The treatment for juvenile idiopathic arthritis has evolved dramatically over the past few decades. Previously, treatment was mainly limited to nonsteroidal anti-inflammatory drugs and glucocorticoids, which generally decreased the immune responses and inflammation. As our understanding of disease pathogenesis has advanced, therapies have been designed to target specific dysregulated immune pathways. Targeted immune therapies have revolutionized the field of rheumatology and have made a significant impact on disease outcome.
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as the initial treatment for inflammatory processes in arthritis. Table 1 provides a list of the most frequently used NSAIDs in juvenile idiopathic arthritis (JIA). NSAIDs work by inhibiting cyclooxygenase (COX) enzymes that convert arachidonic acid to prostaglandins, thromboxanes, and prostacyclins, all of which play a role in inflammation. There are two main COX enzymes (COX-1 and COX-2), and traditional NSAIDs target them both. The discovery that COX-2 primarily mediates inflammation led to COX-2–specific inhibitors such as celecoxib. These specific inhibitors brought the promise of eliminating the unwanted adverse effects of traditional NSAIDs, such as gastrointestinal (GI) toxicity.
Table 1. NSAIDs Commonly Used in JIA
Drug trials later revealed, however, increased cardiovascular toxicity in adults, which led to withdrawal of some COX-2 inhibitors and warnings on all NSAIDs for the potential of increased cardiovascular side effects.1 Although studies were performed in adults, the use of COX-2 inhibitors in pediatric patients markedly declined because of the potential risk.
Naproxen is the most commonly used NSAID for JIA. It is prescribed at an anti-inflammatory dose that is higher than that needed for analgesic effects and is given twice daily. The advantage of naproxen over ibuprofen (the more commonly used NSAID in general pediatrics) is the dosing frequency, which improves compliance. In general, patients tend to have a clinical response within the first 2 weeks on NSAID therapy. However, it should be prescribed for up to 8 weeks to be considered an adequate trial, and in one quarter of the patients it may take up to 12 weeks before a response is seen.2
The side effect profile of NSAID therapy in children is less problematic compared with adults because there are fewer associated comorbidities. The most common side effects seen in pediatric patients are GI manifestations, such as abdominal pain and decreased appetite, which can be improved when the medicine is given with food. Patients also report increased bruising. Less commonly, patients can develop GI ulcers and anemia from GI bleeding, particularly if they are on long-term NSAID therapy.
Another infrequent side effect is cutaneous pseudoporphyria, which is a photosensitive rash. It starts with an erythematous base with tiny vesicles that are usually missed because they rupture immediately; it progresses to superficial erosions that can eventually scar (see Figure 1).
Figure 1. Cutaneous pseudoporphyria induced by naproxen. (A) Patient still on naproxen. (B) Patient no longer taking naproxen.Images courtesy of Schad et al31. Reprinted with permission.
These lesions, except for scars, will typically resolve with discontinuation of the treatment but can continue for weeks to months after stopping the medicine. They are seen more commonly in patients with fair-colored skin, and are also more commonly associated with naproxen than with other NSAIDs. Routine use of sunscreen is encouraged to decrease this side effect. NSAID therapy has also been associated with hepatic and renal toxicities, so patients should have annual or biannual screens of their complete blood counts (CBC), liver enzymes, and serum creatinine.3
Disease-Modifying Anti-Rheumatic Drugs
When NSAID therapy is insufficient to control the inflammation, disease-modifying anti-rheumatic drugs (DMARDs) are the next line of therapy. This includes classical DMARDs and biologic therapy.
Methotrexate is the most commonly used classical DMARD. Other classical DMARDs include leflunomide, hydroxychloroquine, and sulfasalazine. Table 2 lists standard dosing for classical DMARDs used in JIA.
