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Juvenile Idiopathic Arthritis: A Focus on Pharmacologic Management

      Abstract

      Juvenile idiopathic arthritis is a chronic condition that affects many pediatric patients. It is a prevalent disease and has become the most common rheumatologic disease of childhood. The condition encompasses multiple different forms of chronic arthritides classified based on the location and number of joints affected as well as the presence or lack of a number of different inflammatory markers. The exact etiology is unknown but is thought to be multifactorial with genetic, humoral, and environmental factors playing a key role. Many pharmacologic agents are available for use in the treatment of juvenile idiopathic arthritis, with management involving the use of symptom-reducing agents and disease-modifying antirheumatic drugs. Treatment is not without adverse events, with many of the agents require monitoring regimens and patient education. Without treatment, the progression and chronicity of the disease can result in significant morbidity, with the potential for devastating consequences on the child's quality of life.

      Key Words

      • 1
        Describe the pathophysiology, clinical presentation and diagnosis of juvenile idiopathic arthritis (JIA).
      • 2
        Discuss the use of nonsteroidal anti-inflammatory drugs, glucocorticoids, and non-biologic disease modifying anti-rheumatic drugs in the management of JIA.
      • 3
        Explain the role of biologic disease modifying anti-rheumatic drugs in the management of JIA.
      • 4
        Recommend a treatment plan based on classification of JIA and disease activity.
      • 5
        Identify monitoring parameters and adverse effects associated with pharmacologic treatment.

      Introduction

      Juvenile idiopathic arthritis (JIA) is the most common rheumatologic disease and has the potential to cause long-term morbidity and physical disability. Older terms, including juvenile rheumatoid arthritis, which is used more commonly in the United States, and juvenile chronic arthritis, which is preferred in Europe, were replaced by the term JIA at the meeting of the International League of Association for Rheumatology (ILAR) in the late 1990s (
      • European League Against Rheumatism
      EULAR bulletin no. 4: Nomenclature and classification or arthritis in children.
      ). The ILAR highlighted the onset of JIA that begins during childhood and provided a clear distinction from adult-onset rheumatoid arthritis. JIA in itself is not a disease but rather a term that encompasses all forms of arthritides. It is defined as arthritis of unknown etiology that begins before the 16th birthday and persists for at least 6 weeks.
      JIA is a diagnosis of exclusion, so other conditions that present with similar clinical manifestations need to be ruled out, including connective tissue diseases (e.g., systemic lupus erythematosus), trauma, infection (e.g., septic joints, osteomyelitis, viral illnesses, Lyme disease), and malignancies. Therefore, the diagnosis of JIA is usually prolonged, which can delay the initiation of treatment, resulting in devastating consequences such as permanent joint destruction, joint contractures, leg-length discrepancies, and blindness secondary to chronic uveitis. Recent advances in pharmacologic treatment have significantly improved the outcome of JIA in children.

      Epidemiology

      JIA is the most common pediatric autoimmune musculoskeletal condition. Although the exact incidence of JIA in the United States is unknown, the incidence is estimated to be about 2 to 20 per 100,000 children; the prevalence is about 16 to 150 per 100,000 children in Europe and North America (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ). Oligoarthritis is the most common subtype of JIA in North America, with rheumatoid factor–positive (Rf+) polyarthritis being the least common subtype (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ). The disease more commonly affects females than males (> 2:1); however, sex distribution varies with disease subtype (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ,
      • Minden K.
      • Niewerth M.
      • Listing J.
      • Biedermann T.
      • Bollow M.
      • Schontube M.
      • Zink A.
      Long-term outcome in patients with juvenile idiopathic arthritis.
      ). Age at onset of disease also differs among subtypes, with a median age of onset of 4 years in oligoarthritis, 11 years in enthesitis-related arthritis (ERA), and 12 years in Rf+ polyarthritis (
      • Minden K.
      • Niewerth M.
      • Listing J.
      • Biedermann T.
      • Bollow M.
      • Schontube M.
      • Zink A.
      Long-term outcome in patients with juvenile idiopathic arthritis.
      ). In addition, ethnicity can affect the prevalence of disease subtype, highlighting the potential for involvement of genetic predisposition (
      • Schwarz M.M.
      • Simpson P.
      • Kerr K.L.
      • Jarvis J.N.
      Juvenile rheumatoid arthritis in African Americans.
      ). For example, African Americans are more likely to develop polyarticular and Rf+ disease (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ), oligoarthritis is the most common JIA subtype in White children of European descent, and enthesitis-related arthritis tends to be more prevalent in children of Mexican and Asian descent (
      • Woo P.
      • Colbert R.A.
      An overview of genetics of paediatric rheumatic diseases.
      ).

      Pathophysiology

      The exact etiology and pathogenesis of JIA are unknown, although genetic, environmental, and autoimmune factors are thought to play a role in the development of this disease. A genetic predisposition for JIA has been suggested through concordance rates of 25% to 40% in monozygotic twins and siblings having a 15- to 30-fold higher prevalence of JIA compared with the normative population (
      • Woo P.
      • Colbert R.A.
      An overview of genetics of paediatric rheumatic diseases.
      ). The IL2RA/CD25 and VTCN1 genes have been proposed to confer susceptibility toward the development of JIA (
      • Hinks A.
      • Ke X.
      • Barton A.
      • Eyre S.
      • Bowes J.
      • Worthington J.
      • Thomson N.
      Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis.
      ). In patients with ERA, test results for human leukocyte antigen (HLA)-B27 are commonly positive, and HLA-B27 has been correlated with the development of inflammation of the axial skeleton, specifically involving the hip (
      • Woo P.
      • Colbert R.A.
      An overview of genetics of paediatric rheumatic diseases.
      ). Several environmental factors, including breastfeeding and vitamin D and sun exposure, have been identified as having a protective effect against the development of JIA. In contrast, environmental factors such as infection and maternal smoking may increase the risk of developing or worsening the disease (
      • Ellis J.A.
      • Munro J.E.
      • Ponsonby A.L.
      Possible environmental determinants of juvenile idiopathic arthritis.
      ). Further studies are needed to comprehensively examine these environmental hypotheses.
      The exact etiology and pathogenesis of JIA are unknown, although genetic, environmental, and autoimmune factors are thought to play a role in the development of this disease.
      Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. Cell-mediated release of proinflammatory cytokines, such as tumor necrosis factor–alpha (TNF-α), interleukin (IL)-6, and IL-1 secondary to T-cell activation, continues to be the best described pathogenesis of JIA and is the focus of many newer pharmacologic agents. Radiographic models have confirmed this etiology by evidence of a higher percentage of activated T cells in the synovium of patients with JIA. In addition, diagnostic tests show that patients with polyarticular and systemic JIA (SJIA) have higher levels of TNF-α, IL-6, and IL-1 compared with other JIA subtypes (
      • Borchers A.T.
      • Selmi C.
      • Cheema G.
      • Keen C.L.
      • Shoenfeld Y.
      • Gershwin M.E.
      Juvenile idiopathic arthritis.
      ,
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ). Activation of the humoral immune response is evident through the production of autoantibodies such as antinuclear antibodies (ANA), as well as complement activation and an increase in serum immunoglobulins (Igs), such as IgM rheumatoid factor. It is estimated that ANAs are detected in 30% to 50% of patients with JIA, and detection has a positive correlation with development of uveitis, a complication of JIA (
      • Borchers A.T.
      • Selmi C.
      • Cheema G.
      • Keen C.L.
      • Shoenfeld Y.
      • Gershwin M.E.
      Juvenile idiopathic arthritis.
      ).

