may also be identified  by during a full blood screening.

T-lymphocytes play an essential role in the pathophysiology of JIA. They release pro-inflammatory cytokines and favour a type-1 helper T-lymphocyte response. An abnormal interaction between type 1 and type 2 T-helper cells has been hypothesized. Research into T-cell receptor expression; confirm recruitment of T-lymphocytes specific for synovial antigens. Evidence of a disorder in the humoral immune system is identified by the increased presence of autoantibodies, increased serum immunoglobulins, existence of circulating immune complexes  or complement activation. Chronic inflammation of the synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are linked with the release of cytokines, which induce synoviocyte proliferation. (Rabinovich 2010)

JIA, if badly managed, can have a number of consequences  such as growth failure, leg length discrepancy, contractures, scoliosis, blindness (secondary to untreated chronic anterior uveitis), Macrophage activation syndrome, disability and many more. Psychosocial problems are also evident.

JIA sufferers are predominantly affected by pain.  When  treating  children in pain, doctors and parents must first understand the physiology of pain and why children have different reactions. The International Association for the Study of Pain (2007) defines pain as

“An unpleasant sensory and emotional experience which

we primarily associate with tissue damage or describe in

terms of such damage, or both.”

This definition recognises that pain is a perception and not a sensation as many believe.  Pain can be categorised into nociceptive, or neuropathic. Sustained activation of the nociceptive system caused by  tissue injury  results in pain described as nociceptive . While neuroplastic changes are evidently involved, nociceptive pain is alleged to arise as a result of the normal activation of the sensory system by noxious stimuli, a process that utilises transduction, transmission, modulation and perception. Direct injury or dysfunction of the peripheral or central nervous system results in  Neuropathic pain. The injury could be to either neural or non-neural tissues. (American Medical Association, 2010)

There has been several pain mechanism theories proposed over the last 50 years.  The specificity theory, described in 1664 by Rene Descartes, proposes that pain impulses travelled along a dedicated pathway from receptors in the periphery to a specialised pain centre in the brain, resulting in a mechanical behavioural response. Descartes described each nerve as having a specific function, with free nerve endings being called pain receptors. (Thomas 1998, pg 6) It suggests that the greater the damage or injury then the more sever the pain. (Brannon and Feist , 2000) This theory can be supported to the extent that there are some specialised nerves in the human body however others can have numerous functions or detect several types of stimuli. On the other hand this theory does not explain the variable nature of pain. Furthermore no pain centre has ever been identified; current research suggest multiple areas of the brain detect and respond to the  pain stimuli. (David and Waterfield 1999)

In 1962, Weddel (cited by Thomas 1998) states that there is no separate system for perceiving pain, rather that pain is due to intense peripheral stimulation of non-specific receptors. This in turn produces a pattern of nerve impulses, which is interpreted centrally as pain. The pattern theory proposed that strong and mild stimuli produced different patterns of impulses. (Thomas 1998, pg 6) This theory ignores the specialism of some receptors and does not account for conditions in which a gentle touch can trigger episodes of neuralgia (David and Waterfeild 1999)

The best explanation to date is the pain gate theory, proposed by Mezack and Wall in 1965. (David and Lloyd 1999, pg28)  The theory suggests that stimulation of nerve endings evokes nervous impulses that are transmitted by three systems located in the spinal cord. The substania gelatinosa in the dorsal horn of the spinal cord, the dorsal column fibres and the central transmission cells act to stimulate or inhibit nocioceptive impulses. The transmission of impulses from the afferent fibres to the spinal cord transmission cells is modulated by the spinal gating mechanism in the dorsal horn. The gating mechanism is influenced by the amount of activity in the larger-diameter fibres. Larger diameter fibres are thought to be inhibiter, thus closing the pain gate, the opposite occurs when smaller fibres are stimulated: pain is transmitted and the gate opens.(Melzack and Wall, 1996) In addition descending control from various structures in the brain can also inhibit the relay and close the gate. On reaching the brain,  the impulses are further modified and integrated with other sensory input. On arrival at  the brain  the impulses are felt as pain. It is important to understand that those afferent fibres do not have a fixed response but are subject to modification even before they reach the pain gate and after they reach the brain. (David and Lloyd 1999, pg 28) The pain gate theory was the first to appreciate that pain can be affected by   psychological factors.  A person may be able to control pain be altering their state of mind. For example if a person is able to distract themselves from the pain then less impulses are sent to the brain therefore not enough stimuli are present to open the gate. (Salvano and Willems 1996, pg 15)

In summary experiences of pain are influenced by many physical and psychological factors such as beliefs, prior experience, motivation, emotional aspects, anxiety and depression can increase pain by affecting the central control system in the brain. The specificity theory and the pattern theory suggests that pain occurs only due to damage to body tissue while the gate control theory claims that pain may be experienced without any physical injury and individuals interpret pain differently even though the extent of injury is the same. The gate control  theory also suggests that pain can be controlled by the mind.