Table 2. Classical Disease-Modifying Anti-Rheumatic Drugs Used in JIA
Methotrexate (MTX) has been shown to be effective in improving clinical symptoms, decreasing inflammatory markers, and slowing radiographic progression.4 It works through a variety of mechanisms to down-regulate the immune response. MTX can function as a folic acid analogue, inhibiting dihydrofolate reductase (DHR), an enzyme involved in DNA synthesis that decreases lymphocyte proliferation. It also blocks the generation of polyamines in immune cells, which decrease lymphotoxins such as superoxide radicals that promote inflammation. MTX can increase adenosine levels in the body that have a myriad of anti-inflammatory properties, including effects on neutrophil function. It also affects the production of inflammatory cytokines.5
MTX is available as an oral or injectable form and is given weekly. The preferred method of delivery is subcutaneous injections, especially at higher doses, because the oral bioavailability is roughly 70% and can vary depending on age, genetics, and GI absorption. Although serum levels of MTX can be measured, they do not correlate with clinical improvement and are not followed. Patients typically respond in the first 6 to 12 weeks, but some patients can take up to 6 months to see improvement. Once the disease is inactive, it is common practice to discontinue therapy 6 to 12 months after disease quiescence.6 Unfortunately, some patients may relapse when therapy is discontinued, and there are no well-established predictors to identify who will have disease recurrence.
Families are often concerned about the side effect profile of MTX because it is considered a chemotherapeutic agent. However, doses used in treating JIA are several-fold less compared than those used in oncology patients. The most common side effects are nausea and vomiting, which can be helped with anti-nausea medications such as ondansetron. Patients can also experience fatigue, headaches, and stomatitis. Many of these symptoms can be improved with either daily folic acid or weekly leucovorin supplementation.
Hepatotoxicity is the side effect of most concern, and it occurs in roughly 10% of patients. It usually resolves with reduction of the dose or stopping the medication altogether.7 Liver enzymes should be monitored at baseline, 1 month, every 1 to 2 months with dose change, and every 3 to 4 months when the patient is on a stable dose.3 CBCs are also monitored because bone marrow suppression can develop in rare instances.
Infection risk is relatively low because MTX given for inflammation is not considered highly immunosuppressive. Patients can experience prolonged recovery from common illnesses. During severe illnesses or when patients have high fevers, a dose or two can be held until the patient recovers. Also, administration of live vaccines is contraindicated in patients taking MTX.
Patients engaged in high-risk behaviors need to be counseled against alcohol consumption and pregnancy. Alcohol can potentiate the hepatotoxicity risk. MTX is also a potential teratogen, and patients should be instructed on simultaneously using two methods of birth control at all times.
Leflunomide has been shown to be effective for JIA, but it may not be as effective as MTX.8 It is used in patients unable to tolerate the side effects of MTX. It is similar to MTX in that it works as an anti-metabolite, but it inhibits dihydroorotate dehydrogenase enzyme, another enzyme in DNA synthesis. It works by decreasing lymphocyte proliferation as well as by affecting intracellular signaling pathways involved in the inflammatory process. It is taken orally on a daily or every-other-day dosing schedule based on the patient’s weight. The clinical effects are typically seen within the first 1 to 4 months.8
The major side effect is hepatotoxicity, but it is less common compared with MTX. Patients require frequent liver enzyme monitoring because leflunomide has a prolonged half-life (18 days). Alcohol consumption is also strongly discouraged because of the increased risk of liver toxicity.
Other side effects include abdominal pain, nausea, vomiting, diarrhea, rash, and alopecia, all of which generally reverse when the medication is discontinued.
Similar to MTX, leflunomide is a also teratogen, so patients need to be counseled on the importance of using at least two forms of birth control at all times. Also, a prolonged washout period is recommended prior to conception given leflunomide’s long half-life. Lastly, live vaccines are contraindicated in patients taking leflunomide.