      Clinical Presentation and Diagnosis

      The clinical manifestation and treatment algorithms of JIA depend on the subtype of arthritis that is present. Arthritis must be present for 6 weeks before the diagnosis of JIA can be made. Morning stiffness or gelling phenomenon (i.e., stiffness after long periods of sitting or inactivity) are common complaints. Arthralgia often occurs during the morning, with improvements throughout the day. Different classifications of JIA have been developed by organizations including the American College of Rheumatology (ACR), EULAR, and ILAR (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ; EULAR, 1977;
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ,
      • Ringold S.
      • Weiss P.F.
      • Beukelman T.
      • DeWitt E.M.
      • Illowite N.T.
      • Kimura Y.
      • Vehe R.K.
      2013 Update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis.
      ). The progression of the disease nomenclature and their differing classifications are summarized in Table 1. The ILAR 2001 classification was developed in response to a need for a more consistent classification system than what had been previously defined in the ACR 1977 and EULAR 1978 classifications.
      TABLE 1Progression of characteristics/classification systems of JIA
      CharacteristicsACR (1977)EULAR (1978)ILAR (1997, 2001)ACR (2011)
      NomenclatureJuvenile rheumatoid arthritisJuvenile chronic arthritisJuvenile idiopathic arthritisJuvenile idiopathic arthritis
      Age at onset<16 years<16 years<16 years<16 years
      Duration of arthritis≥6 weeks≥3 months≥6 weeks≥6 weeks
      ClassificationsSystemicSystemicSystemicArthritis of ≤ 4
      PolyarticularPolyarticularOligoarticularjoints
      PauciarticularJuvenile rheumatoid arthritis(persistent/extended)Arthritis of ≥ 5 joints
      PauciarticularPolyarticular (Rf+/Rf–)Active sacroiliac arthritis
      Juvenile psoriatic arthritisPsoriatic arthritisSystemic arthritis (without active systemic features)
      Juvenile spondylitisERASystemic arthritis with active systemic features (without active arthritis)
      Undifferentiated
      Note. Data from EULAR (1977),
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      , and
      • Ringold S.
      • Weiss P.F.
      • Beukelman T.
      • DeWitt E.M.
      • Illowite N.T.
      • Kimura Y.
      • Vehe R.K.
      2013 Update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis.
      . ACR, American College of Rheumatology; ERA, enthesitis-related arthritis; EULAR, European League Against Rheumatism; ILAR, International League of Associations for Rheumatology; Rf+, rheumatoid factor positive; Rf–, Rheumatoid factor negative.
      The ILAR 2001 classification identified six distinct subtypes of JIA based on the pattern and number of joints involved at onset of illness, specific serologic markers, and systemic manifestations present during the first 6 months of illness (
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). The ILAR classifications of JIA include systemic, oligoarticular, polyarticular, enthesitis-related, psoriatic, and undifferentiated arthritis. Diagnosis of JIA is typically based on the presence of clinical symptoms and serologic markers associated with each classification. Accurate classification within a subtype is important because it offers insight to prognostic factors, outcomes, and preferred treatment regimens.

      Systemic Juvenile Idiopathic Arthritis

      SJIA is described as a triad of arthritis, remittent fever, and typical rash (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ,
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). The child appears systematically ill with generalized arthralgia and myalgia. Arthritis is defined as the presence of joint effusion alone or two or more of the following symptoms: decreased range of motion, pain or tenderness during movement, and/or increased heat on palpation in one or more joint(s). Fever is typically present for at least 2 weeks' duration with a daily quotidian pattern for at least 3 days, and arthritis is present in one or more joint(s) accompanied by one or more of the following criteria: evanescent erythematous rash, generalized lymph node enlargement, hepatomegaly and/or splenomegaly, or serositis (
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). Muscle tenderness to palpation may be observed. The classic triad does not need to occur at the same time, with fever and rash oftentimes occurring weeks before the onset of arthritis (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ,
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). The characteristic macular, nonpruritic, salmon-colored rash (linear macular rash) is most commonly present at time of fever and is typically distributed over the trunk and extremities. Patients with SJIA are more likely to develop macrophage activation syndrome (MAS) and impaired growth velocity.

      Oligoarthritis

      Oligoarthritis is defined as arthritis affecting four or fewer joints during the first 6 months of disease (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ,
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). This subtype is further classified as persistent (affecting four or fewer joints throughout the disease) or extended (affecting more than 4 joints after the first 6 months of disease). Compared with the other subtypes, oligoarthritis appears to have an earlier onset of illness and is more prevalent in females (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ). Children generally appear well despite ambulating with a limp. Most patients with oligoarthritis present with unilateral pain and swelling of one joint (typically larger, lower extremity joints). Elevated erythrocyte sedimentation rate (ESR) and ANA levels are common diagnostic criteria in this subtype of JIA. Compared with other subtypes, oligoarthritis is associated with the development of iridocyclitis. Therefore, these patients should undergo ophthalmologic examinations more frequently than what is recommended for other patients with JIA.

      Polyarticular JIA (Rheumatoid Factor–Negative [Rf–]/Positive [Rf+] Polyarthritis)

      Polyarticular JIA is defined as arthritis affecting five or more joints during the first 6 months of disease (
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). This subtype is further classified as Rf+ (two positive Rf test results at least 3 months apart during the first 6 months of disease) or Rf– (a test result for Rf is negative), depending on presence of the autoantibody within the bloodstream. Rf+ disease is thought to have a more aggressive disease course characterized by a higher incidence of joint deformities because of the development of erosive joints and rheumatoid nodules (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ,
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). The onset of Rf+ disease tends to occur later compared with other subtypes and predominantly affects females in late childhood to early adolescence (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ).

      Enthesitis-Related Arthritis

      ERA is described as the presence of arthritis and enthesitis (inflammation of tendons and ligaments where they attach to bone) or as the presence of arthritis or enthesitis with at least two of the following: (a) presence of or history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain; (b) presence of the HLA-B27 antigen; (c) onset of arthritis in males older than 6 years; (d) acute (symptomatic) anterior uveitis; or (e) first-degree relative with a history of ankylosing spondylitis, ERA, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, or acute anterior uveitis (
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ). The most common symptoms include pain, swelling, and tenderness with a higher incidence in males older than 8 years of age (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ).

      Psoriatic Arthritis

      Psoriatic arthritis in children is usually mild. Patients are classified as having psoriatic arthritis if there is presence of arthritis and psoriasis or the presence of arthritis and at least two additional criteria: dactylitis (diffuse swelling of fingers extending beyond the joint margin), nail pitting or onycholysis, or psoriasis in a first-degree relative (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ). Children with psoriatic arthritis are often found to have positive test results for ANAs and HLA-B27 and therefore are at a higher risk for development of uveitis (
      • Dannecker G.E.
      • Quartier P.
      Juvenile idiopathic arthritis: Classification, clinical presentation and current treatments.
      ,
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ).

      Undifferentiated Arthritis

      Undifferentiated arthritis is the least common type of JIA and is described as the presence of arthritis that does not fit into any of the other five ILAR subtypes or fits the descriptions of at least two or more of the other five subtypes (
      • Petty R.E.
      • Southwood T.R.
      • Manners P.
      • Baum J.
      • Glass D.N.
      • Goldenberg J.
      • Woo P.
      International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001.
      ).

