Juvenile Inflammatory Arthritis
- Does this patient have juvenile inflammatory arthritis?
What tests to perform?
- White Blood Cell Count (WBC)
- Differential count
- Platelet count
- ESR and/or CRP
- Hepatic function panel
- Lactate dehydrogenase (LDH)
- Rheumatoid factor (RF)
- Anti-cyclic citrullinated peptide antibody (anti-CCP)
- Atypical ANCA/anti-S. cerevisiae antibody panel
- Joint fluid aspiration
- How should patients with juvenile inflammatory arthritis be managed?
What happens to patients with juvenile inflammatory arthritis?
How to utilize team care?
Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this patient have juvenile inflammatory arthritis?
Juvenile inflammatory arthritis (aka juvenile idiopathic arthritis, JIA) is, by definition, a diagnosis of exclusion. The term itself encompasses, at a minimum, seven different patterns of arthritis. The overall definition is "an inflammatory arthritis beginning before the patient's 16th birthday, lasting 6 weeks or more in the absence of any other cause."
The subtypes are:
Oligoarticular arthritis, persistent.
Oligoarticular arthritis, extended.
Polyarticular arthritis, rheumatoid factor negative.
Polyarticular arthritis, rheumatoid factor positive.
Seronegative arthritis and enthesitis.
Each subtype has been strictly defined with its own exclusion criteria, which are necessary and useful for research studies. Practically speaking, there are patients who do not fit neatly into any definition and fall into the last category of "undifferentiated".
The most common presentation of JIA is an oligoarticular arthritis, particularly in the knee, although the ankle and wrist joints are often affected. By definition, oligoarthritis is arthritis in four or fewer joints. Persistent oligoarthritis remains as four or fewer joints through the lifetime of the disorder. It most commonly presents in girls between the ages of 2 and 5, with a female to male ratio of approximately 4:1.
The arthritis is relatively painless and the most common presenting symptom, other than obvious joint swelling, is an altered gait, i.e. "My child walks funny". These children most often have a positive ANA and are at highest risk for an associated asymptomatic anterior uveitis. Extended oligoarthritis remains as such during the first 6 months to 1 year, but a small number of additional joints will become inflamed after that time.
Polyarticular arthritis, rheumatoid factor negative
Polyarticular arthritis, rheumatoid factor negative is an arthritis of five or more joints, developing within the first 6 months of disease. It most often has its onset before age 5, although it is not uncommon to start later in childhood. It is also more common in girls than boys with an estimated ratio of 3:1.
Polyarticular arthritis, rheumatoid factor positive
Polyarticular arthritis, rheumatoid factor (RF) positive disease is an arthritis of five or more joints in the presence of a positive RF, which should remain positive in a second assay, at least 3 months after the initial test. Its most common onset is at puberty or in adolescence, but RF positive arthritis is not uncommon in younger children. It most often mimics adult-onset rheumatoid arthritis with small joint, bilaterally symmetrical arthritis. Like adult RA, it is most predominant in females with the female: male ratio estimated at 6:1 in some studies.
Systemic Onset juvenile idiopathic arthritis
Systemic Onset juvenile idiopathic arthritis (SOJIA) (in the past called Still's disease) can have either a polyarticular or oligoarticular presentation of arthritis, together with fever and rash. The fever is classically described as "quotidian" or a daily fever spike, which will rise to above 101°F or 38.5°C and return to normal within several hours in the absence of antipyretics. There may be one or two fever spikes/day.
Early on in the disease, the fevers may not follow this classic pattern but after 1-2 weeks will develop the quotidian pattern. The rash of Systemic Onset arthritis is a slightly raised, salmon-colored rash. It will come and go (evanescent) and will reappear in different areas of the body (non-fixed) with a predilection for the warmer sites such as the axillae and trunk. It can appear urticarial and in some cases will be pruritic.
The rash most often is seen at the time of the fever, but other physical stimuli such as heat or scratching the skin will bring it out (Koebner phenomenon). Systemic arthritis is seen throughout childhood and adolescence with essentially an equal F:M ratio.