The author’s understanding is that Juvenile idiopathic arthritis produces nociceptive pain, through recurrent inflammation of the joints. Inflammation releases chemicals such as histamine and bradykanin, which are detected by nociceptors which then activate noxious impulses to the dorsal horn. Once enough impulses are generated to “open the gate” neural areas responsible for perception and response activate. The perception and level of response is influenced by the state of mind.

Pain impacts on the lives of children, with arthritis, by limiting activities, disrupting school attendance, and contributing to psychosocial distress (Kimura and Walco 2006). A study by Schanberg et al (2003)  investigated levels of pain in 41 children with arthritis by the daily completion of pain diaries. They found that 70% of the children had significant amounts of pain, on 60% of the days, with 38% having pain daily. Children often describe the pain associated with JIA as “aching,” “sharp,” “burning,” and “uncomfortable” (Antony and Schanberg 2003). Research also suggests that children with JIA have a lower pain threshold than their healthy counterparts. (Hogeweg et al 1995) This could be due to the children’s brains, were pain is processed, changing due to long exposure to noxious impulses. The perception of pain in children with JIA could also be influence by the cognitive capabilities and age. Beales et al (1987, cited in Antony and Schanberg 2003) suggest that cognitive development impacts pain perception due to the association and understanding of the child’s condition. For example all the children , despite their age, described the pain as “aching” but younger children did not associate it with anything unpleasant , older children, however,are more likely to relate their joint  feeling  to their arthritis-related disability. Therefore with cognitive maturation, children become capable of connecting internal sensations with internal pathology and the potentially serious consequences. Hence, older children with arthritis may become more distressed by the sensation, resulting in increased reported pain intensities as the child’s age increases. (Antony and Schanberg 2003).

There is a mounting body of research indicating to the importance of psychosocial variables in the pain incidence of children with JIA, consisting of emotional distress, stress, and mood. Also significant is the child’s perception and coping strategy with their pain. Moreover, a number of studies have described the role of parental and familial factors in child pain, specifically parental psychological health, parental pain history, and the nature of the way in which family members interact with one another. Addressing these issues while managing the condition may help to reduce pain, elevate mood, and improve overall quality of life for children with arthritis. (Antony and Schanberg 2003).

A child’s pain needs to be assessed at each appointment, whether by a doctor or physiotherapist. Pain can be assessed both subjectively and objectively. It is important to gain a good description of areas affected, the intensity, type and severity of the pain. A more objective measurement is a Visual analogue scale, completed by the child and a VAS global assessment of disease and function completed by the parents. (Pounty 2007)

A multidisciplinary approach, to the management of Juvenile idiopathic arthritis, is considered best practice. Treatment is aimed at controlling inflammation and minimising its effects on the joints. For the best outcome, awareness of complications of both disease and therapy and the psychosocial effects of the illness on both the child and family is essential. (Davidson 2000) Treating the pain can sometimes be the only intervention during a physiotherapy session.

Both pharmalogical and non-pharmalogical methods are used to treat pain in JIA.Guidelines for the management of childhood arthritis,   The British Paediatric Rheumatology Group (2001), are available and new research is continuing to improve treatments.

Most JIA children are Initial treatments include intra-articular long-acting corticosteroid injections and NSAIDs. NSAIDs control pain and inflammation and are usually given for 4 to 8 weeks before starting treatment with a second-line agent. Naproxen, tolmentin, diclofenac, and ibuprofen are commonly used and are usually well tolerated with little gastrointestinal discomfort. The choice of NSAID may be based on the taste of the medication and the convenience of the dosing regimen. Naproxen is prescribed most frequently. Indomethacin is a potent anti-inflammatory medication commonly used to treat ERA and SOJIA, however side effects include headaches, difficulty in concentrating, and gastrointestinal upset. These can be counter acted with other medications. (Weiss and Ilowite 2005)

A literature review (Hashkes and Laxer 2005, Cited by Munro et al 2009) looked at the affects of NSAIDS on JIA. These were inconclusive as the participants receiving all forms and doses of NSAIDs achieved significant improvements in the outcome measures and no individual NSAID was shown to have a clear advantage over others.