      Disease Management

      Although the ILAR classifications of JIA continued to be the most widely used classification system, validated guidelines providing recommendations for the treatment of JIA were still lacking. This deficiency led to the development of the 2011 ACR Recommendations for the Treatment of JIA, with revision in 2013 (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ,
      • Ringold S.
      • Weiss P.F.
      • Beukelman T.
      • DeWitt E.M.
      • Illowite N.T.
      • Kimura Y.
      • Vehe R.K.
      2013 Update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis.
      ). The ACR guidelines do not follow the six distinct ILAR classifications, which can lead to a lack of consistency in management. To minimize the number of treatment algorithms and attempt to simplify recommendations for providers, the ACR task force developed their own JIA treatment groups based on the number of joints affected and classifications of prognosis (features of poor prognosis) and disease level activity (low, moderate, high;
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ; Table 2).
      TABLE 2ACR treatment groups and classifications of prognosis and disease level activity
      Treatment groupILAR classificationsFeatures of poor prognosis
      Must satisfy one criterion.
      LDA
      Must satisfy all criteria.
      MDAHDA
      Must satisfy three criteria.
      Arthritis of ≤ 4 jointsPersistent oligoarthritis

      Psoriatic arthritis

      ERA

      Undifferentiated arthritis
      Arthritis of hip or cervical spine

      Arthritis of the ankle or wrist and inflammatory marker elevation

      Radiographic damage
      AJC ≤ 1

      Normal ESR or CRP level

      PhysGA: <3 of 10

      ParGE: <2 of 10
      ≥1 features greater than LDA

      <3 features of HDA
      AJC ≥ 2

      ESR/CRP = 2 × ULN

      PhysGA: ≥7 of 10

      ParGE: ≥4 of 10
      Arthritis of ≥ 5 jointsExtended oligoarthritis

      Rf– polyarthritis

      Rf+ polyarthritis

      Psoriatic arthritis

      ERA

      Undifferentiated arthritis
      Arthritis of hip or cervical spine

      Rf+

      Radiographic damage
      AJC ≤ 4

      Normal ESR or CRP level

      PhysGA: <4 of 10

      ParGE: <2 of 10
      ≥1 features greater than LDA

      <3 features of HDA
      AJC ≥ 8

      ESR/CRP = 2 × ULN

      PhysGA: ≥7 of 10

      ParGE: ≥5 of 10
      Active sacroiliac arthritisERA or psoriatic arthritis with clinical and imaging evidence of active sacroiliac arthritisRadiographic damage of any jointNormal back flexion

      Normal ESR or CRP level

      PhysGA: <4 of 10

      ParGE: <2 of 10
      ≥1 features greater than LDA

      <2 features of HDA
      ESR/CRP = 2 × ULN

      PhysGA: ≥7 of 10

      ParGE: ≥4 of 10
      Systemic arthritis with active systemic features (without active arthritis)Systemic arthritis (active fever, SJIA, no arthritis)6 months of significant active systemic disease (fever, elevated inflammatory markers, or requirement for treatment with systemic glucocorticoids)Two levels of disease activity:
      This criteria applies to all three (LDA, MDA, and HDA).


      Active fever and PhysGA: <7 of 10

      Active fever and systemic features of HDA that result in PhysGA: ≥7 of 10
      Systemic arthritis with active arthritis (without active systemic features)Systemic arthritis (with active arthritis)Arthritis of hip

      Radiographic damage
      AJC ≤ 4

      Normal ESR or CRP level

      PhysGA: <4 of 10

      ParGE: <2 of 10
      ≥1 features greater than LDA

      <3 features of HDA
      AJC ≥ 8

      ESR/CRP = 2 × ULN

      PhysGA: ≥7 of 10

      ParGE: ≥5 of 10
      Note. Data from
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      .
      AJC, active joint count; ACR, American College of Rheumatology; CRP, C-reactive protein; ERA, enthesitis-related arthritis; ESR, erythrocyte sedimentation rate; HDA, high disease activity; ILAR, International League of Associations for Rheumatology; LDA, low disease activity; MDA, moderate disease activity; ParGE, patient/parent general evaluation of overall well-being; PhysGA, physician global assessment of disease activity; Rf–, rheumatoid factor negative; Rf+, rheumatoid factor positive; SJIA, systemic juvenile idiopathic arthritis; ULN, upper limit of normal.
      a Must satisfy one criterion.
      b Must satisfy all criteria.
      c Must satisfy three criteria.
      d This criteria applies to all three (LDA, MDA, and HDA).
      The development of risk stratification through the use of outcomes variables provides a more objective guide to treatment and an objective method for monitoring response to therapy. The six outcomes variables in the ACR guidelines include (a) the physician global assessment of disease activity, which is a subjective assessment made by the provider measured on a 10-point visual analog scale; (b) parent/patient global assessment of well-being (mimics the same 10-point visual analog scale but is completed by the patient/parent); (c) functional assessment; (d) active joint counts; (e) restrictive joint counts; and (f) presence of acute phase reactants such as ESR or C-reactive protein (CRP;
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Recommendations/treatment algorithms for initiation of pharmacologic agents in JIA based on treatment group, prognosis, and disease activity can be found in the ACR guidelines and will be discussed in this review.
      Although this is not part of the ACR guidelines, the ACR Pedi 30 (
      • Consolaro A.
      • Giancane G.
      • Schiappapietra B.
      • Davi S.
      • Calandra S.
      • Lanni S.
      • Ravelli A.
      Clinical outcome measures in juvenile idiopathic arthritis.
      ), which is a tool to assess response to treatment regimens, has been widely used throughout many clinical trials and clinical practice. This tool incorporates the six ACR outcome variables as part of the assessment. A response is defined as a minimum of 30% improvement from baseline in at least three of the six ACR outcome variables and no more than one remaining outcome variable worsening by greater than 30%. Similarly, ACR Pedi 50, 70, 90, and 100 responses are often reported, and these definitions require 50%, 70%, 90%, or 100% improvement, with no more than one variable worsening by 30%.
      The goal of therapy in JIA is to treat the disease by decreasing pain and limiting disability, to minimize adverse effects, and to prevent disease progression (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ). The goal is to achieve clinical remission, defined by the ACR as satisfaction of clinical inactive disease for at least 6 continuous months while taking medication or for at least 12 continuous months while not taking medication (
      • Lovell D.J.
      • Ruperto N.
      • Giannini E.H.
      • Martini A.
      Advances from clinical trials in juvenile idiopathic arthritis.
      ,
      • Wallace C.A.
      • Giannini E.H.
      • Huang B.
      • Itert L.
      • Ruperto N.
      American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis.
      ). The ACR defines clinical inactive disease as the lack of active arthritis, fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA; no active uveitis; normal ESR or CRP levels; and no damage progression determined by radiographic examination.
      A systematic treatment approach begins with a simpler, conservative modality and escalates to more complex therapies if treatment fails (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ). There are four main pharmacologic classes that can be used in the management of JIA. These include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (intra-articular and systemic), nonbiologic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). This review will provide a thorough discussion of each pharmacologic drug class and its place in therapy, dosing regimens, adverse effects, and monitoring parameters (TABLE 3, TABLE 4).

      Nonpharmacologic Treatment

      The management of JIA involves a multidisciplinary approach. Nonpharmacologic therapy such as physical, occupational, and psychosocial (e.g., mental health, psychiatric) therapies have all been used to help manage the disease process in conjunction with pharmacologic agents (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ,
      • Ostring G.T.
      • Singh-Grewal D.
      Juvenile idiopathic arthritis in the new world of biologics.
      ). Assistive device (wheelchairs, walkers), aerobic conditioning, and splinting are all techniques used to help maintain physical functioning and prevent development of disability. Psychiatric counseling has also proven beneficial, because many children with JIA suffer from anxiety and/or depression secondary to chronic pain and emotional distress due to decreased ability to perform normal childhood activities. Initiation of pharmacologic therapy and education on the disease should include the child to ensure optimal medication compliance. Providers and parents should work to create an environment that minimizes time away from school. Surgery may be indicated in patients who are unresponsive to pharmacologic treatment.
      The management of JIA involves a multidisciplinary approach.