Hydroxychloroquine is an anti-malarial medication that is effective in adults with rheumatoid arthritis (RA) and was part of the triple therapy used frequently prior to biologic therapy. It has not been shown to be clinically beneficial in JIA patients,9 although it is commonly used in other pediatric rheumatic conditions such as systemic lupus erythematosus. It is thought to play a role in modulating the immune response by affecting antigen presentation. It is well-tolerated with minimal side effects, including abdominal pain and increased skin hyperpigmentation. Patients require ophthalmologic monitoring roughly every 6 to 12 months for retinal toxicity, which can lead to deficiency in peripheral and color vision.
Young children unable to distinguish colors or cooperate for eye exams are not started on this medicine. It is also important to screen for glucose-6-phosphate-dehydrogenase (G6PD) deficiency prior to starting this medicine, because it can precipitate hemolytic anemia.
Sulfasalazine is a 5-aminosalicyclic acid (5-ASA) analogue that is now used primarily for inflammatory bowel disease but is effective for certain types of JIA.10 It is believed to act in multiple ways, including decreasing bacterial growth in the GI tract and affecting enzymes involved in the inflammatory pathways. Prior to starting therapy, patients should be screened for sulfa or salicylate allergies, G6PD deficiency, and renal or hepatic dysfunction. It is taken orally, usually two to three times daily, and patients generally respond within 1 to 3 months of starting treatment.10
The most common side effects are GI symptoms (abdominal pain, nausea, vomiting, diarrhea, and anorexia) and maculopapular rash in sun-exposed areas. Rarely, patients can develop Stevens-Johnson syndrome. Also, liver dysfunction and hematologic abnormalities such as neutropenia and thrombocytopenia can occur, so CBCs and liver enzymes need to be monitored.
The development of biologic therapy has significantly enriched our armamentarium for treating juvenile arthritis. Targeting key inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), results in fewer systemic side effects compared with other therapies that diminish the immune response. Table 3 summarizes commonly used biologic therapies for JIA. For all biologic therapies, the risk of intercurrent infections is increased and live vaccines are contraindicated.
Table 3. Biologic Therapies Used in JIA
TNF-alpha is one of the major inflammatory cytokines in the pathogenesis of JIA, as well as RA in adults. It has been shown that JIA patients have higher levels of both TNF-alpha and the soluble TNF receptor in the synovial fluid and serum. TNF-alpha mediates its effects through two receptors, TNFR1 and TNFR2, which have a role in promoting a proinflammatory state (TNFR1) and an immunoregulatory state (TNFR2).
Three anti-TNF inhibitors are approved for pediatric patients, and they have been shown to be effective in treating JIA.11–13 TNF inhibitors are given parenterally, and the frequency of administration varies. Clinical improvement is usually seen by the third or fourth dose.
Infliximab was the first inhibitor designed and it is a chimeric antibody composed of part of the human IgG1 antibody with a mouse-derived binding domain for TNF. Patients have a higher risk for reacting against the mouse component and developing antibodies called humanized antichimeric antibodies (HACAs) that can interfere with the effectiveness of the medication.
Methotrexate is co-administered to prevent development of these antibodies.14 Etanercept is a humanized fusion protein with the binding site for TNFR2, one of the receptors for TNF-alpha. It was the first TNF-alpha inhibitor used in children and was shown to be safe and efficacious in a randomized, double-blind, placebo-controlled trial.12 Adalimumab is a fully humanized antibody against TNF. There are two TNF inhibitors that have not yet been approved for children.
Golimumab is a fully humanized anti-TNF antibody given monthly by subcutaneous injection. Certolizumab is composed of the antibody’s binding domain for TNF attached to pegol, a chemical structure. Unlike the other anti-TNF agents, certolizumab lacks the Fc portion of the antibody, so theoretically it should lack the Fc portion–mediated side effects.
