- JRA Types
- Symptoms & Signs
Facts you should know about juvenile rheumatoid arthritis (JRA)
- JRA (juvenile rheumatoid arthritis or juvenile RA) is now sometimes referred to as juvenile idiopathic arthritis (JIA).
- Epidemiologic studies estimate that approximately 294,000 American children are affected by JRA.
- Children of European ancestry are more likely to develop the condition while those of Japanese and Filipino background are less likely.
- When considering the manifestation options of JRA, those children with European background are more likely to experience the oligoarticular version of JRA (see below) while those of African-American heritage are more likely have the rheumatoid factor (RF) positive, polyarticular juvenile rheumatoid arthritis version (see below).
- Among Caucasian children developing oligoarticular JRA, younger girls (2-4 years of age) are the most commonly affected.
- Genes seemed to play a role both in the development of JRA, as well as the clinical manifestations that may affect a child.
What is juvenile rheumatoid arthritis (JRA)?
Juvenile rheumatoid arthritis (JRA) is the umbrella term under which several forms of chronic arthritis in children are categorized. Regardless of type, all of these conditions have several historical and/or clinical characteristics in common. One or more joints must demonstrate evidence of inflammation characterized by swollen joints, limitation in the range of motion of the involved joint(s), tenderness when the joint is moved, and increased warmth of the joint region. These symptoms must be present (even intermittently) for at least six weeks and affect a child less than 16 years of age.
JRA is the most frequent chronic rheumatologic disease of childhood, and the cause(s) are not well understood. Both environmental and genetic influences are felt to contribute to the development of signs and symptoms of JRA. Knowledgeable specialists (pediatric rheumatologists usually affiliated with pediatric teaching hospitals) can help to limit the possibility of complications of juvenile rheumatoid arthritis including leg-length discrepancy, joint contractures, and destruction and blindness due to inflammation of the eye (iritis).
Until the late 1990s, JIA was known in the U.S. as JRA (juvenile rheumatoid arthritis) and JCA (juvenile chronic arthritis) in Europe. The revised name was devised in order to better distinguish the childhood disease from rheumatoid arthritis (RA) that affects adults. This new nomenclature has enabled the categorization of six JIA subtypes. This updated classification has helped to foster better communication among those doing research on causation, clinical manifestations, and therapy of JIA.
JRA is considered a diagnosis of exclusion; the diagnosis can only be confidently made when (1) the patient's history, physical exam, and laboratory findings are consistent with those described in the literature by the International League of Associations for Rheumatology and (2) other conditions have been excluded. These include infection, malignancy, trauma, reactive arthritis, immunodeficiency, and other connective tissue/rheumatologic diseases (for example, systemic lupus erythematosus).
What are the types of juvenile rheumatoid arthritis (JRA)?
There are six broad categories of JRA. These include
- systemic onset JRA,
- oligoarticular JRA (containing two subgroups),
- polyarticular JRA (containing two subgroups),
- psoriatic arthritis,
- enthesitis related arthritis, and
- undifferentiated arthritis.
The specific criteria necessary to establish a diagnosis and prognosis for each category are detailed below.
What are causes and risk factors of juvenile rheumatoid arthritis (JRA) arthritis?
While no specific cause(s) of JRA have been determined, there is strong evidence of both genetic and environmental factors being implicated in the development of the disease. Studies of the frequency of JRA have shown that if one identical twin develops the disease that the likelihood of their identical sibling developing JRA is 25%-40%. Studies of nonidentical siblings show evidence that if one child develops JRA there is a 15 to 30 times increased risk that a sibling will develop the condition when compared to the general pediatric population.
The biologic and clinical manifestations of JRA provide strong evidence that a general theme of an immune system misdirection is evident. The immune system has two "arms" -- the cell based (lymphocytes, etc.) and humeral based (antibodies). Rheumatologists have demonstrated that both of these elements of the immune system react against the patient's own body structures (joints, muscles, eye tissues, etc.). Much research is currently focused in an effort to better understand this auto-inflammatory process in the hope that understanding the cause of JRA will enable better and more effective treatments and ultimately a cure for the condition.
What are juvenile rheumatoid arthritis (JRA) symptoms and signs, and how are the different types of juvenile rheumatoid arthritis (JRA) diagnosed?
The International League of Associations of Rheumatology has classified JRA into six distinct patterns that vary by clinical presentation and evolution of symptoms, laboratory implications, potential complications, and therapeutic options. While some similarities exist among these diseases, the uniqueness of each manifestation of JRA is strong enough to justify the breakdown into the six patterns. One characteristic common to all six forms of JRA is that of "morning stiffness" that improves during the day as more movement is done. Likewise, spontaneous patterns of worsening and lessening of symptoms (which may be independent of therapy) is characteristic.
1. Systemic onset JRA: By definition, systemic onset JRA must have arthritis (swelling, pain, and warmth) of one or more joints associated with a minimum of two weeks of daily spiking fevers. The fever is often greater than 102 F (39 C) and usually spikes once or twice a day and may have the unique pattern of returning to below normal between rises. In addition, a characteristic intermittent salmon-colored rash; swollen lymph nodes, liver, and spleen; and inflammation of the lungs, the pericardium (the "sack" surrounding the heart), and other organs may occur. During febrile episodes, children appear moderately sick, but with resolution of fever they are much improved. Systemic onset JRA affects approximately 10%-15% all children suffering from JRA. There is no gender preference (the frequency in boys and girls is equal), with symptoms generally starting between 3-5 years of age. There is no unique laboratory test for JRA, but children typically have anemia and elevation of white blood cell and platelet counts, as well as alterations of general markers of inflammation. Complications of systemic onset JRA may include slower than expected growth, weakening of bones, abnormalities of liver and lung function, and consequences of therapy (see below). The prognosis is generally noted to depend upon the severity of arthritis with many/most of the systemic symptoms resolving over months to years. The low mortality rate (<0.3% in North America) is reassuring. Since the diagnosis of systemic onset of JRA is one of exclusion, the possibility of infection, malignancy, collagen vascular disease, and rheumatic fever must also be considered.
2. Oligoarticular JRA: Oligoarticular is defined as arthritis that affects four or fewer joints in the first six months of the disease. This form of JRA accounts for about 50% of all cases of pediatric chronic arthritis and may be subdivided into two groups. One group consists of those children who continue throughout the entire course of their disease having four or fewer joints involved. The other group eventually develops greater than four-joint involvement after the first six months of illness. The onset of disease is between 2-4 years of age with a female gender bias of approximately 3:1. Children with oligoarticular JRA most commonly have a single large joint (knee in approximately 90% of cases) involvement. Symptoms of joint pain and tenderness are worse in the morning in association with the previously described morning stiffness (see systemic onset JRA). The primary complication of oligoarticular JRA is inflammation of the iris (the colored region of the eye). Iritis is found in approximately 15%-20% with this form of JRA and is often without symptoms. Complications of iritis may include clouding of the cornea (cataracts), glaucoma, and vision loss. Since outcome is linked to early diagnosis, it is imperative an ophthalmologist evaluate children with oligoarticular JRA every three to four months. Conditions that should be eliminated prior to establishing a diagnosis of oligoarticular JRA include trauma, infection, malignancy, and arthritis following an infection.
3. Polyarticular juvenile rheumatoid arthritis: Children who have five or more joints involved with arthritis during the first six months of their disease are classified into the polyarticular JRA form of illness. Two subgroups of polyarticular JRA exist based upon a constellation of various laboratory studies. One group (rheumatoid factor "RF" positive) affects between 5%-10% of all patients with JRA. Late childhood through young teenage girls are the most likely to develop this pattern. Generally, small joints (such as the hands and feet) tend to be involved, and a more aggressive course has been observed. "RF negative" polyarticular JRA affected individuals tend to have a milder course and thus a better outcome. Fatigue, anemia, suboptimal growth, and iritis (to a lesser degree than oligoarticular JRA) are complications. Other conditions that must be considered and eliminated prior to establishing the diagnosis of polyarticular JRA include infection, malignancy, and collagen vascular disease (including systemic lupus erythematosus).
4. Psoriatic arthritis (PsA): Establishing the diagnosis of psoriatic arthritis involves demonstration of both large and small joint arthritis and a characteristic rash (psoriasis). Should the rash not be present, two of the following must exist: (a) family history of psoriasis in an immediate family member, (b) diffuse swelling of the fingers, and (c) pitting of the nails. Children with psoriatic arthritis may also develop iritis and should have ophthalmologic evaluation every six months.
5. Enthesitis-related arthritis (ERA): Enthesitis (inflammation at the site of tendon insertion on the bone) most profoundly affects males over 8 years of age and often involves the lower back, sacroiliac joints, and joints of the legs, ankles, and feet. Patients with a particular genetic marker (HLA-B27) may also develop iritis, inflammatory bowel disease, psoriasis, and/or ankylosing spondylitis (inflammation of the pelvic joints -- most commonly the sacroiliac region). The male to female ratio is 7:1.
6. Undifferentiated arthritis: Children who either do not fit clearly into the above unique subtypes of JRA or who have symptoms/laboratory studies that overlap more than one subtype are classified as having undifferentiated arthritis. By their nature, the patient population with this form of JRA often presents with nonclassical history and/or findings on physical exam and laboratory studies. Providing an accurate prognosis and developing a treatment program are challenges.
What is the treatment for juvenile rheumatoid arthritis (JRA)? What medications treat JRA?
While there currently is no cure for JRA, an integrated and coordinated approach has been shown to be helpful in lessening the morbidity (nonlethal side effects) of JRA. Goals include lessening pain, joint contractures, and growth disturbances (see above). Monitoring for the development of iritis and aggressive treatment are also paramount. Often patients are best served at a pediatric teaching hospital where access to pediatric rheumatologists, physical and occupational therapists, pharmacologists, and social support providers may allow "one stop shopping."
Therapies for JRA patients include the following:
1. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as the first line of therapy due to their positive effect of reducing inflammation in arthritis and relatively few side effects. Medications such as ibuprofen (Advil, Motrin), naproxen (Aleve), and indomethacin (Indocin) are examples of this class of therapy.
2. Steroids are another common class of medications for those experiencing moderate to severe arthritis or nonarthritis inflammatory consequences of JRA. These medications may be administered orally (prednisone [Deltasone], prednisolone [Pediapred]), intravenously (methylprednisolone [Solu-Medrol], dexamethasone [Decadron], hydrocortisone [Solu-Cortef]), or injected directly into an involved joint (methylprednisolone [Depo-Medrol], triamcinolone [Kenalog]). Side effects of steroids may be considerable, and pediatric rheumatologists strive to use the lowest possible dosage. Side effects are most commonly seen at dosages over 20 mg/day and may include immune system depression, increased appetite resulting in weight gain, acne, mood changes, osteoporosis, bruising, cataracts, glaucoma, and diabetes.
3. Antirheumatic medications (also known as disease-modifying antirheumatic drugs or DMARDs) are needed in approximately two-thirds of children to control the joint changes and prevent damage of JRA. These medications are generally considered when the medications previously described are not providing effective control of the illness. Medicines in this category include methotrexate (Trexall), now considered the "gold standard" for JRA, sulfasalazine (Azulfidine), azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), and others. These medications are administered orally or intravenously. Antirheumatic medications are more potent in effect but also can have significant side effects. All of these medications require regular blood testing to monitor for side effects. Problems include immune suppression, which may cause an increased risk of infection, certain cancers, bone marrow toxicity, pulmonary toxicity, liver function abnormalities, abdominal pain, and decrease in appetite.
4. Biologic agents can lessen the morbidity for children with JRA. These agents are administered either by superficial injection under the skin or intravenously. Their general chemical classification is that of "monoclonal antibodies" that work by accurately targeting various mechanisms of the immune system that are overactive and misdirected in JRA. They are associated with an increased risk of infections and (rarely) development of certain malignancies. As such, close clinical monitoring and various laboratory studies are required. Examples of biologics used in the treatment of JRA include etanercept (Enbrel), anakinra (Kineret), adalimumab (Humira), tocilizumab (Actemra), and abatacept (Orencia).
5. Autologous stem cell transplantation is reserved only for those children with JRA who have failed the above therapeutic options. This procedure requires hospitalization and is a two-step process. The initial goal is utilization of high-dose immune suppression medications to remove the patient's lymphocytes (a type of white blood cell) that are attacking the patient's joint(s). Once removed, new stem cells from the patient (autologous) that were previously harvested and treated are introduced back into the patient's body via the bloodstream. This process requires expertise found only in a few pediatric referral centers.
What are complications of juvenile rheumatoid arthritis (JRA)?
Perhaps the most insidious and most devastating complication of JRA is a form of eye inflammation of the iris of the eye called iritis. The risk for iritis is variable depending upon the subtype of JRA. The highest risk group is oligoarticular JRA while patients with systemic onset JRA are at a low risk of this complication. It is imperative that all JRA patients have thorough ophthalmologic examinations in order to detect any changes that would herald the onset of iritis.
Another common complication of JRA is growth disturbances (such as a difference in leg lengths). Interestingly, the involved joint (such as the knee) has an increase in blood flow due to the inflammatory nature of the local arthritis. This increase in blood flow encourages the area of bone growth (growth plate) to maximum activity and thus the involved leg is longer than the non-involved limb. However, as the disease progresses, the chronic nature of arthritis can damage the growth plate region causing premature fusion and thus the involved leg will be retarded relative to the uninvolved limb. Many patients experience moderate pain of the joints involved resulting in limited use of the region. As a result, loss of calcium from the bone can result in osteoporosis.
These children and their parents may also fall victim to emotional stress associated with any chronic illness. Long-term low-grade pain may stimulate a sense of helplessness and hopelessness and thus depression. Children often have a limited social life (especially with their peers) due to school absenteeism.
It must also be remembered that the medical therapies commonly used to treat JRA can have many have prominent side effects (see above).
What is the prognosis of juvenile rheumatoid arthritis (JRA)?
Approximately 50% of children with JRA continue to have active disease into adulthood. In patients who have active disease into adulthood, there can be significant disability with functional limitations. Outcome may reflect duration of disease, presence of polyarticular involvement, and the need for systemic steroids. In the United States and Canada, death is rare (29 out of 10,000 patients) and is most likely with systemic onset JRA.
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