      Pharmacologic Treatment

      Nonsteroidal anti-inflammatory drugs

      NSAIDs remain first-line therapy (approved by the U.S. Food and Drug Administration [FDA]) and the most commonly used agents in the treatment of JIA. NSAIDs provide both anti-inflammatory and analgesic properties by blocking the production of prostaglandins through cyclooxygenase-1 and cyclooxygenase-2 enzyme inhibition. Dosing for anti-inflammatory effects is often twice the manufacturer recommended analgesia dose; however, the lowest possible dose should be used to minimize adverse effects (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ). Commonly used NSAID regimens include naproxen, 10 to 15 mg/kg/day divided twice daily (range = 7-20 mg/kg/day, maximum = 1,000 mg/day); ibuprofen, 30 to 40 mg/kg/day divided 3 to 4 times daily (maximum = 2,400 mg/day); and indomethacin, 1 to 2 mg/kg/day divided 2 to 4 times daily (maximum = 4 mg/kg/day or 150-200 mg/day;
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Aspirin is not recommended for treatment of JIA because of its association with Reye syndrome. Cyclooxygenase-2 inhibitors (celecoxib) may be considered for patients with severe gastrointestinal adverse effects. A 2-month trial of NSAID monotherapy is indicated for patients with low-disease-activity (LDA) arthritis in fewer than four joints, without joint contracture, and without features of poor prognosis (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Some experts suggest that a lack of response to one NSAID does not confer response to all agents in the class; a trial of an alternate NSAID may be warranted (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ).
      Because NSAIDs provide only symptomatic relief from pain and stiffness associated with arthritis and do not stop the destructive inflammatory process associated with this illness, most patients inflicted with moderate to severe JIA receive NSAIDs as adjunctive therapy. Adverse reactions associated with NSAID use include abdominal discomfort, gastritis/peptic ulcer disease, and thrombocytopenia. Long-term use may result in renal toxicity such as renal papillary necrosis (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). A complete blood count (CBC), liver function tests (LFTs), and serum creatinine should be completed before initiation and at least twice yearly for chronic daily use and once yearly for routine use (3-4 days per week;
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ).

      Intra-articular glucocorticoid injections

      Intra-articular glucocorticoid injections are reserved for patients with localized disease. Triamcinolone hexacetonide ([TH], available as a 5 mg/ml and 20 mg/ml injection) and triamcinolone acetonide ([TA], available as a 10 mg/ml and 40 mg/ml injection) have both been used in the treatment of JIA. TH is the more commonly used agent because it has shown superior efficacy (e.g., longer time to relapse) because of its lower solubility, resulting in slower absorption from the injected joint and a longer duration of action compared with TA (
      • Eberhard B.A.
      • Sison M.C.
      • Gottlieb B.S.
      • Ilowite N.T.
      Comparison of the intraarticular effectiveness of triamcinolone hexacetonide and triamcinolone acetonide in treatment of juvenile rheumatoid arthritis.
      ). These are considered first-line therapies in patients with moderate disease activity (MDA) or high disease activity (HDA) arthritis in fewer than four joints and those who failed a trial of NSAIDs (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). The typical dosage of TH is based on the size of the child and the affected joint. Those with larger joints typically receive TH at 10 to 20 mg/dose, and those with smaller joints receive 2 to 6 mg/dose every 3 to 4 weeks (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Previous studies in children have used a TH dose of 1 mg/kg (maximum = 40 mg/dose or 2 ml using 20 mg/ml injection) and a TA dose of 2 mg/kg (maximum = 80 mg/dose or 2 ml using 40 mg/ml solution;
      • Zulian F.
      • Martini G.
      • Gobber D.
      • Plebani M.
      • Zacchello F.
      • Manner P.
      Triamcinolone acetonid and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: A double-blind trial.
      ). Clinical improvement should last at least 4 months after joint injection (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Improvement for less than 4 months may indicate the need for escalation of therapy. Common adverse events include skin hypopigmentation and subcutaneous (SC) skin atrophy (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ,
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      Systemic glucocorticoids

      Systemic glucocorticoids, prednisone and methylprednisolone, are potent anti-inflammatory drugs that were historically used as a bridge therapy until DMARDs became effective. Because of the adverse event profile and the advent of newer therapeutic options, systemic glucocorticoids have fallen out of favor. The ACR guidelines do not include recommendations for use of systemic glucocorticoids (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). However, they remain a therapeutic option for treatment of systemic arthritis with active systemic features (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Glucocorticoids can be given as high-dose “pulse” intravenous (IV) methylprednisolone at 15 to 30 mg/kg/day up to 1,000 mg/day for 1 to 3 days (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). However, because of the short duration of action, some patients may require chronic oral prednisolone at 1 to 2 mg/kg/day in 1 to 2 divided doses (maximum = 60 mg/day;
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ,
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Common adverse effects associated with long-term use include weight gain, growth suppression, osteoporosis, acne, and adrenal suppression (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      Nonbiologic disease-modifying antirheumatic drugs

      DMARDs are medications that slow the progression of JIA and prevent long-term morbidity by controlling disease before irreversible damage occurs. Treatment with DMARD therapy may eliminate the need for anti-inflammatory drugs. Because DMARDs do not provide immediate symptom reduction, with benefits typically evident weeks to months after initiation, bridging therapy may be necessary until the full onset occurs. Although DMARDS are considered first-line disease-modifying therapy, long-term outcomes in children with JIA are limited because of the change in the definition of JIA, different patient characteristics, and variations in comparator. Table 3 provides an overview of DMARDs, including their mechanism of action, approved indications, detailed dosing information, adverse effects, and monitoring parameters.
      TABLE 3Disease-modifying antirheumatic drugs used in the treatment of JIA
      AgentMechanism of actionFDA-approved indicationDosing regimenCommon adverse effectsSerious adverse effectsMonitoring parameters
      MethotrexateInhibits dihydrofolate reductase, interferes with purine synthesis and DNA replicationPolyarticular JIA10–15 mg/m2/dose PO/SQ/IM weeklyN/VInfectionPlatelets
      Maximum = 30 mg/m2/doseAbdominal painCirrhosisCBC
      Pulmonary toxicityLFTs
      SCr
      PFT
      LeflunomideInhibits dihydroorotate dehydrogenase, reversibly inhibiting de novo pyrimidine synthesisOff-label use for JIA ≥ 3 years of ageLoading dose: 100 mg PO × 1–3 days (duration based on patient's weight)N/DHepatic toxicityCBC
      HeadacheLFTs
      Maintenance: 10–20 mg PO dailyRash
      Maximum = 20 mg/doseAlopecia
      SulfasalazineInhibits multiple inflammatory pathways including leukotrienes, prostaglandins, and possibly TNF-αJIA ≥ 6 years of ageUsual dose = 30–50 mg/kg/day PO in 2 divided dosesN/V/DHepatitisCBC
      Hematologic effectsSkin reactions (SJS, drug-induced SLE)LFTs
      Maximum = 2,000 mg/day
      ThalidomideMultiple immunomodulatory characteristics, may suppress TNF-α and IL-6Off-label use for SJIA ≥ 3 years of ageInitial dosage of 2 mg/kg/day PO, increased at 2-week intervals to 3–5 mg/kg/dayDrowsinessTeratogenicityCBC
      NeutropeniaPeripheral neuropathyCPK
      Somnolence
      Myalgias
      CyclosporineInhibits the production and release of IL-2→ inhibition of IL-2–induced T-lymphocyte activationOff-label use for JIA2–5 mg/kg/day PO BIDN/VRenal fibrosisBP
      Maximum = 5 mg/kg/dayHypertensionHepatic toxicitySCr
      HirsutismInfectionLFTs
      Gingival hyperplasiaCBC
      HydroxychloroquineAnti-inflammatory effects may be due to the inhibition of migration of neutrophils/eosinophils and prostaglandin inhibitionOff-label use for JIA3–5 mg/kg/day (as sulfate) PO in 1–2 divided dosesAgranulocytosisOcularOphthalmic examination
      Maximum = 7 mg/kg/day or 400 mg/dayLeukopeniaDermatologic (alopecia)CBC
      ThrombocytopeniaLFT
      Aplastic anemia
      CyclophosphamideAlkylating agent that interferes with normal function of DNANot approved500 mg/m2/dose IV monthlyN/VHemorrhagic cystitisCBC
      Maximum = 1,000 mg/m2/doseAnorexiaSterilityLFTs
      Bone marrow toxicitySCr
      AzathioprinePrevents purine metabolism, inhibiting synthesis of DNA, RNA, and proteinsOff-label use for JIA and JIA-associated uveitisJIA: 2–2.5 mg/kg/dose PO once dailyN/DBone marrowCBC
      Uveitis: Initial 2.4 mg/kg/dose PO once daily (range = 1.4–3.2 mg/kg/day)suppression
      Pancytopenia
      Note. Data from
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      , Taketomo, Hodding, and Krause (2017), and
      • Brent R.L.
      Teratogen update: Reproductive risks of leflunomide (Arava); A pyrimidine synthesis inhibitor: Counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child.
      .
      BID, twice daily; BP, blood pressure; CBC, complete blood count; CPK, creatinine phosphokinase; D, diarrhea; FDA, U.S. Food and Drug Administration; IL, interleukin; IM, intramuscular; IV, intravenous; JIA, juvenile idiopathic arthritis; LFT, liver function test; N, nausea; PFT, pulmonary function test; PO, by mouth; SCr, serum creatinine; SJS, Stevens–Johnson syndrome; SLE, systemic lupus erythematosus; SQ, subcutaneous; TNF-α, tumor necrosis factor-α; V, vomiting.