The most common complaints are pain and redness at the site of injection, more frequently noted with adalimumab in our patients. Laboratory monitoring of CBC, aspartate aminotransferase (AST), alanine transaminase (ALT), and creatinine should be done every 3 to 6 months.3
TNF inhibitors increase the risk for tuberculosis and histoplasmosis.15 All patients require tuberculosis screening prior to starting therapy, and then once annually while on the medication.3 If there is a positive TB test with a negative chest X-ray, the patient should receive a 9-month course of isoniazid (INH). TNF inhibitors can be started from days to weeks after initiation of INH therapy.16 There is also a potential increased risk for other infections, although recent data show no increased risk for serious bacterial infections in JIA patients on TNF therapy.17
In our experience, patients may take longer to recover from common illnesses, so we recommend holding a dose or two of the medication during a severe febrile illness, similar to patients on MTX. Live vaccines are contraindicated in patients on TNF therapy.
One of the main concerns for a patient’s family is the association of TNF inhibitors with malignancy. Early reports suggested an increased association of malignancy in patients using TNF inhibitors, which led the Food and Drug Administration (FDA) in 2009 to issue a black box warning on all TNF inhibitors for children. However, a recently published study in a large pediatric US cohort did not report increased risk for malignancy in children on TNF inhibitors,18 but it did show an increased risk of malignancy in JIA patients compared with controls, regardless of treatment.18
Demyelinating syndromes such as multiple sclerosis and Guillain-Barré syndrome have been reported in patients on anti-TNF therapy, although the rate reported for these conditions was comparable to the rates in the general population.19 Nevertheless, anti-TNF therapy is not recommended in patients with a prior history of or a first-degree relative with demyelinating syndromes.
Other rare neuropsychiatric effects include headaches, difficulty concentrating, anxiety or depression, and psychosis.15 An uncommon but important side effect, is lupus-like syndrome. Paradoxically, psoriasis and inflammatory bowel disease can be both treated and induced by anti-TNF agents.15
IL-1 is another key inflammatory cytokine. Anti–IL-1 agents are used to treat chronic arthritis, particularly systemic JIA.20 Anakinra is a genetically engineered protein that is the equivalent of the naturally occurring IL-1 receptor antagonist. It is given as a daily subcutaneous injection, and a response is usually seen within the first several doses.20
The most common side effects are pain and rash at the injection site, which have led some patients to discontinue therapy. There is an increased risk of serious infections, and live vaccines are contraindicated. Neutropenia can also occur, so neutrophil counts should be monitored.
Rilonacept, also known as IL-1 Trap, functions as a decoy receptor by binding to IL-1and preventing it from signaling via the endogenous receptor. It is given as a weekly subcutaneous injection and is approved for cryopyrin-associated periodic fever syndrome. It is currently being used in a clinical trial to assess effectiveness in systemic JIA (Randomized Placebo Phase Study of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis [RAPPORT]). Side effects are similar to anakinra but the injections tend to be less painful. In some patients, the lipid profile was increased, so screening is recommended while on the therapy.
Canakinumab, another IL-1 signaling inhibitor, is a humanized monoclonal antibody against IL-1 beta. It has been shown to be effective in systemic JIA patients and is awaiting FDA approval.21 One major benefit is the prolonged half-life, which is so significant that it only needs to be given every 2 months. Adverse side effects include headaches, vertigo, GI symptoms, injection site reactions, and increased risk of infection. CBC and liver function tests should be monitored.
IL-6, like TNF-alpha and IL-1, is a proinflammatory cytokine. Tocilizumab is a humanized monoclonal antibody designed to bind the IL-6 receptor, both the membrane and the soluble form. It is given as an infusion every 2 to 4 weeks and has been effective for systemic JIA.22
Side effects include infusion reactions, elevated liver enzymes, lipid abnormalities, and hematologic abnormalities (eg, thrombocytopenia, neutropenia). The most severe complication in adults is the risk of colonic ulceration usually associated with diverticulitis.22 It is contraindicated in patients with established cardiac failure. Similar to other biologic therapies, patients are at increased risk for infections and live vaccines are contraindicated.
Abatacept is a fusion protein of the Fc portion of an antibody and the extracellular domain of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). This molecule blocks the co-stimulatory signal necessary for T-cell activation. It was shown to be effective in JIA patients compared with patients given placebo23 and is approved by the FDA for use in polyarticular JIA. It is usually given as an infusion on a monthly basis, but a weekly subcutaneous form is available for adults. Patients typically respond by the third or fourth dose.23 Adverse side effects include infusion reaction, headaches, upper respiratory infections, cough, GI symptoms, and fever.
Similar to initiation of TNF inhibitors, patients should be screened for tuberculosis prior to starting, and lab tests should be monitored every few months. Live vaccines are contraindicated.
Rituximab is a chimeric monoclonal antibody that binds CD20, which is a marker expressed on most types of B cells. It is speculated to work by decreasing the number of antigen presenting cells and autoreactive B cells. For JIA and RA, it is given as two infusions separated by 2 weeks, and antihistamines and corticosteroids are given prior to infusion. It is typically used in refractory arthritis.24 B cells and immunoglobulins are generally monitored before and after treatment.
The main side effects include infusion reaction, hepatic and renal toxicity, and infection (particularly viral infections). The most serious side effect-related infection, although very rare and not reported in children, is the development of progressive multifocal leukoencephalopathy (PML). Two cases of PML reported in adults were associated with combination immunosuppressive therapy.25
Steroids are potent immunosuppressive medications that have been in use since the 1950s. They work on both the genomic and nongenomic level. At the genomic level, they bind cytoplasmic receptors, translocate to the nucleus, and effect expression of genes involved in the immune response and inflammation. It has been speculated that about 1% of gene expression is altered by steroids. At the nongenomic level, steroids can affect ion transport, such as calcium, and interact with proteins that directly impact immune and inflammatory signaling pathways.26 It is speculated that high serum steroid levels lead to more nongenomic effects and that lower levels lead to more genomic effects.
In arthritis, steroids can be given locally by joint injections or systemically via either oral or intravenous means. The latter is usually preferred when there are multiple inflamed joints or prominent systemic inflammation (eg, systemic JIA). Although effective at achieving rapid control of inflammation, they serve as bridging therapy and are not considered a disease-modifying therapy.
Systemic steroids have a diverse side effect profile with both early and long-term consequences. Early side effects include increased appetite and water retention, which can lead to weight gain. Patients develop a cushingoid appearance with truncal obesity, “buffalo hump,” and moon facies, which can have a psychological impact, especially in the adolescent period.
These effects are generally reversible as the steroid dose is tapered down. To counter weight gain, we encourage patients to maintain a healthy diet that is low in sodium, fat, and concentrated sweets and to participate in regular exercise. Other reversible side effects include hirsutism, acne, mood changes, hypertension, and steroid-induced diabetes.
Long-term use of glucocorticoids impacts bone health by reducing bone formation and increasing bone resorption. This can lead to the development of early osteoporosis, placing these patients at risk for fractures. Dual energy X-ray absorptiometry (DEXA) scans can be followed, but normative values, especially for young children, are not well standardized.
Patients are started on calcium and vitamin D supplementation to help preserve bone health. Avascular necrosis (AVN) of the bone can also occur, and it presents with acute pain in the joint where the arthritis is well controlled. X-rays are used as initial screening for AVN, but additional imaging such as MRI is usually needed.
Other long-term consequences include cataract and glaucoma, so patients should have yearly ophthalmologic screening. Also, steroid-induced myopathy can occur and present with proximal muscle weakness in the setting of normal muscle enzyme labs. Patients on long-term steroid treatment are at risk for adrenal crisis and may require stress dosing during infection or when steroids are tapered rapidly.
Local steroids injected into a joint have few associated side effects, with the most common being atrophic skin changes at the site of injection. Other rare side effects include infection, self-resolving crystal-inducing synovitis, and calcifications that are usually asymptomatic.
Two forms of steroids are typically used — triamcinolone acetonide and triamcinolone hexacetonide — with the latter shown to be superior in efficacy.27 The response occurs within the first few days and can last for several months. The amount injected depends on the joint and the patient’s weight. Patients are not typically injected in the same joint more than three times per year. Usually, the procedure is performed with local anesthesia, but some children may need generalized sedation.
Other Immunosuppressive Medications
Cyclosporine A (CsA) is more commonly used in transplantation and works by inhibiting calcineurin, which leads to decreased T cell function. It is the mainstay therapy for macrophage activation syndrome, a life-threatening complication of systemic JIA. Side effects include liver and renal toxicity, hypertension, oral ulcers, hypertrichosis, paresthesias, gingival hyperplasia, and GI symptoms.
Cyclophosphamide has been used in refractory JIA cases and is rarely used nowadays because of its side effect profile. It cross-links DNA and inhibits DNA synthesis. Side effects include decreased fertility, hair loss, GI symptoms, and hemorrhagic cystitis. With both of these medications, patients have an increased risk for infections.
Thalidomide has also been used in refractory cases of JIA, especially for systemic JIA.28 It impacts both the innate and adaptive immune response and angiogenesis. The major side effects are peripheral neuropathy, drowsiness, hypothyroidism, and hypoglycemia. Peripheral neuropathy presents as painful paresthesias in a glove-and-stocking distribution and may be irreversible. It is also known to cause severe birth defects and requires monthly monitoring via System for Thalidomide Education and Prescribing Safety program (STEPS).
Hematopoietic stem cell transplantation (HSCT) replaces autoreactive cells with naïve cells that are expected to be able to tolerate self-antigens. It has been used since the late 1990s to treat refractory JIA. However, with the increased use of biologic therapy, fewer patients are candidates for HSCT. There are two primary methods: autologous (using the patient’s own stems cells), and allogenic (using donor stem cells).
The benefit of autologous transplantation is the lack of graft-versus-host disease (GVHD), but there is a potential increased risk for disease recurrence given that the same stem cells capable of breaching tolerance are used. In both cases, patients have to undergo conditioning that leaves patients at high risk for infection and macrophage activation syndrome.
Mesenchymal stromal cell therapy uses non-hematopoietic stem cells that have immunosuppressive properties. It has been used to treat GVHD and has been used more recently to treat refractory cases of rheumatic conditions. This treatment does not require conditioning, which is its main advantage over HSCT. A pilot study in the Netherlands is assessing the utility of this therapy in refractory JIA patients.29
Treatment for JIA has advanced from NSAIDs and steroids to more targeted therapies. Although these therapies have fewer systemic side effects, it is important to counsel and monitor patients (Table 4). The use of new therapies and the change in treatment paradigm is changing the clinical course and outcome ins JIA. We have learned that early diagnosis and early treatment as well as the use of combination therapies are keys to achieving faster clinical remission.30 In the future, we hope to achieve long-term remission and prevent relapses by resetting the immune response that went awry.
Table 4. Important Counseling and Screenings for Commonly Used Therapies in JIA
- Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR STUDY GROUP. N Engl J Med. 2000;343(21):1520–1528. doi:10.1056/NEJM200011233432103 [CrossRef]
- Lovell DJ, Giannini EH, Brewer EJ Jr, . Time course of response to nonsteroidal anti-inflammatory drugs in juvenile rheumatoid arthritis. Arthritis Rheum. 1984;27(12):1433–1437. doi:10.1002/art.1780271216 [CrossRef]
- Beukelman T, Patkar NM, Saag KG, et al. 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.. 2011;63(4):465–482. doi:10.1002/acr.20460 [CrossRef]
- Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatolgy Collaborative Study Group and the Cooperative Children’s Study Group. N Engl J Med. 1992;326(16):1043–1049. doi:10.1056/NEJM199204163261602 [CrossRef]
- Chan ES, Cronstein BN. Methotrexate—how does it really work?Nat Rev Rheumatol. 2010;6(3):175–178. doi:10.1038/nrrheum.2010.5 [CrossRef]
- Foell D, Wulffraat N, Wedderburn LR, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission. JAMA. 2010;303(13):1266–1273. doi:10.1001/jama.2010.375 [CrossRef]
- Singsen BH, Goldbach-Mansky R. Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatic and nonrheumatic disorders. Rheum Dis Clin North Am. 1997;23(4):811–840. doi:10.1016/S0889-857X(05)70362-8 [CrossRef]
- Silverman E, Mouy R, Spiegel L, et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med. 2005;352(16):1655–1666. doi:10.1056/NEJMoa041810 [CrossRef]
- Brewer EJ, Giannini EH, Kuzmina N, Alekseev L. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind placebo-controlled trial. N Engl J Med. 1986;314(20):1269–1276. doi:10.1056/NEJM198605153142001 [CrossRef]
- van Rossum MA, Fiselier TJ, Franssen MJ, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Group. Arthritis Rheum. 1998;41(5):808–816. doi:10.1002/1529-0131(199805)41:5<808::AID-ART6>3.0.CO;2-T [CrossRef]
- Lahdenne P, Vähäsalo P, Honkanen V. Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis. 2003;62(3):245–247. doi:10.1136/ard.62.3.245 [CrossRef]
- Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342(11):763–769. doi:10.1056/NEJM200003163421103 [CrossRef]
- Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810–820. doi:10.1056/NEJMoa0706290 [CrossRef]
- Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552–1563. doi:10.1002/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W [CrossRef]
- Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol. 2010;6(10):561–571. doi:10.1038/nrrheum.2010.142 [CrossRef]
- Bieber J, Kavanaugh A. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments. Rheum Dis Clin North Am. 2004;30(2):257–270. doi:10.1016/j.rdc.2004.01.003 [CrossRef]
- Beukelman T, Xie F, Chen L, et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(8):2773–2780. doi:10.1002/art.34458 [CrossRef]
- Beukelman T, Haynes K, Curtis JR, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64:1263–1271. doi:10.1002/art.34348 [CrossRef]
- Magnano MD, Robinson WH, Genovese MC. Demyelination and inhibition of tumor necrosis factor (TNF). Clin Exp Rheumatol. 2004;22(5 Suppl 35):S134–S140.
- Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63(2):545–555. doi:10.1002/art.30128 [CrossRef]
- Ruperto N, Quartier P, Wulffraat N, et al. 2.2 A phase II trial with canakinumab, a new IL-1beta blocking monoclonal antibody (ACZ885), to evaluate preliminary dosing, safety and efficacy profile in children with systemic juvenile idiopathic arthritis (sJIA). Pediatr Rheumatol2008;6:1–1. doi:10.1186/1546-0096-6-S1-S2 [CrossRef]
- Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998–1006. doi:10.1016/S0140-6736(08)60454-7 [CrossRef]
- Ruperto N, Lovell DJ, Quartier P, et al. Abatacept in children with juvenile idiopathic arthritis: A randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372(9636):383–391. doi:10.1016/S0140-6736(08)60998-8 [CrossRef]
- Kuek A, Hazleman BL, Gaston JH, Östör AJ. Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab. Rheumatology (Oxford). 2006;45(11):1448–1449. doi:10.1093/rheumatology/kel301 [CrossRef]
- Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the research on adverse drug events and reports project. Blood. 2009;113(20):4834–4840. doi:10.1182/blood-2008-10-186999 [CrossRef]
- Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004;50(11):3408–3417. doi:10.1002/art.20583 [CrossRef]
- Zulian F, Martini G, Gobber D, Agosto C, Gigante C, Zacchello F. Comparison of intra-articular triamcinolone hexacetonide and triamcinolone acetonide in oligoarticular juvenile idiopathic arthritis. Rheumatology (Oxford). 2003;42(10):1254–1259. doi:10.1093/rheumatology/keg358 [CrossRef]
- Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr. 2002;140(1):125–127. doi:10.1067/mpd.2002.120835 [CrossRef]
- Tyndall A. Application of autologous stem cell transplantation in various adult and pediatric rheumatic diseases. Pediatr Res. 2012;71(4 Pt 2):433–438. doi:10.1038/pr.2011.66 [CrossRef]
- Wallace CA, Giannini EH, Spalding SJ, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2012;64(6):2012–2021. doi:10.1002/art.34343 [CrossRef]
- Schad SG, Kraus A, Haubitz I, Trcka J, Hamm H, Girschick HJ. Early onset pauciarticular arthritis is the major risk factor for naproxen-induced pseudoporphyria in juvenile idiopathic arthritis. Arthritis Res Ther. 2007;9(1): R10. doi:10.1186/ar2117 [CrossRef]
NSAIDs Commonly Used in JIA
||10–15 mg/kg/day (1,000 mg)
||Suspension, capsule, tablet
||30–40 mg/kg/day (2,400 mg)
||Suspension, capsule, tablet
||1–3 mg/kg/day (200 mg)
||0.125 mg/kg/day (15 mg)
||22 kg-31 kg (600 mg)
32 kg-54 kg (900 mg)
55 kg (1200 mg)
||15 mg/kg/day-30 mg/kg/day (200 mg)
||10–25 kg (50 mg)
> 25 kg (100 mg)
Classical Disease-Modifying Anti-Rheumatic Drugs Used in JIA
||10 mg/m2-15 mg/m2 (20 mg)
|10 mg/m2-15 mg/m2 (25 mg)
||< 20 kg: 100 mg load then10 mg
||Load x 1 day, then every 2 days
|20 kg-40 kg: 100-mg load, then 10 mg
||Load x 2 days, then daily
|> 40 kg: 100-mg load then 20 mg
||Load x 3 days, then daily
||30 kg-50 mg/kg/day (2 g)
||Divided BID or TID
||4 mg/kg/day-6 mg/kg/day (400 mg)
Biologic Therapies Used in JIA
||0.4 mg/kg (25 mg)
|0.8 mg/kg (50 mg)
||< 30 kg: 20 mg
≥30 kg: 40 mg
||Every 2 weeks
||0, 2, 6, then every 8 weeks
||1mg/kg-2 mg/kg (100 mg)
||Load 4.4 mg/kg (320 mg), then 2.2 mg/kg (160 mg)
||4 mg/kg (300 mg)
||Every 8 weeks
||< 20 kg: 12 mg/kg
≥20 kg: 8 mg/kg
||Every 2 weeks
||10 mg/kg (1 g)
||0, 2, 4 then every 4 weeks
|125 mg (adults only)
||750 mg/m2 (1 g)
||0 and 2 weeks
Important Counseling and Screenings for Commonly Used Therapies in JIA
Take with food.
||Labs (CBC, AST/ALT, Cr) at baseline, then biannually or annually.
||No alcohol consumption.
Precautions for pregnancy.
No live vaccines.
Hold dose if severely ill.
||Labs (CBC, AST/ALT, Cr) at baseline, 1 month, then every 1–2 months with dose increase or every 3–4 months if same dose.
||No alcohol consumption.
Precautions for pregnancy.
No live vaccines.
Hold dose if severely ill.
||Labs (CBC, AST/ALT) at baseline, every month for 6 months then every 6–8 weeks.
||No live vaccines.
Hold dose if severely ill.
||Labs (CBC, AST/ALT) at baseline then every 3–6 months; PPD screening yearly.
||No live vaccines.
Hold dose if severely ill.
||Labs (CBC, Cr, AST/ALT/TB, lipid profile) every few months (frequency not well-established); PPD.
||No live vaccines.
Hold dose if severely ill.
||Labs (CBC, AST/ALT, lipid profile) usually monthly (frequency not well-established); PPD.
||Healthy diet and regular exercise.
Take calcium and vitamin D.
Stress dose steroids if severely ill.
No live vaccines.
||Annual eye exams, urine dipsticks.