Medication Summary
Optimal care of patients with juvenile idiopathic arthritis (JIA) requires an integrated approach of nonpharmacologic and pharmacologic therapies. Classes of medications used include disease-modifying antirheumatic drugs (DMARDs), biologicals, NSAIDs, and corticosteroids.
Nonsteroidal Anti-inflammatory Drugs
Class Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. NSAIDs are used to treat all subtypes of JIA. They may help with pain and decrease swelling. Commonly used NSAIDs include naproxen, ibuprofen, tolmetin, diclofenac, and indomethacin.
Aspirin is no longer the drug of first choice because of the increased frequency of gastric toxicity and hepatotoxicity when compared to other NSAID medications. The cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex) may have a role in treatment when a bleeding diathesis is a potential problem.
Several dozen NSAIDs are available and can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac. [46] Predicting which patient will respond to a particular NSAID is not possible and many children who do not respond to one may benefit by changing to a different NSAID. Indomethacin is particularly effective for fever and pericarditis and is usually preferred for children with active systemic JIA.
Meloxicam (Mobic)
Meloxicam is a member of the enolic class of NSAIDs and is structurally related to piroxicam. The pediatric dosage is 0.125 mg/kg/d for patients aged 2 years or older, up to 7.5 mg qd.
Naproxen (Aleve, Naprelan, Naprosyn)
Naproxen is used for analgesic and anti-inflammatory properties, treating arthralgia and arthritis. It inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis. The pediatric dosage is 7-20 mg/kg/d PO divided bid/tid, not to exceed 1 g/d
Ibuprofen (Advil, Motrin)
Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. The adult dosage is 400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist, not to exceed 3.2 g/d; the pediatric dosage is 30-50 mg/kg/d PO divided qid, not to exceed 2.4 g/d.
Diclofenac (Voltaren, Cataflam)
This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.
Celecoxib (Celebrex)
Celecoxib inhibits primarily COX-2. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, incidence of GI toxicity, such as endoscopic peptic ulcers, bleeding ulcers, perforations, and obstructions, may be decreased when compared with nonselective NSAIDs.
Seek the lowest dose for each patient. The adult dosage is 100-200 mg PO bid; the pediatric dosage has not been established for patients younger than 2 years, is 50 mg PO bid for patients 2 years or older whose weight is ≥10 kg to ≤25 kg, and is 100 mg PO bid for patients 2 years or older whose weight is greater than 25 kg.
Tolmetin (Tolectin)
Tolmetin inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase, which in turn decreases formation of prostaglandin precursors. The pediatric dosage is 20 mg/kg/d PO divided tid/qid initially, then 15-30 mg/kg/d, not to exceed 30 mg/kg/d
Indomethacin (Indocin)
Indomethacin is rapidly absorbed, and metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. It inhibits prostaglandin synthesis. The adult dosage is 25-50 mg PO bid/tid, not to exceed 200 mg/d, and the ER product may be administered qd or bid; the pediatric dosage is 1-2 mg/kg/d PO divided bid/qid, not to exceed 4 mg/kg/d or 150-200 mg/d
Disease-Modifying Antirheumatic Drugs
Class Summary
Disease-modifying antirheumatic drugs (DMARDs) can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.
Sulfasalazine (Azulfidine, EN-tabs)
Sulfasalazine decreases the inflammatory response and systemically inhibits prostaglandin synthesis. The pediatric dosage has not been established for patients younger than 6 years; for patients 6 years or older, the typical dose range is 30-50 mg/kg/d; to lessen GI irritation, start at one half to one third of maintenance dose, increasing the dose weekly, not to exceed 2 g/d.
Methotrexate (Rheumatrex, Trexall)
Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. It ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response. Consider SC route for patients who do not respond to PO methotrexate or who have GI intolerance to PO dosing.
The pediatric dosage is 10-25 mg/m2/wk PO/IM/SC as a single dose or divided into 2 doses weekly; many pediatric rheumatologists increase the dose (not to exceed 30 mg/m2, approximately equivalent to 1 mg/kg); administer with folic acid 1-2 mg PO qd or folinic acid 2.5-5 mg PO qwk
Corticosteroids
Class Summary
Corticosteroids are potent anti-inflammatory drugs used in patients with JIA to bridge the time until DMARDs are effective. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.
Methylprednisolone (Solu-Medrol, Medrol, A-Methapred)
Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. It is used temporarily for JIA until longer-term treatment provides effective relief. The pediatric dosage is 15-30 mg/kg IV qd administered over 30-60 min for 2-3 d.