      Methotrexate

      Methotrexate (MTX) has an unknown mechanism of action as an anti-inflammatory agent. MTX affects the immune function and is a folic acid analog that inhibits dihydrofolate reductase, interfering with purine synthesis and DNA replication. MTX is recommended as the first-line nonbiologic DMARD for patients with HDA and features of poor prognosis; for patients with joint arthritis involving fewer than four joints; and for patients with HDA, irrespective of prognosis, with involvement of five or more joints (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). MTX dosages in the range of 10 to 15 mg/m2/week are commonly used (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ,
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). At this relatively lower dose, MTX functions as an anti-inflammatory agent rather than a cytotoxic drug. It is typically administered orally initially, but may be given intramuscularly or SC in instances of non-compliance, intolerance, or poor response to oral therapy given the lower oral bioavailability of 70%. Higher dosages of 30 mg/m2/week did not show improved therapeutic response in patients with polyarticular JIA for whom 6 months of standard MTX doses failed (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ). Clinical improvement should be seen 6 to 12 weeks after initiation of therapy, but it could take up to 6 months to see maximal benefit.
      Gastrointestinal (GI) adverse effects are the most prominent, with abdominal pain and nausea occurring within the first 24 to 36 hours after administration (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Other adverse events include oral ulcers, infection, and hematologic and liver toxicity. Transient transaminitis usually resolves upon discontinuation of MTX; no reports of irreversible liver fibrosis have occurred. Glossitis and macrocytic anemia are thought to be due to folate antagonism, and therefore folate supplementation with folic acid or folinic acid may be considered. A retrospective, noncontrolled study of pediatric patients showed a reduction in the mean number of episodes per patient–year of hepatic and GI toxicities after folinic acid supplementation (
      • Ravelli A.
      • Migliavacca D.
      • Viola S.
      • Ruperto N.
      • Pistorio A.
      • Martini A.
      Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis.
      ). Further studies are needed to assess the efficacy of folic acid/folinic acid and to develop an appropriate dosing regimen. Monitoring parameters include a CBC, LFTs, and serum creatinine before initiation, 1 month after initiation, 1 to 2 months after dose escalation, and every 3 to 4 months once the patient stable receiving a dosing regimen with prior normal laboratory test values (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ).
      Methotrexate is contraindicated in pregnant patients (because of the teratogenic potential) when used for the management of arthritis, mainly because there are many other therapies available. Fetal anomalies and congenital malformations have been reported in pregnant patients exposed to methotrexate. Pregnancy should be excluded in all patients of childbearing age before the initiation of therapy and should be avoided for at least 3 months after treatment in males and at least one ovulatory cycle in females (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      Leflunomide

      Leflunomide is an immunomodulatory drug that inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, reversibly inhibiting de novo pyrimidine synthesis (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ,
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). It is recommended as a second-line nonbiologic DMARD in patients mainly because of the greater degree of clinical experience associated with MTX (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). In patients with arthritis in five or more joints, leflunomide may be considered as an approach to initial treatment for patients with HDA and features of poor prognosis. Leflunomide is a prodrug that is rapidly converted to its active plasma metabolite, teriflunomide (
      • Sanofi-Aventis U.S.
      Arava (leflunomide) [package insert].
      ,
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Teriflunomide is highly protein bound, with a prolonged half-life of approximately 18 days. Given the prolonged half-life and time to reach steady state, some experts consider the administration of loading doses of 100 mg orally for the first 3 days of therapy. However, loading doses may precipitate GI effects. Because of the lower steady state plasma concentration of the active metabolite of leflunomide in children less than 40 kg, as reported in pharmacokinetic studies, the FDA does not recommend its use for the treatment of JIA (Sanofi-Aventis U.S., 2016;
      • Silverman E.
      • Mouy R.
      • Spiegel L.
      • Jung L.K.
      • Saurenmann R.K.
      • Lahdenne P.
      • Strand V.
      Leflunomide or methotrexate for juvenile rheumatoid arthritis.
      ).
      Because leflunomide has been shown to be embryotoxic and teratogenic, the FDA considers this drug to be contraindicated in pregnancy (Sanofi-Aventis U.S., 2016;
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Women of childbearing potential must have a negative pregnancy test result before initiation of leflunomide therapy, and contraceptive practices of patients should be documented. In addition, women who wish to conceive while taking leflunomide must complete an enhanced drug elimination procedure using cholestyramine 8 g three times a day for 11 days. This will reduce the half-life of teriflunomide to about 1 day (
      • Brent R.L.
      Teratogen update: Reproductive risks of leflunomide (Arava); A pyrimidine synthesis inhibitor: Counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child.
      ). They should also have two separate documented teriflunomide drug levels of less than 0.02 µg/ml at least 2 weeks before trying to conceive (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). The most common adverse effects include GI symptoms, headache, and dermatologic symptoms (i.e., alopecia, skin rash;
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). In addition, patients should be monitored for hepatotoxicity, because this drug can cause severe liver injury and is contraindicated in hepatic failure. Liver enzyme level and CBC should be obtained every 4 to 12 weeks. Monitoring of serum teriflunomide trough levels may be considered when evaluating therapeutic efficacy; however, therapeutic trough concentrations have not been established for the treatment of JIA (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      Sulfasalazine

      Sulfasalazine is a 5-aminosalicyclic acid analog that interferes with several inflammatory pathways, including leukotriene and prostaglandin production. It is a combination of sulfonamide (an antibiotic) and 5-aminosalicyclic acid (anti-inflammatory agent). The ACR guidelines recommend sulfasalazine for treatment of ERA in patients with a history of arthritis of fewer than four joints with MDA or HDA after a trial of NSAIDs and/or glucocorticoid joint injections (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Because of conflicting results, the ACR guidelines do not recommend its use in non-ERA patients. Some literature recommends reserving sulfasalazine as an add-on therapy for patients with refractory disease receiving combination therapy because of conflicting results and adverse effects.
      • Van Rossum M.A.
      • Fiselier T.J.
      • Franssen M.J.
      • Zwinderman A.H.
      • ten Cate R.
      • van Suijlekom-Smit L.W.
      • Diikmans B.A.
      Sulfasalazine in the treatment of juvenile chronic arthritis: A randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group.
      reported that 31% of children with JIA discontinued sulfasalazine therapy because of drug toxicity. Adverse effects include nausea, vomiting, diarrhea, anorexia, rash, bone marrow suppression, and hepatitis. Because sulfasalazine inhibits dihydrofolate reductase, it may cause folate deficiency and megaloblastic anemia. Because the data on FA or FLA supplementation in those who are taking sulfasalazine are limited, it is not commonly prescribed compared with MTX. Some clinicians may initiate therapy at half to one third of the maintenance dose with weekly dose titrations to decrease GI effects. Patients with a sulfa allergy should avoid sulfasalazine because of the possible development of Stevens–Johnson syndrome. CBC and liver enzyme level should be periodically monitored.

