Chapter 179

Treatment of Rheumatic Diseases

Jeffrey A. Dvergsten, Esi Morgan, C. Egla Rabinovich

Nonpharmacologic as well as pharmacologic interventions are often necessary to meet the desired goals of disease management. Optimal disease management requires family-centered care delivered by a multidisciplinary team of healthcare professionals providing medical, psychological, social, and school support. Rheumatologic conditions most often follow a course marked by flares and periods of remission, although some children have unremitting disease. The goals of treatment are to control disease, relieve discomfort, avoid or limit drug toxicity, prevent or reduce organ damage, and maximize the physical function and quality of life of affected children. Nonpharmacologic therapy is an important adjunct to medical management of rheumatic diseases (see Chapter 76 ). A key predictor of long-term outcome is early recognition and referral to a rheumatology team experienced in the specialized care of children with rheumatic diseases. Significant differences in outcome are seen 10 yr after disease onset in patients with juvenile idiopathic arthritis (JIA) depending on whether referral to a pediatric rheumatology center was accomplished within 6 mo of onset.

Pediatric Rheumatology Teams and Primary Care Physicians

The multidisciplinary pediatric rheumatology team offers coordinated services for children and their families (Table 179.1 ). General principles of treatment include: early recognition of signs and symptoms of rheumatic disease with timely referral to rheumatology for prompt initiation of treatment; monitoring for disease complications and adverse effects of treatment; coordination of subspecialty care and rehabilitation services with communication of clinical information; and child- and family-centered chronic illness care, including self-management support, alliance with community resources, partnership with schools, resources for dealing with the financial burdens of disease, and connection with advocacy groups. Planning for transition to adult care providers needs to start in adolescence. Central to effective care is partnership with the primary care provider, who helps coordinate care, monitor compliance with treatment plans, ensure appropriate immunization, monitor for medication toxicities, and identify disease exacerbations and concomitant infections. Communication between the primary care provider and subspecialty team permits timely intervention when needed.

Table 179.1

Multidisciplinary Treatment of Rheumatic Diseases in Childhood

Accurate diagnosis and education of family	Pediatric rheumatologist Pediatrician
	Nurse: • Disease-related education • Medication administration (injection teaching) • Safety monitoring
	Social worker: • Facilitation of school services • Resource identification (community, government, financial, advocacy groups, vocational rehabilitation)
Physical medicine and rehabilitation	Physical therapy: • Addressing deficits in joint or muscle mobility, limb length discrepancies, gait abnormalities, and weakness
	Occupational therapy: • Splinting to reduce joint contractures/deformities and lessen stress on joints; adaptive devices for activities of daily living
Consultant team	Ophthalmology: • Eye screening for uveitis (see Table 180.4 ) • Screening for medication-related ocular toxicity (hydroxychloroquine, glucocorticoids)
	Nephrology
	Orthopedics
	Dermatology
	Gastroenterology
Physical and psychosocial growth and development	Nutrition: • Addressing undernourishment from systemic illness and obesity/overnourishment from glucocorticoids
	School integration: • Individualized educational plan (IEP) or 504 plan
	Peer-group relationships
	Individual and family counseling
Coordination of care	Involvement of patient and family as active team members
	Communication among healthcare providers
	Involvement of school (school nurse) and community (social worker) resources

Therapeutics

A key principle of pharmacologic management of rheumatic diseases is that early disease control, striving for induction of remission, leads to less tissue and organ damage with improved short- and long-term outcomes. Medications are chosen from broad therapeutic classes on the basis of diagnosis, disease severity, anthropometrics, and adverse effect profile. Many drug therapies used do not have U.S. Food and Drug Administration (FDA) indications for pediatric rheumatic diseases given the relative rarity of these conditions. The evidence base may be limited to case series, uncontrolled studies, or extrapolation from use in adults. The exception is JIA, for which there is a growing body of randomized controlled trial (RCT) evidence, particularly for newer therapeutics. Therapeutic agents used for treatment of childhood rheumatic diseases have various mechanisms of action, but all suppress inflammation (Table 179.2 ). Both biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs ) directly affect the immune system. DMARDs should be prescribed by specialists. Live vaccines are contraindicated in patients taking immunosuppressive glucocorticoids or DMARDs. A negative test result for tuberculosis (purified protein derivative and/or QuantiFERON-TB Gold) should be verified and the patient's immunization status updated, if possible, before such treatment is initiated. Killed vaccines are not contraindicated, and annual injectable influenza vaccine is recommended.