The immune system can be suppressed and the progress of arthritis  slowed down, as well reducing the inflammation, by the use of  diseases modifying anti-rheumatic drugs (DMARDs) (National Rheumatology Society 2008) Methotrexate is most commonly used for JIA.  Random controlled placebo trials and dose finding trials have shown that DMARDs can be effective in polyarticular and oligoarticular arthritis although not in systemic arthritis. (Prince et al 2010)

Both physiotherapy and occupational therapy can reduce the impact of JIA, on the daily lives of children. Physiotherapy has a number of treatments that can be utilised to reduce pain.

Physical therapy and exercise programs have been shown to be helpful in reducing pain in children with arthritis and should therefore be encouraged, especially since children with arthritis tend to be less physically active and may have become de-conditioned (Kimuru and Walco 2006). Exercise can have an analgesic effect.  If using the Pain gate theory, movement can help to close the gate by providing a distraction. Exercise is also good for the healing process. Satallite cells, which can only be activated through exercise, are important for muscle growth and repair. They can be stimulared to either replace damaged muscle cells or add muscle cells.  (Poutney 2007, pg 234)

A literature review, by Long and Rouster-Stevens (2010), highlighted the importance of exercise in the treatment of JIA. Current studies show that inactivity can lead to deconditioning, disability, decreased bone mass, and reduced quality of life. While progress in pharmacology has improved the lives of patients with JIA, management should also consist of a moderate, regular exercise program or more active lifestyle. The literature suggests physical activity may improve exercise capacity, reduce disability in adulthood, improve quality of life and, in some patients, lessen disease restrictions.  .

There is however limited evidence of the effect of strength training in children with JIA. Fisher et al (2001) monitored the effects of resistance exercise, via isokinetic equipment, in 19 children with JIA. Children were given an 8 week, personalised progressive programme.   Participants demonstrated significant improvement in quadriceps and hamstring strength and endurance, contraction speed of the hamstrings, functional status, disability and performance of timed tasks.  Despite the limited evidence, it is recommended that a programme of strength training may be beneficial with JIA. Recommendations for healthy children can be used as a guide. The American Academy of Paediatrics (2001, cited by Maillard 2010) recommends that to increase strength and fitness, low resistance for 15 repetitions is ideal for children. They suggest twenty to thirty minute sessions, two to three times weekly. There is evidence that there is no benefit to increasing the amount of sessions. (Maillard 2010)

Hydrotherapy is also advocated for JIA. The effects of hydrotherapy are gained with the combined effect of the warmth, the buoyancy and the fun element of the treatment. Hydrotherapy aims to reduce pain and muscle spasms, increase joint range of movement, and increase muscle strength. Epps et al (2005) found that following two months of hydrotherapy combined with land based exercise there was an increased quality of life and reductions in the impact of the disease in 47% of children with active juvenile arthritis.

Pain relief from the heat generated from the pool could be replicated using heat pads or a hot bath. Heat relaxes your muscles and stimulates blood circulation. In relation to the pain gate theory thermal receptors may detect a raise in temperature, impulses are generated which help to close the gate in the dorsal horn, reducing the amount of noxious impulse to the perception area therefore providing relief  Conversely cold packs could be used to reduce inflammation and therefore reduce the amount of impulses generated by chemorecepters.  (Arthritis Foundation 2011)

Alternative therapies are often used to aid pain relief (Feldman et al 2004). Massage is found to be effective on depression, anxiety, mood, and pain (Walach et al 2003).  Field et al (1997) investigated the use of massage on children with JIA. Parents massaged their child for 15 minutes per day, for 30 days. They found that the self assessed pain scales decreased as well as cortisol levels lowering, reducing their stress and anxiety. It is possible that the touch from massage helps to reduce pain by closing the gate in the dorsal horn.

In conclusion, juvenile arthritis is a painful condition that affects a child’s social, educational and physical life. Pain is a major contributor to the lowered quality of life experienced by these children. Relief can be found in many interventions. A multidisciplinary approach is best practice. The evidence suggests that a combined programme of physiotherapy and medication can help to reduce pain and improve function in these children



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