      Other nonbiologic disease-modifying antirheumatic agents

      Other nonbiologic DMARDs, including thalidomide, cyclosporine, tacrolimus, hydroxychloroquine, cyclophosphamide, and azathioprine, have been previously described in the treatment of JIA (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ). These agents are not included in the ACR guidelines, because there are no clear recommendations as to where they fit within the disease subtypes and treatment groups. These agents may play a role in refractory disease.
      Combination therapy involving multiple nonbiologic DMARDs has also been studied; however, with combination therapy there is a risk of additive immunosuppression and adverse effects. Thalidomide is one agent that should be used with extreme caution because of its potent teratogenic potential. All patients, male and female, should receive birth control while receiving thalidomide therapy, and additional caution should be taken in adolescents and those of childbearing potential. Permanent peripheral neuropathy may occur with prolonged thalidomide exposure, and patients should be monitored with regular neurologic examinations (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Thalidomide use has been described in children with systemic JIA irresponsive to other therapies; however, published data are limited to case series and small sample sizes. (
      • Lehman T.J.
      • Schechter S.J.
      • Sundel R.P.
      • Oliveira S.K.
      • Huttenlocher A.
      • Onel K.B.
      Thalidomide for severe systemic onset juvenile rheumatoid arthritis: A multicenter study.
      ). Cyclosporine and tacrolimus are drugs with a narrow therapeutic index and, therefore, require therapeutic drug monitoring. Hydroxychloroquine can cause ocular abnormality and bone marrow suppression; ophthalmologic examinations and periodic CBC should be monitored. Cyclophosphamide may cause hemorrhagic cystitis; a urine analysis and chemistries should be monitored. There are limited data for azathioprine in the pediatric population for treatment of JIA, and it is considered a last-line nonbiologic DMARD therapy.

      Biologic disease-modifying antirheumatic drugs

      The development of biologic agents has greatly changed the outcomes and morbidity associated with this disease. Biologic agents are substances that are made from a living organism or its products and may include monoclonal antibodies, receptor antagonists, or soluble cytokine receptors that target specific proteins involved in the inflammatory cascade. Biologic agents are administered via the IV or SC routes, which may be more challenging and can affect medication compliance. The financial implications associated with these agents are substantial, and pharmacoeconomic analyses evaluating the cost per treatment among regimens are lacking. Costs associated with these agents must include IV administration and the requirement for infusion clinics.
      Before initiation of these therapies, providers should take into consideration insurance coverage and the financial impact that will be placed on the patient and family. Because of their relatively new advent in the 1990s, long-term outcomes and safety data are sparse. Biologic agents also carry the risk of severe immunosuppression, and routine monitoring and close follow-up are extremely important. Table 4 provides a detailed review of biologic agents that have been used in the treatment of JIA.
      TABLE 4Biologic disease-modifying antirheumatic drugs used in the treatment of JIA
      MedicationMechanism of actionFDA-approved indicationDosing regimenCommon adverse effectsSerious adverse effectsMonitoring parameters
      TNF-α inhibitors
      Etanercept (Enbrel; Amgen, Thousand Oaks, CA)Soluble, dimeric, fusion protein that binds to TNF-α preventing binding to cell-surface receptorsModerate to severe PJIA ≥ 2 years of ageWeekly: 0.8 mg/kg/dose SC once weekly; maximum = 50 mg/doseInjection site reactionInfectionHBsAg
      Twice weekly: 0.4 mg/kg/dose given 72–96 hours apart; maximum = 25 mg/dose twice weeklyURIAnaphylaxisPPD
      UrticariaAutoantibodiesDermatologic examination
      Malignancy
      TB reactivation
      Adalimumab (Humira; Abbvie, North Chicago, IL)Fully humanized recombinant IgG monoclonal Ab that binds to TNF-αModerate to severe PJIA ≥ 2 years of agePJIAInjection site reactionInfectionHBsAg
      Off-label use for JIA-associated uveitis10 to <15 kg: 10 mg SC every other weekURIAnaphylaxisPPD
      15 to <30 kg: 20 mg SC every other weekUrticariaAutoantibodies
      ≥30 kg: 40 mg SC every other weekMalignancy
      UveitisTB reactivation

      <30 kg: 20 mg every other week
      ≥30 kg: 40 mg every other week
      Infliximab (Remicade; Janssen, Raritan, NJ)Monoclonal Ab that binds to both soluble and membrane-bound TNF-αOff-label use for JIA and uveitisAge ≥ 4 years: 3 mg/kg/dose IV at 0, 2, and 6 weeks, then 3–6 mg/kg/dose every 8 weeks + MTXInjection site reactionInfectionHBsAg
      MyalgiaAnaphylaxisPPD
      URIAutoantibodies
      UrticariaPNA
      Malignancy
      TB reactivation
      T-cell co-stimulation blocker
      Abatacept (Orencia; Bristol-Myers Squibb, New York, NY)T-cell co-stimulator inhibitor through binding to CD80/CD86Moderate to severe PJIA ≥6 years of age<75 kg: 10 mg/kg/doseHeadacheVaricellaCBC
      75–100 kg: 750 mg/doseNauseaAnaphylaxisPPD
      >100 kg: 1,000 mg/doseURITB reactivation
      IV at 0, 2, and 4 weeks, then every 4 weeks thereafterOvarian cyst
      ALL
      IL-1 inhibitors
      Anakinra (Kineret; Swedish Orphan Biovitrum, Stockholm, Sweden)Human recombinant IL-1 receptor antagonistOff-label use for SJIA and PJIASJIAInjection site reactionHepatitisSCr
      Initial: 1–2 mg/kg/dose SC daily (maximum = 100 mg/day); may increase to 4 mg/kg/day at 2-week intervals (maximum = 200 mg/day)

      PJIA:

      1 mg/kg/dose SC daily; Max 100 mg/day
      URIInfectionsANC
      HeadacheSecondary malignanciesCBC
      Nausea
      Diarrhea
      Neutropenia
      Arthralgia
      Rilonacept (Arcalyst; Regeneron, Tarryton, NY)Binds to IL-1 receptor preventing interaction with cell surface receptorsNot approvedAge 12–17 yearsInjection site reactionSerious infectionsCBC
      Loading dose: 4.4 mg/kg/dose SC (maximum = 320 mg/dose)URI
      May divide into 1–2 injections (maximum injection volume = 2 ml)
      Maintenance: 2.2 mg/kg/dose SC weekly (maximum = 160 mg/dose)
      Canakinumab (Ilaris; Novartis, East Hanover, NY)Humanized monoclonal Ab that selectively blocks IL-1βSJIA ≥2 years of ageAge ≥ 2 years: 4 mg/kg/dose SC every 4 weeks

      Maximum = 300 mg/dose
      URISerious infectionsCBC
      Abdominal pain
      Injection site reaction
      IL-6 inhibitor
      Tocilizumab (Actemra; Genetech, South San Francisco, CA)Anti–IL-6 receptor monoclonal AbSJIA and PJIA ≥2 yearsSJIA:URISerious infectionsBP
      <30 kg: 12 mg/kg/dose IV every 2 weeksHeadache(PNA, UTI, herpesCBC
      ≥30 kg: 8 mg/kg/dose IV every 2 weeksHTNzoster)PPD
      Maximum = 800 mg/doseIncreased ALTGI perforationLFT
      PJIA:AnaphylaxisANC
      <30 kg: 10 mg/kg/dose IV every 4 weeksTBLipid panel
      ≥30 kg: 8 mg/kg/dose IV every 4 weeks
      Maximum = 800 mg/dose
      Other drug
      Rituximab (Rituxan; Biogen, Cambridge, MA)Anti-CD20 B-cell depleting monoclonal AbOff-label use for refractory PJIA and SJIA375 mg/m2/dose IV infusion once weekly for 2–4 weeks

      Maximum = 1,000 mg/dose
      Infusion reactionsNeuropathyCBC
      HTNTumor lysis syndromeECG
      Increased ALTSJSHBsAg
      Ab, antibody; ALL, acute lymphocytic leukemia; ALT, alanine aminotransferase; ANC, absolute neutrophil count; BP, blood pressure; CBC, complete blood count; ECG, electrocardiography; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; HBsAg, hepatitis B surface antigen; HTN, hypertension; Ig, immunoglobulin; IL, interleukin; IV, intravenous; LFT, liver function test; MTX, methotrexate; PJIA, polyarticular juvenile idiopathic arthritis; PNA, pneumonia; PPD, purified protein derivative of tuberculin; SC, subcutaneous; SJIA, systemic juvenile idiopathic arthritis; SJS, Stevens–Johnson Syndrome; TB, tuberculosis; TNF-α, tumor necrosis factor-α; URI, upper respiratory infection; UTI, urinary tract infection.