Prednisone
Prednisone is an immunosuppressant for treatment of JIA. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, and it stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. The pediatric dosage is 4-5 mg/m2/d PO; alternatively, the dosage is 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve and other antirheumatic drugs take effect.
Triamcinolone (Aristospan, Kenalog)
Triamcinolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Immunomodulators
Class Summary
The recognition of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)–1 as central proinflammatory cytokines has led to the development of agents that block these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. The TNF blockers, which bind TNF and thus prevent its interaction with its receptors, include etanercept, infliximab, and adalimumab. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually methotrexate (MTX), has been administered without sufficient success, although one study reported better results with etanercept in patients with less disability and when used before methotrexate. [41]
Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies, occasional drug-induced lupuslike syndromes, and infections. Rarely, demyelinating disorders and bone marrow suppression occur. Acute and chronic infections, demyelinating disorders, class 3 or 4 heart failure, and recent malignancies are contraindications for TNF blockers. Thoroughly searching for latent tuberculosis using chest radiography and/or purified protein derivative (PPD) testing is recommended before these agents are started. [47]
Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)
Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human TNF. It reduces inflammation and inhibits progression of structural damage. The pediatric dosage has not been established for patients younger than 2 years for Humira. FDA approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd for patients 4 years or older, as biosimilars and not as interchangeable drugs.
Etanercept (Enbrel)
Etanercept acts by binding and inhibiting TNF, a cytokine that contributes to inflammatory and immune response. The pediatric dosage is not established for patients younger than 4 years. For patients 4-17 years, the dosage is 0.4 mg/kg SC 2 times weekly (administered at least 72-96 h apart), not to exceed 25 mg/dose. For patients older than 17 years, the dosage is administered as in adults.
Abatacept (Orencia)
Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CED86, thereby blocking CD28 interaction. It is indicated for reducing signs and symptoms of RA, slowing progression of structural damage and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, MTX, or TNF antagonists. It is not recommended for concomitant use with anakinra because of insufficient experience.
The pediatric dosage is not established for patients younger than 6 years. For pediatric patients 6-17 years, the dosage is according to body weight, and the drug is administered on days 1, 15, and 29, then q4wk thereafter; infuse IV over 30 min. For pediatric patients less than or equal to 74 kg, use 10 mg/kg IV; for pediatric patients 75-100 kg, use 750 mg IV; and for pediatric patients heavier than 100 kg, use 1000 mg IV.
Anakinra (Kineret)
Anakinra competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). By blocking IL-1 binding, inflammation and pain associated with rheumatoid arthritis are inhibited. It is indicated for rheumatoid arthritis in patients who have failed 1 or more DMARDs. The dose should be administered at approximately the same time every day. The adult dosage is 100 mg SC qd; the pediatric dosage has not been established.
Tocilizumab (Actemra)
Tocilizumab is an IL-6 receptor antagonist that inhibits IL-6 mediated signaling that results in decreased inflammatory cytokine production. It is indicated for systemic JIA and PJIA. The safety and efficacy of tocilizumab has not been established in patients younger than 2 years old.
Canakinumab (Ilaris)
Canakinumab is recombinant, human monoclonal antibody that inhibits interleukin-beta1.
Tofacitinib (Xeljanz)
Janus kinases (JAKs) pathways inhibitor. Modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of signal transducers and activators of transcription. These signals are essential in maintaining the inflammatory condition in rheumatoid arthritis (RA); inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA. It is indicated for active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients aged 2 years and older. Available as an oral solution or tablet.
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Patient with active polyarticular arthritis. Note swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to boney overgrowth. Also note lack of distal interphalangeal joint (DIP) involvement. The patient has interosseus muscle wasting (observed on the dorsum of the hands), and subluxation and ulnar deviation of the wrists are present. Image courtesy of Barry L. Myones, MD.
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Wrist radiographs of the patient with active polyarticular arthritis shown in Media file 2. Note severe loss of cartilage in the intercarpal spaces and the radiocarpal space of the right wrist. A large erosion is present in the articular surface of the ulnar epiphysis. The view of the left wrist shows boney ankylosis involving the lateral 4 carpal bones with sparing of the pisiform. Erosions are present in the distal radius and ulna. Almost a loss of cartilage has occurred between the radius and ulna and the carpus. Narrowing of the carpal/metacarpal joints is present. Image courtesy of Barry L. Myones, MD.
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Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Media files 2 and 3. Synovial thickening and effusion, as well as boney overgrowth, are present at the PIP joints bilaterally. Image courtesy of Barry L. Myones, MD.
