Cytokine profiles and biologic treatment of systemic-onset juvenile idiopathic arthritis

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)

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 prolonged washout period was recommended prior to conception given leflunomide's long half-life. Lastly, live vaccines were contraindicated in patients taking leflunomide.

The Hydroxychloroquine Treatment

Many physicians were unaware that the anti-malarial medication Hydroxychloroquine was also very effective for treating adults suffering from rheumatoid arthritis (RA), and was part of the triple therapy frequently utilized prior to biologic treatment. It has not been proven to be clinically helpful in JA patients, (Halbig, 2009) even though it was usually used in other pediatric rheumatic conditions such as complete lupus erythematosus. Hydroxychloroquine was believed to play a role in moderating the immune response by influencing antigen performance. It was well- tolerated and had minimal side effects, although abdominal pain and skin hyperpigmentation were noted to emerge over time with prolonged use. Patients needed ophthalmologic monitoring after six to twelve months for possible retinal poisoning that could lead to diminished color and peripheral vision.

Furthermore, young children incapable of differentiating colors or cooperating for eye examinations were not put on this type of medicine. It was also important to look for absence of glucose-6-phosphate-dehydrogenase (G6PD) prior to beginning this medicine since it could cause rapid hemolytic anemia.

The Sulfasalazine Treatment

Sulfasalazine was a 5-aminosalicyclic acid (5-ASA) equivalent that has now been utilized first and foremost for inflammatory bowel disease but was also operative for specific kinds of JA (Zak, 2014). It was supposed to act in numerous ways, including reducing bacterial growth in the GI tract involving enzymes included in the inflammatory routes. Prior to starting therapy, patients needed to be screened to determine whether they had sulfa or salicylate allergies, G6PD deficiency, and renal or hepatic dysfunction. Sulfasalazine was taken orally, typically two to three times daily, and patients usually responded within one to three months of beginning treatment (Tanaka, 2009). The most typical side effects were GI symptoms (nausea, abdominal pain, vomiting, diarrhea, and anorexia) and maculopapular rash in sun-exposed parts. Infrequently, patients could develop Stevens-Johnson condition. Other potential side effects were liver dysfunction and hematologic abnormalities such as thrombocytopenia and neutropenia, so CBCs and liver enzymes needed to be checked.

The Biologic Treatment

The expansion of biologic therapy meaningfully developed our armamentarium for treating juvenile arthritis. Clinicians were able to target important inflammatory cytokines, for instance growth necrosis interleukin-1 (IL-1), interleukin-6 (IL-6), and factor-alpha (TNF-alpha), and patient outcomes showed fewer universal side effects than occurred with other therapies that reduced the immune response (Halbig, 2009).

Discussion

Juvenile idiopathic arthritis is comprised by a group of rheumatic diseases with onset prior to age sixteen. JIA is not just a single disease and is a term used to describe various and chronic forms of arthritis in children with similar features and includes: (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 . JIA may manifest in the joints, skin, or eyes and may even affect multiple organs. Remissions are reported to take place in some fifty to seventy percent of patients however, for patients diagnosed with RF positive polyarticular JIA, the prognosis is not as favorable. Management of JIA has been traditionally accomplished through nonsteroidal medications and additional traditional anti-rheumatic drugs including sulfasalzine or methotrexate with avoidance of systemic corticosteroids. However, most recently intra-articular corticosteroid injections have been used as a treatment approach. Various treatment approaches have been reviewed in this study, many of them still in the trial phase. Treatment with Methotrexate requires clinical monitoring of the liver enzyme as does use of leflunomide. Side effects of these drugs are noted. Hydroxychloriquine is also used frequently treating rheumatoid arthritis although it has not been proven to be clinically effective in patients with JIA. Sulfasalazine has been utilized in some types of JIA but has side effects that are severe in nature.

Conclusion

Presently treatments used in treating JIA are expanding to include more types of drug treatment, although these have not been fully tested and are still undergoing clinical trials. It is necessary to understand the decision making process that is currently used in treating JIA. While effectiveness of use of certain medications in adults the acceptance in using these medications to treat JIA has been slow and this is likely due to the nature of the treatment and the phase of trials since the effectiveness of the medications, while seemingly proven in treating adults has still not passed the clinical trial phase and therefore is not accepted for use in children.