      TNF-α inhibitors

      TNF-α inhibitors (TNFi) remain the most commonly prescribed biologic agents for the treatment of JIA. Elevated levels of the proinflammatory cytokine TNF-α are found in children with JIA, and therefore inhibitors of these cytokines play an important role in modifying the inflammatory disease progression. Available agents in this class include etanercept, adalimumab, and infliximab. Although all three agents target TNF-α, they differ slightly in the manner in which they achieve inhibition. Adalimumab and infliximab are monoclonal antibodies, whereas etanercept is a soluble receptor antagonist. The monoclonal antibodies differ in terms of their antibody type: adalimumab is a fully humanized monoclonal antibody, whereas infliximab is a chimeric monoclonal antibody, thus resulting in a potentially higher immunogenicity. Other differences include their route of administration. Infliximab is given via IV infusion, whereas etanercept and adalimumab are SC injections. Given the concern for the risk of infusion-related reactions associated with infliximab, etanercept and adalimumab may be the more preferable agents. Etanercept was the first biologic agent approved in the treatment of moderate to severe polyarticular JIA in children 2 years of age and older in 1999. In 2008, adalimumab received FDA approval for use in children 4 years of age and older with polyarticular JIA (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Currently, clinical trials on the use of other TNFi agents such as golimumab and certolizumab, both approved for adult rheumatoid arthritis, for the treatment of JIA are underway. Golimumab and certolizumab are currently not addressed in the ACR guidelines (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ).
      In patients with arthritis of fewer than four joints, TNFi agents are indicated after a 3-month trial of MTX plus glucocorticoid joint injections in patients with MDA or HDA with poor prognosis or after a 6-month trial of MTX plus glucocorticoid joint injections for patients with HDA without features of poor prognosis (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Furthermore, in patients with arthritis of five or more joints, a TNFi may be consider after 3 months of MTX or leflunomide in patients with MDA or had, irrespective of poor prognosis, or after 6 months of MTX or leflunomide in patients with LDA, irrespective of poor prognosis. Additionally, they can be used in patients with systemic arthritis with active arthritis (without active systemic features) after 3 months of MTX in patients with MDA or had, irrespective of poor prognosis. Because response is delayed, a 4-month trial of a TNFi is indicated. If response is not optimal after the initial bDMARD trial, it is reasonable to try a different TNFi or switch to a different bDMARD. Infliximab did not show a statistically significant benefit compared with placebo in its primary endpoint (ACR Pedi 30) at week 14 of therapy in a Phase 3 study, and therefore it is not FDA approved for JIA treatment (
      • Ruperto N.
      • Lovell D.J.
      • Cuttica R.
      • Wilkinson N.
      • Woo P.
      • Espada G.
      • Giannini E.H.
      A randomized, placebo controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis.
      ). The ACR guidelines, however, do acknowledge infliximab as an available TNFi option. Currently, there are no clinical trials comparing TNFi agents head to head for the treatment of JIA.

      Abatacept

      Abatacept is a soluble fusion protein that is a selective co-stimulation modulator. It inhibits T-cell activation by binding to CD80 or CD86 on antigen-presenting cells, preventing interaction of the antigen-presenting cells with CD28 (
      • Harris J.G.
      • Kessler E.A.
      • Verbsky J.W.
      Update on the treatment of juvenile idiopathic arthritis.
      ). Abatacept is typically reserved for patients for whom therapy with a TNFi has failed, which highlights the potential for other inflammatory mediators and cytokines playing a role in the pathogenesis of JIA. Clinical trials showed that of patients who discontinued a TNFi, 25% achieved an ACR Pedi 50 after 4 months of abatacept therapy (
      • Ruperto N.
      • Lovell D.J.
      • Quartier P.
      • Paz E.
      • Rubio-Perez N.
      • Silva C.A.
      • Giannini E.H.
      Abatacept in children with juvenile idiopathic arthritis: A randomized, double-blind, placebo-controlled withdrawal trial.
      ). Initial improvement in clinical symptoms is typically seen by the third or fourth dose; however, response may be delayed in some patients. Abatacept is recommended for the following patients: (a) patients with arthritis in five or more joints and who have received a TNFi for 4 months who and have HDA, irrespective of poor prognosis, or MDA with features of poor prognosis; (b) patients with arthritis in five or more joints who have received more than one TNFi and have MDA or HAD, irrespective of poor prognostic features, or LDA with poor prognosis; and (c) patients who have received MTX and a TNFi who have HAD, irrespective of poor prognosis, or MDA with features of poor prognosis (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Abatacept is administered as an IV infusion every 2 weeks for the first month and monthly thereafter because of its long half-life of 8 to 25 days (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Adverse events were common and included headache, nausea, diarrhea, cough, and upper respiratory infection (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Serious adverse effects such as arthritis flare, varicella, ovarian cyst, and acute lymphocytic leukemia were seen in 3% of patients (
      • Ruperto N.
      • Lovell D.J.
      • Quartier P.
      • Paz E.
      • Rubio-Perez N.
      • Silva C.A.
      • Giannini E.H.
      Abatacept in children with juvenile idiopathic arthritis: A randomized, double-blind, placebo-controlled withdrawal trial.
      ). Because abatacept can alter the immune response against infections and malignancies because of T-cell inhibition, consideration should be made to hold abatacept doses in patients with suspected infection. Absence of latent or active tuberculosis should be documented before initiation of therapy, with periodic monitoring of CBC and LFTs every 4 to 12 weeks while taking abatacept (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Providers should be educated that glucose readings on the day of infusion may be falsely elevated because the powder for reconstitution contains maltose (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      IL-1 inhibitors

      IL-1 inhibitors include anakinra, canakinumab, and rilonacept; anakinra and rilonacept are IL-1 receptor antagonists, and canakinumab is an anti-IL-1 monoclonal antibody (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ). All three agents were evaluated for the treatment of JIA by the current ACR guidelines (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). IL-1 inhibitors are indicated for patients with systemic arthritis with active systemic features who have fever and features of poor prognosis (irrespective of current therapy level) or those with ongoing disease activity while receiving systemic glucocorticoids. It is also indicated in patients with systemic arthritis with active arthritis and MDA or HDA, irrespective of features of poor prognosis, after an unsuccessful 3-month trial of MTX or a 4-month trial of a TNFi (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Anakinra should not be used in combination with a TNFi because of the risk of severe neutropenia. A CBC with differential should be obtained before initiation, monthly for 3 months and then quarterly thereafter while receiving therapy (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). IL-1 inhibitors are administered SC, and their frequency is drug dependent. Anakinra has a short half-life of 4 to 7 hours and thus requires daily injections. Rilonacept has a half-life of approximately 8 days and therefore can be administered once a week. Canakinumab has a prolonged half-life of 23 to 26 days and therefore can be administered every 4 weeks (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      IL-6 inhibitors

      Tocilizumab is a recombinant humanized monoclonal antibody approved for the treatment of JIA and is currently the only agent that functions as an IL-6 receptor antagonist. Tocilizumab received FDA approval for the treatment of SJIA and polyarticular JIA in patients 2 years of age or older (
      • Frampton J.E.
      Tocilizumab: A review of its use in the treatment of juvenile idiopathic arthritis.
      ). It is indicated in patients with continued disease activity after glucocorticoid monotherapy, MTX, leflunomide, or anakinra (
      • Frampton J.E.
      Tocilizumab: A review of its use in the treatment of juvenile idiopathic arthritis.
      ). Tocilizumab is administered as a 1-hour infusion every 2 weeks for SJIA and every 4 weeks for polyarticular JIA. Adverse effects include neutropenia, thrombocytopenia, liver transaminitis, hypertriglyceridemia, hypercholesterolemia, and GI perforation (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Tocilizumab should not be initiated in patients with an active infection, absolute neutrophil count less than 2,000/mm3, platelet count less than 100,000/mm3, or alanine aminotransferase or aspartate aminotransferase level more than 1.5 times the upper limit of normal. LFT and CBC should be monitored before therapy initiation, with the second infusion, and every 2 to 4 weeks (for SJIA) or every 4 to 8 weeks (for polyarticular). A lipid panel should also be obtained before therapy, about 4 to 8 weeks after initiation and every 6 months thereafter while receiving therapy (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ).