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Patient with inactive polyarticular arthritis. Long-term sequelae of polyarticular disease includes joint subluxation (note both wrists and thumbs), joint contractures (at proximal interphalangeal joints [PIPs] and distal interphalangeal joints [DIPs]), boney overgrowth (at all PIPs), and finger deformities (eg, swan-neck or boutonniere deformities). Image courtesy of Barry L. Myones, MD.
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Hand and wrist radiographs of the patient with inactive polyarticular arthritis shown in Media file 5. Long-term sequelae of polyarticular disease includes periarticular osteopenia, generalized increase in the size of epiphyses, accelerated bone age, narrowed joint spaces (especially at the fourth and fifth proximal interphalangeal joints [PIPs] bilaterally), boutonniere deformities (at left third and fourth interphalangeal joints), and medial subluxation of the first metacarpophalangeal joints (MCPs) bilaterally. Flattening and erosion of the radial carpal articular surface is present in both wrists. Mild narrowing of the joint spaces exists at the carpometacarpal joints and intercarpal rows bilaterally, with sclerotic change of the intercarpal row (right > left). The trapezium and trapezoid may be fused bilaterally. Image courtesy of Barry L. Myones, MD.
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Sequelae of chronic anterior uveitis. Note the posterior synechiae (weblike attachments of the pupillary margin to the anterior lens capsule) of the right eye secondary to chronic anterior uveitis. This patient has a positive antinuclear antibodies (ANAs) and initially had a pauciarticular course of her arthritis. She now has polyarticular involvement but no active uveitis. Image courtesy of Carlos A. Gonzales, MD.
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One set of suggested algorithms for the treatment of patients with juvenile arthritis. This should not be considered dogmatic because treatment is not standardized and remains empiric and, at times, controversial.
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Systemic juvenile idiopathic arthritis (JIA) rash.
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Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis (JIA).
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Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA).
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Temporal-mandibular joint (TMJ) MRI postgadolinium infusion. Abnormal increased uptake indicative of synovitis in child with polyarticular juvenile idiopathic arthritis (JIA).
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Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.
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Ankylosis in the cervical spine at several levels due to long-standing juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).
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Widespread osteopenia, carpal crowding (due to cartilage loss), and several erosions affecting the carpal bones and metacarpal heads in particular in a child with advanced juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).
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(A) T2-weighted MRI shows high signal in both hips, which may be due to hip effusions or synovitis. High signal intensity in the left femoral head indicates avascular necrosis. (B) Coronal fat-saturated gadolinium-enhanced T1-weighted MRI shows bilateral enhancement in the hips. This indicated bilateral active synovitis, which is most pronounced on the right. Because the image was obtained with fat saturation, the hyperintensity in both hips is pathologic, reflecting an inflamed pannus.
Tables
Classification |
ACR(1977) |
ILAR (1997) |
Nomenclature |
Juvenile rheumatoid arthritis |
Juvenile idiopathic arthritis |
Minimum duration |
≥6 wk |
≥6 wk |
Age at onset |
< 16 y |
< 16 y |
≤ 4 joints in first 6 mo after presentation |
Pauciarticular juvenile rheumatoid arthritis |
Oligoarticular juvenile idiopathic arthritis: (A) Persistent < 4 joints for course of disease; (B) Extended >4 joints after 6 mo |
>4 joints in first 6 mo after presentation |
Polyarticular juvenile rheumatoid arthritis |
Polyarticular juvenile idiopathic arthritis-rheumatoid factor negative Polyarticular juvenile arthritis-rheumatoid factor positive |
Fever, rash, arthritis |
Systemic juvenile rheumatoid arthritis |
Systemic juvenile idiopathic arthritis |
Other categories included |
Exclusion of other forms |
Psoriatic juvenile idiopathic arthritis Enthesitis-related arthritis Undifferentiated: (A) Fits no other category; (B) Fits more than 1 category |
Inclusion of psoriatic arthritis, inflammatory bowel disease, juvenile ankylosing spondylitis |
No |
Yes |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- History of Arthritis in 4 or Fewer Joints
- History of Arthritis in 5 or More Joints
- Active Sacroiliac Arthritis
- Systemic Arthritis with Active Systemic Features and without Active Arthritis
- Systemic Arthritis with Active Arthritis and without Active Systemic Features
- Hospital Admission
- Exercise and Other Nonpharmacologic Therapy
- Surgical Treatment
- Treatment of Macrophage Activation Syndrome
- Treatment of Uveitis
- Diet and Activity
- Consultations
- Long-Term Monitoring
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