Enthesitis-related arthritis (ERA) may be an oligoarticular or polyarticular disorder, accompanied by tenderness at the entheses. This definition encompasses a group of disorders including juvenile ankylosing spondylitis, arthritis associated with inflammatory bowel disease and what in past was labeled type II pauciarticular JRA. It is often HLA-B27 positive and has an onset after age 6. It is more common in males with a sex ratio F:M of 1:7 or more.
The involved joints are most commonly hips, knees, ankles and sacroiliac joints, but spinal involvement often occurs later on in the course of the arthritis. Acute anterior uveitis is an associated feature. It is often symptomatic, but may be silent, similar to that seen in oligoarticular JIA.
Psoriatic arthritis is an arthritis associated with psoriasis. In the absence of psoriasis, dactylitis and the typical psoriatic nail changes such as pitting and onycholysis are sufficient to make the diagnosis. Similarly in the absence of psoriasis, arthritis with either of the above manifestations along with a first degree relative with psoriasis is diagnostic of psoriatic arthritis.
It is usually an asymmetric oligoarthritis involving small and medium to large joints. It may involve the entheses and at times is difficult to distinguish from ERA. The female to male ratio is approximately 2:1. The mean age of onset has been reported as 6 years.
The differential diagnoses of the arthritis in children are dependent on the duration of the arthritis, pattern of expression and associated signs and symptoms.
An acute onset monoarticular arthritis associated with severe pain is suggestive of a septic joint, associated osteomyelitis or tumor. The pain can be of such severity that the patient has difficulty falling asleep or can be awakened with pain. The patient may or may not have fever. However, Toxic Synovitis, particularly of the hip, can be extremely painful. It is not usually associated with fever.
Lyme arthritis, which must be considered in any patient living in or having visited an endemic area, is usually painless. It is often an intermittent arthritis of several days duration associated with an extremely large effusion.
Pain is a much more common complaint in patients with polyarticular JIA. However, with exquisitely painful arthritis, a tumor diagnosis - leukemia, lymphoma or metastatic solid tumor - must be considered. A bacterial etiology, in the absence of immune dysfunction, is unlikely in polyarticular disease. Chronic recurrent multifocal osteomyelitis, a sterile bone inflammation of unknown etiology, is also to be considered.
A multi-joint arthritis can be triggered by any number of viruses, with rubella and hepatitis B being the most common in unvaccinated persons and parvovirus B19 likely the most frequent in North America. Alpha viruses triggering arthritis and rash are seen in Australia and South Asia. Epstein-Barr virus, cytomegalovirus, adenovirus, and herpes viruses have also been reported to cause arthritides in susceptible individuals.
Gastrointestinal infections with salmonella, shigella, yersinia and campylobacter can trigger a reactive arthritis.
Other rheumatologic disorders such as Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), and Sarcoidosis, among others can mimic JIA.
What tests to perform?
Laboratory evaluation is dependent on the associated signs and symptoms as well as the number of joints involved. Recommended laboratory tests, reason for ordering and interpretation are as follows:
White Blood Cell Count (WBC)
WBC will be elevated in Systemic Onset JIA often to over 20,000. WBC may be modestly elevated in polyarticular disease. It should be normal in oligoarticular JIA, psoriatic arthritis, and ERA. WBC may be normal, elevated or low in leukemic disease; there may be blast forms. WBC is low in SLE.
The hemoglobin may be modestly to severely low (below 7g) in SOJIA, arthritis associated with active inflammatory bowel disease, or other rheumatologic disorders. It may be modestly low in polyarticular arthritis. It may be normal or very low in leukemic disease. It should be normal in oligoarticular arthritis.
In SOJIA there is most often a neutrophil predominance that may be indistinguishable from a bacterial infection. In leukemic disease there may be blast forms. The differential is usually normal in both polyarticular and oligoarticular juvenile arthritis.
In both SOJIA and polyarticular JIA the platelet count is elevated, reflecting an inflammatory process. In SOJIA, it may be as high as 1 million. In leukemias, the platelet count is most often low to normal. In oligoarticular JIA, the platelet count should be in the normal range.
ESR and/or CRP
These are markedly elevated in SOJIA and usually somewhat elevated in polyarticular JIA and ERA. They are essentially normal in oligoarticular arthritis; if elevated a consideration of another inflammatory process such as IBD should be entertained.
Hepatic function panel
Transaminases are usually normal to very modestly elevated in SOJIA. A marked elevation is suggestive of a potentially life-threatening complication of Macrophage Activation Syndrome (MAS).
In an acute polyarthritis in the absence of features suggestive of SOJIA, elevated transaminases are suggestive of a viral associated arthritis or SLE. These are normal in polyarticular and oligoarticular JIA. It is also needed as a baseline level to monitor toxicity of therapeutic agents.
Albumin, globulin, A/G ratio often shows a reversal in IBD as well as acute rheumatic fever. Some patients with SLE or MCTD have a markedly reversed A/G ratio even in the absence of renal disease.
Elevated ferritin is found in SOJIA; excessive elevations are suggestive of macrophage activation syndrome (MAS).
Lactate dehydrogenase (LDH)
LDH is a marker of cell death. It is elevated in leukemia and other tumors and high levels, particularly in the presence of severe pain, would suggest an evaluation for tumor should be pursued. Elevations would also be suggestive of a hemolytic process more common to SLE than the juvenile arthritides.
This marker of active fibrin degradation is elevated in Systemic Onset JIA.
Rheumatoid factor (RF)
Rheumatoid factor should be ordered in patients with polyarticular arthritis and for research classification. As patients with SLE and chronic bacterial infections can be RF positive, it is not diagnostic for RF positive polyarticular JIA. It is not positive in the oligoarticular disorders, psoriatic arthritis or ERA. It may be useful to follow as some patients RF turns negative when their disease is controlled. Two positive tests, 12 weeks or more apart, are necessary to classify patients with having RF positive arthritis.
Anti-cyclic citrullinated peptide antibody (anti-CCP)
This test is more specific than RF for classic rheumatoid arthritis. It is useful as an aid to diagnosis in polyarticular arthritis, but like RF should be ordered in polyarticular disease and for research classification.
ANA is positive in a large fraction of the healthy population; it is therefore not a helpful screen for rheumatologic disease. ANA is only useful as a diagnostic test in those rare situations where it is necessary to help distinguish JIA from SLE. In patients with JIA, ANA should be tested in order to classify the frequency of ophthalmologic examinations to evaluate for uveitis. Patients who are ANA positive are at the highest risk for this complication.
This should be ordered for research classification purposes as it is not useful as a diagnostic test. Approximately 8-10% of the Caucasian population will be positive.
Atypical ANCA/anti-S. cerevisiae antibody panel
Patients with enthesitis-related arthritis and whose symptoms (low hemoglobin, weight loss, abdominal pain) are suggestive of IBD might benefit from a serologic screen for these diseases. Even if these are negative, a high index of suspicion suggests consideration of a gastroenterology evaluation.
Joint fluid aspiration
A joint fluid aspiration with bacterial culture and Gram stain is strongly recommended in patients with acute arthritis, fever and pain, particularly with refusal to bear weight. Joint fluid WBC count and differential is also recommended. However, WBC of over 25,000 with a predominance of neutrophils can be seen in JIA and Lyme arthritis as well as in a septic joint
Patients with arthritis should have standard x-rays of the affected joints performed to evaluate for signs of early erosive disease, tumor or infection at initial diagnosis.
Patients who have pain at rest or whose pain is out of proportion to what is commonly seen in arthritis should have the affected area imaged by MRI. In general, evaluation for structural derangement (e.g. torn meniscus) does not require intravenous gadolinium contrast media. However, evaluation of active synovitis is best seen by comparison of pre- and post-contrast images.
The use of diagnostic ultrasound in pediatric arthritis is a developing field. Follow-up x-rays can be considered every 1-2 years, depending on response to therapy.
Biopsies in JIA per se are rarely required. Patients with fever and arthritis who do not demonstrate the classic SOJIA rash, quotidian fever or laboratory abnormalities of this disorder should be considered for a bone marrow aspiration +/- biopsy as leukemia can have an arthritic presentation in a minority of cases. Similarly, patients whose imaging studies are suggestive of another disorder should be considered for a biopsy of the suspicious lesion.
There are no large scale, long term outcome data for the various types of JIA. The relatively recent availability of biologic agents may have a significant effect on improving the long term outcome. However retrospective chart reviews have been performed to evaluate periods of clinical remission off medication (remaining in remission for >1 year off medication).
How should patients with juvenile inflammatory arthritis be managed?
Management strategies differ depending on the type of JIA. As uveitis has been reported in all types of JIA, a slit lamp examination at diagnosis and follow up at appropriate intervals is critical.
Patients with an oligoarticular pattern of arthritis should be managed with anti-inflammatory doses of NSAIDs while the evaluation for JIA mimics is proceeding. After other diagnoses are eliminated from consideration, intra-articular long-acting corticosteroid injection (IACI) is recommended. In many studies using hexacetonide as the remittive agent has provided the longest duration of response.
As to the number of joints that can be injected, it is left to the discretion of the treating physician after consideration of the age of the patient, need for general anesthesia and any co-morbid conditions.
The response rate and duration has been reported as 60-80% at 6 months. In the face of complete resolution of the arthritis, concomitant therapy is not necessary. Unless the response is of short duration, i.e. less than 3-4 months, a relapse can be treated with a second injection. Those patients who do not respond to IACI should be treated with the same regimen as patients with polyarticular disease.
Polyarticular arthritis (RF-positive and -negative)
As with oligoarticular arthritis, NSAIDs are the agent of choice while other diagnoses are under consideration. Once the diagnosis is assured, the early use of disease-modifying anti-rheumatic drugs (DMARDs) is recommended.
Methotrexate is generally accepted as the initial DMARD to be used at doses of 15 mg/m² or 0.6 mg/kg once weekly, preferably subcutaneously. Some investigators have demonstrated that doses higher than these do not give any additional improvement, but others have recommended doses as high as 1 mg/kg, up to 40 mg if there is an inadequate response to initial therapy.
Methotrexate alone has been demonstrated to elicit remission while on medication in up to 60% of patients after a mean of 17 months of therapy. Currently, it has been recommended that if significantly active disease remains between 3-6 months after starting methotrexate therapy, a biologic agent, most commonly a TNF-alpha inhibitor should be started. There is no consensus as to whether methotrexate should be continued with the initiation of the biologic agent. Those patients who do not respond to an initial TNF-alpha inhibitor after 3-6 months should be treated with either a second TNF-alpha inhibitor or abatacept.
Corticosteroid injections to particularly painful joints or those resistant to therapy are recommended. Systemic corticosteroids should be reserved to treat those patients whose activities of daily living are severely compromised, with the goal of tapering rapidly as response to long term management is achieved. Although leflunomide has been demonstrated to be effective in JIA, it has not been approved for use in this disease.
Systemic Onset arthritis
Management is distinct depending on the features of the disease. If systemic features predominate (fever, rash), NSAIDs and corticosteroids are initial therapy. If these features are mild, a trial of 2 weeks of NSAIDs alone may be attempted before corticosteroids are given. Upon response, the steroids should be withdrawn via a slow (2-3 months) taper. As some patients have a monocyclic course of SOJIA, some patients may find this course of therapy to be adequate.
If arthritis is a primary feature, NSAIDs and methotrexate can be initiated, similar to therapy for polyarticular JIA. The place for biologic therapy in SOJIA is not yet clear. Tocilizumab, an IL-6 receptor inhibitor (8-12 mg/kg i.v. q 2 weeks), is approved for use in SOJIA and was highly effective in published studies. However, its use is somewhat limited by the need for I.V. infusions.
Anakinra, an IL-1 receptor antagonist, has also been demonstrated to be effective in SOJIA but is not approved for this disease. It is given as a daily injection and has the convenience of self-administration.
Canakinumab, a monoclonal antibody which inhibits IL-1 has recently been approved for use in SOJIA. It is a monthly injection. The TNF-alpha inhibitors are approved for polyarticular juvenile arthritis and can be used in patients with SOJIA. However, they appear to be less effective in this disease than in other types of polyarticular disease.
What happens to patients with juvenile inflammatory arthritis?
The outlook for patients with JIA is markedly improved from 40 years ago due to the use of methotrexate and biologic agents. However, it has become clear that these disease(s) do not vanish upon achieving majority. In a review of over 400 patients, 89% achieved a state of inactive disease, but only 26% were able to maintain that state off medication for 1 year. Of those, only 6 % remained in remission after 5 years.
Untreated or unresponsive disease can result in short stature, limb length discrepancy, joint erosions, joint contractures, muscle atrophy of an affected limb, all of which can adversely affect the quality of life.
Methotrexate can provoke nausea and vomiting, which leads to discontinuation of therapy. Methotrexate can cause birth defects in exposed fetuses and can cause early abortions. Hence, adolescents must be cautioned about appropriate contraception.
TNF-alpha inhibitors render patients more susceptible to intracellular pathogens and certain fungi. Testing for tuberculosis before starting anti-TNF therapy is recommended.
The causal role of TNF-alpha inhibitor in causing hematologic malignancies remains unclear in JIA as it does in adult disease. An increased incidence of these cancers has been reported. However, it is not known whether children with JIA experience these cancers with an increased frequency as compared to the general population.
How to utilize team care?
Ophthalmologic consultation is mandatory to diagnose and treat occult uveitis. Hematology consultation may be helpful to diagnose Systemic Onset JIA if arthritis is minimal and a bone marrow aspiration is necessary.
Orthopedic consultation to perform a joint aspiration for culture may be important in painful monoarticular arthritis when a septic joint is under consideration. Pain consultation will help in the management of significant arthritis-associated pain.
Nursing is critical to help teaching for joint injections and instruct patients on medications and side effects.
Pharmacy has an important role in detection of any drug interactions.
Dieticians are helpful in providing advice regarding healthful diets and assuring adequate calories for growth and development.
Physical and Occupational therapists are essential to maintain joint motion and recommend any aids to maintain activities of daily living.
Child Life Therapy is of great assistance in helping the child cope with the frequent needle sticks needed to administer medications and blood draws to monitor disease activity and drug toxicity.
Are there clinical practice guidelines to inform decision making?
An updated set of guidelines for JIA therapy has recently been published. Guidelines recommending frequency of ophthalmologic follow up are available. Guidelines are limited in that recommendations include off-label use of available medications and do not consider the most recently approved therapy.
What is the evidence?
Beukelman, T, Patkar, NM, Saag, KG, Tolleson-Rinehart, S, Cron, RQ, DeWitt, EM. "2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features". Arthritis Care Res (Hoboken ). vol. 63. 2011. pp. 465-82.(An algorithm for therapy of all types of JIA, with stratification for higher risk subgroups using consensus criteria. An excellent reference but the recommendations include off-label use of some drugs and have not considered tocilizumab.)
Gottlieb, BS, Keenan, GF, Lu, T, Ilowite, NT. "Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis". Pediatrics. vol. 100. 1997. pp. 994-7.(A retrospective review demonstrating differences in time to achieve remission varies with type of JRA and that 50% of children will relapse in less than 1 year off methotrexate as a solo agent.)
Heiligenhaus, A, Niewerth, M, Ganser, G, Heinz, C, Minden, K. "Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines". Rheumatology (Oxford). vol. 46. 2007. pp. 1015-9.(An analysis of the recommendations for the frequency of ophthalmologic examinations based on JIA type, age of onset and duration of disease.)
Lovell, DJ, Ruperto, N, Goodman, S, Reiff, A, Jung, L, Jarosova, K. "Adalimumab with or without methotrexate in juvenile rheumatoid arthritis". N Engl J Med. vol. 359. 2008. pp. 810-20.(An open label run-in study which demonstrates the efficacy of adding adalimumab to the therapy of patients who have active disease on methotrexate.)
Lovell, DJ, Giannini, EH, Reiff, A, Cawkwell, GD, Silverman, ED, Nocton, JJ. "Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group". N Engl J Med. vol. 342. 2000. pp. 763-9.(A landmark study which piloted the open label lead-in design. It was the first double-blind placebo controlled study of a biologic agent in children and demonstrated the efficacy of this TNF-alpha inhibitor in polyarticular course JIA.)
Lovell, DJ, Reiff, A, Ilowite, NT, Wallace, CA, Chon, Y, Lin, SL. "Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis". Arthritis Rheum. vol. 58. 2008. pp. 1496-504.(The study demonstrates the durability of response and safety of etanercept as a follow up to the original 58 children who remained on open-label extension. Twenty six were in the 8th year of study. The most common SAE was disease flare.)
Niehues, T, Horneff, G, Michels, H, Hock, MS, Schuchmann, L. "Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria". Rheumatol Int. vol. 25. 2005. pp. 169-78.(A working group report which upon literature review reaches the consensus that methotrexate is efficacious in JIA.)
Petty, RE, Southwood, TR, Manners, P, Baum, J, Glass, DN, Goldenberg, J. "International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001". J. vol. 31. Rheumatol 2004. pp. 390-2.(The current definitions, criteria and exclusions for Juvenile Idiopathic Arthritis.)
Pascual, V, Allantaz, F, Arce, E, Punaro, M, Banchereau, J. "Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade". J Exp Med. vol. 201. 2005. pp. 1479-86.(This study demonstrates the role of IL-1 in Systemic Onset JIA and explores the molecular biology of this disease as well as the response to an IL-1 receptor antagonist.)
Ringold, S, Seidel, KD, Koepsell, TD, Wallace, CA. "Inactive disease in polyarticular juvenile idiopathic arthritis: current patterns and associations". Rheumatology (Oxford). vol. 48. 2009. pp. 972-7.(This retrospective study demonstrates that of 104 children with polyarticular JIA followed over 30 months, 78% achieved inactive disease by the end of the first year. However, the duration of inactive disease was on average only 8 months.)
Ringold, S, Weiss, PF, Beukelman, T, Dewitt, EM, Ilowite, NT, Kimura, Y. "2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications". Arthritis Rheum. vol. 65. 2013Oct. pp. 2499-512.(An update of the initial algorithm of therapy with the inclusion of more biologic agents and suggestions for their early use in disease.)
Ruperto, N, Murray, KJ, Gerloni, V, Wulffraat, N, de Oliveira, SK, Falcini, F. "A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate". Arthritis Rheum. vol. 50. 2004. pp. 2191-201.(An open label trial that demonstrates 15 mg/m2 parenteral methotrexate, to a maximum of 20 mg/week is adequate therapy. Higher doses have no additional benefit.)
Ruperto, N, Lovell, DJ, Quartier, P, Paz, E, Rubio-Perez, N, Silva, CA. "Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial". Lancet. vol. 372. 2008. pp. 383-91.(Using the same open-label run in period as was used in the initial etanercept trial, abatacept was shown to be effective therapy as measured by time-to-flare on treatment, with some children achieving inactive disease status.)
Ruperto, N, Lovell, DJ, Quartier, P, Paz, E, Rubio-Perez, N, Silva, CA. "Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis". Arthritis Rheum. vol. 62. 2010. pp. 1792-802.(They show that abatacept treatment resulted in maintained or improved response after 21 months of therapy, with 39% achieving an ACR100 status. Of those children who did not achieve an ACR30 at the end of the initial open label run in, clinically meaningful responses were achieved after long term open label therapy in 73%.)
Ruperto, N, Lovell, DJ, Cuttica, R, Woo, P, Meiorin, S, Wouters, C. "Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension". Ann Rheum Dis. vol. 69. 2010. pp. 718-22.(Of the original efficacy trial, 39 patients completed a 4 year open label extension. Ten percent achieved an inactive disease status by year 4 but there was a high drop out rate.)
Wallace, CA, Giannini, EH, Huang, B, Itert, L, Ruperto, N,. "American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis". Arthritis Care Res (Hoboken ). vol. 63. 2011. pp. 929-36.(Validation of the criteria to define remission, both on and off medications in JIA.)
Yokota, S, Imagawa, T, Mori, M, Miyamae, T, Aihara, Y, Takei, S. "Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial". Lancet. vol. 371. 2008. pp. 998-1006.(The first controlled study showing an IL-6 receptor antagonist is efficacious in Systemic Onset JIA, with 90% of patients achieving a 70% improvement by 48 weeks.)
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