      Rituximab

      Rituximab is a monoclonal antibody directed against the CD20 antigen on the B-lymphocyte surface, which thereby inhibits the inflammatory cascade. The ACR guidelines suggest that rituximab may be used in patients with fewer than five joints involved for whom both an IL-1 inhibitor and tocilizumab sequentially or a DMARD plus IL-1 inhibitor or tocilizumab failed. In addition, it can also be used in patients with five or more joints involved for whom both an IL-1 inhibitor and tocilizumab or a DMARD plus IL-1 inhibitor, tocilizumab, TNFi, or abatacept failed (
      • Beukelman T.
      • Patkar N.M.
      • Saag K.G.
      • Tolleson-Rinehart S.
      • Cron R.Q.
      • DeWitt E.M.
      • Ruperto N.
      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.
      ). Furthermore, rituximab use has also been reported in limited case reports for refractory JIA (
      • Giancane G.
      • Consolaro A.
      • Lanni S.
      • Davi S.
      • Schiappapeitra B.
      • Ravelli A.
      Juvenile idiopathic arthritis: Diagnosis and treatment.
      ). Boxed warnings include severe and occasionally fatal infusion-related reactions. Pretreatment with acetaminophen, an antihistamine, and methylprednisolone should be considered, and medications for the treatment of hypersensitivity reactions (e.g., epinephrine, bronchodilators) should be available for immediate use. Other boxed warnings include severe mucocutaneous reactions such as Stevens–Johnson syndrome, the development of progressive multifocal leukoencephalopathy, and the potential for reactivation of hepatitis B (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Because of significant adverse events, the use of rituximab in the management of JIA has decreased significantly. Patients should be watched closely for infusion-related reactions and should receive continuous electrocardiographic and vital sign monitoring during and immediately after infusion. B-cell levels should be evaluated before and 1 month after infusion, with quantitative immunoglobulin levels assessed every 3 months. Clinical improvement with rituximab is typically seen within 1 month of the initial infusion.

      Adverse effects/monitoring parameters for bDMARDs

      The risk of infection is one of the most serious adverse effects associated with bDMARDs. Concerns regarding serious infection risks including the development of opportunistic infections secondary to immunosuppression, hepatitis B and tuberculosis reactivation, and a decreased response to vaccination (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Patients should be screened for hepatitis B surface antigen, hepatitis B core antibody, and tuberculosis using chest radiography and/or purified protein derivative testing and/or tuberculosis blood tests (interferon-γ release assay) before initiation of therapy (
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric and neonatal dosage handbook.
      ). Patients should be monitored for symptoms of hepatitis B virus reactivation during treatment and for several months after therapy. Purified protein derivative testing should be repeated yearly throughout therapy. All efforts should be made to ensure that patients are fully vaccinated before the initiation of therapy. As with all forms of immunosuppression, live vaccines should be avoided concurrently and for 3 months after biologic therapy. Secondary malignancies have also been associated with the use of bDMARDs and are therefore contraindicated in patients with active malignancy. Further studies are needed to address this associated risk, because many of these cases may have been compounded by concomitant immunosuppression use and underlying illnesses.

      Complications

      Untreated or inadequately treated JIA can result in many long-term consequences such as anemia, pericarditis, chronic pain, slow rate of growth, and uveitis. Iridocyclitis, a chronic anterior uveitis, is one of the most common complications of JIA occurring in approximately 15% to 20% of children inflicted with this disease (
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ). If left untreated, uveitis can result in cataracts, glaucoma, and blindness. Patients with ANA-positive titer results have been found to be at a higher risk for development of uveitis and should undergo monitoring with slit lamp examinations by an ophthalmologist more frequently than children with JIA who have negative ANA titer results. Primary treatment of uveitis involves the use of topical ocular corticosteroid drops; however, some patients may require systemic or intraocular corticosteroid injections (
      • Borchers A.T.
      • Selmi C.
      • Cheema G.
      • Keen C.L.
      • Shoenfeld Y.
      • Gershwin M.E.
      Juvenile idiopathic arthritis.
      ,
      • Ostring G.T.
      • Singh-Grewal D.
      Juvenile idiopathic arthritis in the new world of biologics.
      ).
      Chronic, persistent arthritis in the knee can also lead to growth disturbances, specifically leg length disturbances, secondary to accelerated growth in affected joints (
      • Borchers A.T.
      • Selmi C.
      • Cheema G.
      • Keen C.L.
      • Shoenfeld Y.
      • Gershwin M.E.
      Juvenile idiopathic arthritis.
      ,
      • Espinosa M.
      • Gottlieb B.S.
      Juvenile idiopathic arthritis.
      ). Growth retardation may be seen in patients with persistent arthritis in the wrist and ankles. A higher incidence of osteopenia and osteoporosis have been seen in patients with JIA, possibly secondary to bone loss and reduced bone density (due to corticosteroid treatment), decreased weight-bearing activity, and malnutrition. In addition, persistent arthritis can result in limited mobility, decreased quality of life, joint damage, and psychosocial issues.
      MAS is a rare but potentially life-threatening syndrome that most frequently occurs in SJIA patients. It is thought to be secondary to organ infiltration by activated macrophages due to a cytokine storm. Patients with MAS present with fever, pancytopenia, liver failure, coagulopathy with hemorrhage or thrombophilia, encephalopathy, and seizures. Treatment of MAS typically requires admission to an intensive care unit and administration of immunosuppressive agents (
      • Brent R.L.
      Teratogen update: Reproductive risks of leflunomide (Arava); A pyrimidine synthesis inhibitor: Counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child.
      ).

      Summary

      JIA is a chronic, debilitating childhood condition with many long-term consequences. The development of the ILAR classification system and ACR treatment guidelines better define this childhood disease and provide a more objective manner in which to treat and monitor patients with JIA. Diagnosis is based mainly on clinical symptoms, and accurate classification of JIA disease subtype is extremely important. Chronic pain and inflammation are hallmark characteristics of this disorder, and without treatment many patients will develop disability. Many pharmacotherapeutic agents are available for the management of JIA. DMARDs have been shown to be the most effective in preventing long-term consequences of this disease. MTX continues to be a preferred agent because of its affordability, proven efficacy, safety, and tolerability. bDMARDs have revolutionized treatment of JIA, having shown promise in promoting disease remission, but they are associated with high costs and many safety concerns. Clinicians should evaluate the efficacy and safety of all available treatment options and tailor each medication regimen to the individual patient. The importance of routine monitoring and close follow-up should be emphasized, given the complexity of the regimens at hand. More studies are needed to assess the long-term safety and efficacy of the bDMARDs for JIA. In addition, the completion of head-to-head comparative trials of different treatment options could help identify preferred drug therapy.
      The development of the ILAR classification system and ACR treatment guidelines better define this childhood disease and provide a more objective manner in which to treat and monitor patients with JIA.

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      Biography

      Jessica L. Jacobson, Clinical Pharmacy Specialist-PICU/Pediatrics, Department of Pharmacy, Rush University Medical Center, Chicago, IL.
      Jennifer T. Pham, Clinical Pharmacist–Neonatal/Pediatrics and Clinical Assistant Professor, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL.