Juvenile Arthritis Research Paper

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JIA

Juvenile Arthritis accounts for a comparatively small number of patients suffering from juvenile arthritis (JA). This paper discusses the clinical manifestations that are considered unique among the subsections of juvenile arthritis, and explores those studies of cytokine profiles that suggest differences between the fundamental mechanisms of the different forms of these diseases. Systemic-onset juvenile arthritis may, in reality, be better classified as differentiated from other subtypes of juvenile arthritis. However, new biologic agents such as the cytokines interleukin-1 and interleukin-6, are presently being licensed or tested, and these look to be promising in treating systemic-onset juvenile arthritis. By comparison, anti-tumor necrosis-factor therapy has proven to be not very effective, if effective at all, in treating this subgroup of JA.

Introduction

Juvenile idiopathic arthritis (JIA) is described by The Merck Manual as "a group of rheumatic diseases that begins at or before age 16." (2014, p. 1) Juvenile idiopathic arthritis is reported to be more than a single disease and is a term applicable to various and chronic arthritides occurring in children although they do have some similar features. (The Merck Manual, 2014, paraphrased) Some of the categories of JIA stated in The Merck Manual include the following categories: (1) Oligoarticular JIA (persistent or extended); (2) Polyarticular JIA (rheumatoid factor [RF] negative or positive); (3) Enthesitis-related arthritis; (4) Psoriatic JIA; (5) Undifferentiated JIA; and (5) Systemic JIA (The Merck Manual, 2014, p. 1) Oligoarticular JIA is reported as the form that is most common generally impact girls who are young and stated to be characterized by more than four joints during the first six months of the disease occurring. There are two types of Oligoarticular JIA including persistent and extended. Polyarticular JIA is reported as the second most commonly occurring form of JIA affecting more than five joints and categorized as RF Negative and RF Positive. (The Merck Manual, 2014, paraphrased) The third type of JIA is Enthesitis-related arthritis and occurs more often among boys who are older with symptoms of inflammation that is painful at the site of tendons and ligaments insertion. This may result in the development of "one of the spondyloarthropathies such as ankylosing spolndylitis or reactive arthritis." (The Merck Manual, 2014, p.1 ) This type of JIA most often occurs in the lower extremities. The fourth type of JIA is Psoriatic JIA and is reported to "typically occurs in young girls and is associated with psoriasis, dactylitis (swollen digits), nail pits, or a family history of psoriasis in a 1st-degree relative. Arthritis is frequently oligoarticular." (The Merck Manual, 2014, p. 1) Undifferentiated JIA is reported to be the diagnosis given when the criteria is not met for any of the aforementioned categories. Finally, Systemic JIA is reported as the form of JIA that is leased common and is such that involves both "fever and systemic manifestations." (The Merck Manual, 2014, p. 1)

The Merck Manual reports that manifestations of JIA include joint involvement and often involvement of the eyes or skin. JIA is such that is reported to potentially impact multiple organs. (2014, paraphrased) Symptoms in children include "joint stiffness, swelling, effusion, pain and tenderness" although it is reported that there is no pain experienced by some children. The manifestations in the joints are reported to be either symmetric or asymmetric and to involve small or large joints. JIA may interfere with the child's development and growth with the reported most common ocular abnormality being "iridocyclitis (inflammation of the anterior chamber and anterior vitreous." (The Merck Manual, 2014, p.1 ) This is reported to be "typically asymptomatic but sometimes causes blurring of vision and miosis. Rarely, in enthesitis-related arthritis, there is conjunctival injection, pain, and photophobia. Iridocyclitis can result in scarring (synechia), glaucoma, or band keratopathy. Iridocyclitis is most common in oligoarticular JIA, developing in nearly 20% of patients, especially if patients are positive for antinuclear antibodies (ANA). It may occur in the other forms but is rare in polyarticular RF-positive JIA and systemic JIA." (The Merck Manual, 2014, p. 1) It is reported that psoriatic JIA is characterized by abnormalities in the skin such as psoriatic skin lesions and systematic JIA is characterized often by a "typical transient rash" reported to appear often with a fever. Systemic JIA is characterized by "high fever, rash, splenomegaly, generalized adenopathy (especially of the axillary nodes), and serositis with pericarditis or pleuritis. These symptoms may precede the development of arthritis.
Fever occurs daily (quotidian) and is often highest in the afternoon or evening and may recur for weeks." (The Merck Manual, 2014, p.1) Diagnosis is accomplished through: (1) Clinical criteria; and (2) RF, ANA, and HLA-B27 testing. (The Merck Manual, 2014, p.1 )

Prognosis

It is reported that remissions are known to occur in approximately fifty percent to seventy percent of patients receiving treatment although patients "with RF-positive polyarticular JIA have a less favorable prognosis." (The Merck Manual, 2014, p. 1)

Treatment: Traditional Therapy

The management of JIA has traditionally been reliant on treatment with nonsteroidal medications then slowly additional traditional anti-rheumatic drugs such as sulfasalazine or methotrexate and avoiding systemic corticosteroids. However, it is reported that intra-articular corticosteroid injections have been recently used in the approach to treatment. (Hayward and Wallace, 2009, paraphrased) There has been a growth in the types of agents used for JIA treatment due to biological therapeutics over the past decade. (Hayward and Wallace, 20009, paraphrased) it is reported that TNFa is a "potential proinflammatory cytokine" and that there are three biologic agents "targeting TNFa being used currently in the treatment of JIA." (Hayward and Wallace, 2009, p. 1)

It is reported that Etanercept also known as Enbrel "is a fusion protein consisting of the extracellular domain of the TNF? receptor combined with the Fc portion of the human immunoglobulin molecule. Etanercept binds to soluble TNF? And thus decreases downstream TNF? receptor-mediated signaling. Etanercept was the first TNF? antagonist to be approved for use in JIA in 1999, and recently has received FDA approval for treatment of moderate to severe polyarticular JIA in patients as young as 2 years old." (Hayward and Wallace, 2009, p. 1)

Infliximab, also known as Remicade is reported as a "chimeric monoclonal antibody that combines human and mouse components to create a molecule with high affinity for TNF?. Unlike etanercept, infliximab binds both soluble as well as membrane-bound TNF?. Infliximab has FDA approval in the United States for a variety of indications, including adult rheumatoid arthritis, psoriasis, and adult and pediatric Crohn's disease (for children older than 6 years of age). Use in juvenile arthritis is not formally approved but remains a common application." (Hayward and Wallace, 2009, p. 1)

Adalimumab, also known as Humira is reported as the "second TNF? antagonist to receive FDA approval for treatment of moderate to severe active polyarticular JIA in patients 4 years and older. Adalimumab is a fully humanized monoclonal antibody that binds soluble and membrane-bound TNF?.." (Hayward and Wallace, 2009, p. 1) IL-1 is reported as a proinflammatory cytokine used to mediate effects that are of a diverse nature such as degradation of cartilage and resorption of bone. One IL-1-blocking agent is reported as being currently used in JIA with children and several others to still be under development. Anakinra, also known as Kineret is reported as a "recombinant form of the human IL-1 receptor" and used to block "endogenous IL-1 signaling." (Hayward and Wallace, 2009, p. 1)

The Leflunomide Treatment

For quite some time leflunomide treatment had been viewed as very effective for JA, but some experts now made the point that it might not be as effective as Methotrexate (Herlin, 2012). Leflunomide was typically used with patients unable to tolerate the side effects of Methotrexate. It was very close to Methotrexate in that it worked as an anti-metabolite, but it constrained the dihydroorotate dehydrogenase enzyme from working properly, another enzyme in DNA synthesis. Likewise it worked by lessening lymphocyte proliferation along with touching intracellular signaling pathways complicated in the inflammatory development. It was taken orally on a day-to-day or every-other-day dosing agenda based on the patient's weight. The clinical effects were naturally seen within the first one to five months (Halbig, 2009).

The major side effect was hepatotoxicity, but doctor's observed that this side effect is less common than the hepatotoxicity associated with Methotrexate. Patients needed frequent liver enzyme monitoring since leflunomide had a lengthy half-life (eighteen days). Ingesting alcohol needed to be strenuously discouraged because with leflunomide the danger of liver toxicity increased significantly.

Other side effects included vomiting, abdominal pain, rash, nausea, diarrhea, and alopecia, all of which normally reversed when the medication ceased. Similar to MTX, leflunomide was also teratogen, so patients needed to be counseled on the importance of using at least two forms of birth control at all times. Also, a.....

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