Table 179.2

Therapeutics for Childhood Rheumatic Diseases*

CLASSIFICATION	THERAPEUTIC †	DOSE	INDICATION †	ADVERSE REACTIONS	MONITORING
Nonsteroidal antiinflammatory drugs (NSAIDs) ‡	Etodolac a	PO once-daily dose: 20-30 kg: 400 mg 31-45 kg: 600 mg 46-60 kg: 800 mg >60 kg: 1,000 mg	JIA Spondyloarthropathy Pain Serositis Cutaneous vasculitis Uveitis	GI intolerance (abdominal pain, nausea), gastritis, hepatitis, tinnitus, anemia, pseudoporphyria, aseptic meningitis, headache, renal disease	CBC, LFTs, BUN/creatinine, urinalysis at baseline, then every 6-12 mo
	Ibuprofen a	40 mg/kg/day PO in 3 divided doses Max: 2400 mg/day
	Naproxen a	15 mg/kg/day PO in 2 divided doses Max 1,000 mg/day
	Celecoxib a	10-25 kg: 50 mg PO bid >25 kg: 100 mg PO bid
	Meloxicam a	0.125 mg/kg PO qd Max 7.5 mg
Disease-modifying antirheumatic drugs (DMARDs)	Methotrexate a	10-20 mg/m2 /wk (0.35-0.65 mg/kg/wk) PO 20-30 mg/m2 /wk (0.65-1 mg/kg/wk) SC; higher doses better absorbed by SC injection	JIA Uveitis	GI intolerance (nausea, vomiting), hepatitis, myelosuppression, mucositis, teratogenesis, lymphoma, interstitial pneumonitis	CBC, LFTs at baseline, monthly ×3, then every 8-12 wk
	Leflunomide	PO once daily: 10 to <20 kg: 10 mg 20-40 kg: 15 mg >40 kg: 20 mg	JIA	Hepatitis, hepatic necrosis, cytopenias, mucositis, teratogenesis, peripheral neuropathy	CBC, LFTs, at baseline, monthly ×6, then every 8-12 wk
	Hydroxychloroquine	5 mg/kg PO qd; do not exceed 5 mg/kg/daily Max 400 mg daily	SLE JDMS Antiphospholipid antibody syndrome	Retinal toxicity, GI intolerance, rash, skin discoloration, anemia, cytopenias, myopathy, CNS stimulation, death (overdose)	Ophthalmologic screening every 6-12 mo
	Sulfasalazine a	30-50 mg/kg/day in 2 divided doses Adult max 3 g/day	Spondyloarthropathy, JIA	GI intolerance, rash, hypersensitivity reactions, Stevens-Johnson syndrome, cytopenias, hepatitis, headache	CBC, LFTs, BUN/creatinine, urinalysis at baseline, every other wk ×3 mo, monthly ×3, then every 3 mo
Tumor necrosis factor (TNF)-α antagonists	Adalimumab a	SC once every other wk: 10 to <15 kg: 10 mg 15 to <30 kg: 20 mg ≥30 kg: 40 mg	JIA Spondyloarthropathy Psoriatic arthritis Uveitis	Injection site reaction, infection, rash, cytopenias, lupus-like syndrome, potential increased malignancy risk	TB test; anti-dsDNA, CBC
	Etanercept a	0.8 mg/kg SC once weekly (max 50 mg/dose) or 0.4 mg/kg SC twice weekly (max 25 mg/dose)	JIA	Injection site reactions, infections, rash, demyelinating disorders, cytopenias, potential increased malignancy risk	TB test; CBC
	Infliximab	5-10 mg/kg IV every 4-8 wk	JIA Spondyloarthropathy Uveitis Sarcoidosis	Infusion reactions, hepatitis, potential increased malignancy risk	TB test; anti-dsDNA, LFTs
Modulate T-cell activation	Abatacept a	IV every 2 wk ×3 doses, then monthly for ≥6 yr of age: <75 kg: 10 mg/kg 75-100 kg: 750 mg >100 kg: 1,000 mg	JIA	Infection, headache, potential increased malignancy risk
		SC once weekly: 10 to <25 kg: 50 mg ≥25 to <50 kg: 87.5 mg ≥50 kg: 125 mg
Anti-CD20 (B-cell) antibody	Rituximab	575 mg/m2 , max 1,000 mg, IV on days 1 and 15	SLE	Infusion reactions, lymphopenia, reactivation hepatitis B, rash, serum sickness, arthritis, PML	CBC, BMP; consider monitoring quantitative IgG
Anti-BLyS antibody	Belimumab e	10 mg/kg IV every 2 wk ×3 doses, then every 4 wk	SLE	Infusion reactions, infection, depression
Interleukin (IL)-1 antagonist	Anakinra	1-2 mg/kg/daily Adult max 100 mg	Systemic JIA CAPS	Injection site reactions, infection	CBC
	Canakinumab b	Given SC every 8 wk (CAPS) every 4 wk (systemic JIA): 15-40 kg: 2 mg/kg (up to 3 mg/kg if needed) >40 kg: 150 mg	CAPS Systemic JIA	Injection site reaction, infection, diarrhea, nausea, vertigo, headache
		IV: <30 kg: 10 mg/kg/dose every 4 wk ≥30 kg: 8 mg/kg/dose every 4 wk; maximum dose: 800 mg/dose SC: <30 kg: 162 mg/dose once every 3 wk ≥30 kg: 162 mg/dose once every 2 wk	Polyarticular JIA
IL-6 antagonist	Tocilizumab a	≥2 yr and ≥30 kg: 8 mg/kg/dose every 2 wk ≥2 yr and ≤30 kg: 12 mg/kg/dose every 2 wk	Systemic JIA	Infusion reactions, elevated LFTs, elevated lipids, thrombocytopenia, infections	CBC, LFTs, platelet count, serum lipid profile
Intravenous immune globulin	IVIG c	1,000-2,000 mg/kg IV infusion For JDMS, give monthly	Kawasaki disease JDMS SLE	Infusion reaction, aseptic meningitis, renal failure	Serum creatinine, BUN, IgG level
Cytotoxic	Cyclophosphamide	0.5-1 g/m2 IV (max 1.5 g) monthly for 6 mo induction, then every 2-3 mo Oral regimen: 1-2 mg/kg/daily; max 150 mg/daily	SLE Vasculitis JDMS Pulmonary hemorrhage	Nausea, vomiting, myelosuppression, mucositis, hyponatremia, alopecia, hemorrhagic cystitis, gonadal failure, teratogenesis, secondary malignancy	CBC
Immunosuppressive	Mycophenolate mofetil	Oral suspension: max 1,200 mg/m2 /day PO (up to 2 g/day) divided bid Capsules: max 1,500 mg/day PO for BSA 1.25-1.5 m2 , 2 g/day PO for BSA >1.5 m2 divided bid	SLE Uveitis	GI intolerance (diarrhea, nausea, vomiting), renal impairment, neutropenia, teratogenesis, secondary malignancy, PML	CBC, BMP
Glucocorticoids	Prednisone a , d - f	0.05-2 mg/kg/day PO given in 1-4 divided doses; max varies by individual (80 mg/daily) Adverse effects are dose dependent; lowest effective dose should be used	SLE JDMS Vasculitis JIA Uveitis Sarcoidosis	Cushing syndrome, osteoporosis, increased appetite, weight gain, striae, hypertension, adrenal suppression, hyperglycemia, infection, avascular necrosis	Blood glucose, potassium Blood pressure
	Methylprednisolone a , d - g	0.5-1.7 mg/kg/day or 5-25 mg/m2 /day IM/IV in divided doses every 6-12 hr For severe manifestations: 30 mg/kg/dose (max 1 g) daily for 1-5 days	SLE JDMS Vasculitis Sarcoidosis Localized scleroderma
	Intraarticular	Dose varies by joint and formulation	JIA	Subcutaneous atrophy, skin hypopigmentation, calcification, infection
	Prednisolone ophthalmic suspension	1-2 drops into eye up to every hr while awake Needs monitoring by ophthalmologist	Uveitis	Ocular hypertension, glaucoma, nerve damage, cataract, infection	Ophthalmologic exam

^* Consult a clinical pharmacology reference for current dosing and monitoring guidelines, and complete list of known adverse effects.

^† Therapeutics used in practice may not have a FDA-approved indication. Individual therapeutics annotated with FDA-approved indication as follows: a , JIA; b , CAPS; c , Kawasaki disease; d , sarcoidosis; e , SLE; f , uveitis; g , dermatomyositis.

^‡ Many more products available in this class.

qd, Once daily; bid, twice daily; Blys, B-lymphocyte stimulator; BMP, basic metabolic panel; BSA, body surface area; BUN, blood urea nitrogen; CAPS, cryopyrin-associated periodic syndrome; CBC, complete blood count; CNS, central nervous system; dsDNA, double-stranded DNA; GI, gastrointestinal; IM, intramuscular(ly); IV, intravenous(ly); IVIG, intravenous immune globulin; JDMS, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; PML, progressive multifocal leukoencephalopathy; PO, by mouth; SC, subcutaneous(ly); SLE, systemic lupus erythematosus; TB, tuberculosis.

Nonsteroidal Antiinflammatory Drugs

NSAIDs are prescribed to decrease both the pain and the acute and chronic inflammation associated with arthritis, pleuritis, pericarditis, uveitis, and cutaneous vasculitis, but they are not disease modifying. NSAID antiinflammatory effects require regular administration at adequate doses based on weight (mg/kg) or body surface area (mg/m² ), for longer periods than needed for analgesia alone. The mean time to achieve antiinflammatory effect in JIA is 4-6 wk of consistent administration. NSAIDs work primarily by inhibiting the enzyme cyclooxygenase (COX), which is critical in the production of prostaglandins , a family of substances that promote inflammation. Two types of COX receptors have been demonstrated; selective COX-2 inhibitors such as celecoxib and meloxicam inhibit receptors responsible for promoting inflammation, with potential for fewer gastrointestinal (GI) adverse effects. Clinical trials in children with JIA found that celecoxib and meloxicam were similar in effectiveness and tolerability to the nonselective NSAID naproxen .

The most frequent adverse effects of NSAIDs in children are nausea, decreased appetite, and abdominal pain. Gastritis or ulceration occurs less frequently in children. Less common adverse effects(≤5% of children undergoing long-term NSAID therapy), include mood change, concentration difficulty that can simulate attention deficit disorder, sleepiness, irritability, headache, tinnitus, alopecia, anemia, elevated liver enzyme values, proteinuria, and hematuria. Certain agents (indomethacin) have a higher risk of toxicity than others (ibuprofen); naproxen has an intermediate risk. These NSAID-associated adverse effects reverse quickly once the medication is stopped. Additional rare NSAID-specific adverse reactions may also occur. Aseptic meningitis has been associated with ibuprofen, primarily in patients with lupus. Naproxen is more likely than other NSAIDs to cause a unique skin reaction called pseudoporphyria , which is characterized by small, hypopigmented depressed scars occurring in areas of minor skin trauma, such as fingernail scratches. Pseudoporphyria is more likely to occur in fair-skinned individuals and on sun-exposed areas. If pseudoporphyria develops, the inciting NSAID should be discontinued because scars can persist for years or may be permanent. NSAIDs should be used cautiously in patients with dermatomyositis or systemic vasculitis because of an increased frequency of GI ulceration with these disorders. Salicylates have been supplanted by other NSAIDs because of the relative frequency of salicylate hepatotoxicity and the association with Reye syndrome.

The response to NSAIDs varies greatly among individual patients, but overall, 40–60% of children with JIA experience improvement in their arthritis with NSAID therapy. Patients may try several different NSAIDs for 6 wk trials before finding one that demonstrates clinical benefit. NSAIDs with longer half-lives or sustained-release formulations allow for once- or twice-daily dosing and improve compliance. Laboratory monitoring for toxicity includes a complete blood count (CBC), serum creatinine, liver function tests (LFTs), and urinalysis every 6-12 mo, although guidelines for frequency of testing are not established.

Nonbiologic Disease-Modifying Antirheumatic Drugs

Methotrexate

Methotrexate (MTX), an antimetabolite, is a cornerstone of therapy in pediatric rheumatology because of its sustained effectiveness and relative low toxicity over prolonged periods of treatment. The mechanism of action low-dose MTX in arthritis is complex but is believed to result from the inhibition of folate-dependent processes by MTX polyglutamates, primarily their effect on the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, leading to an increase of extracellular adenosine and consequently, cyclic adenosine monophosphate (cAMP), which inhibits the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β and their downstream effects on lymphocyte activation and proliferation.

MTX has a central role in the treatment of arthritis, especially in children with polyarticular JIA. The response to oral MTX (10 mg/m² once a week) is better than the response to placebo (63% vs 36%). Children who show no response to standard doses of MTX often do show response to higher doses (15 or 30 mg/m² /wk). Subcutaneous (SC) administration of MTX is similar in absorption and pharmacokinetic properties to intramuscular (IM) injection, with less pain. MTX is typically used in treatment of juvenile dermatomyositis as a steroid-sparing agent, with efficacy in 70% of patients. It has also been used successfully at a dosage of 10-20 mg/m² /wk in patients with systemic lupus erythematosus (SLE) to treat arthritis, serositis, and rash.

Because of the lower dose used in treating rheumatic diseases, MTX is well tolerated by children, with toxicity being milder and qualitatively different from that observed with treatment of neoplasms. Adverse effects include elevated liver enzyme values (15%), GI toxicity (13%), stomatitis (3%), headache (1–2%), and leukopenia, interstitial pneumonitis, rash, and alopecia (<1%). Hepatotoxicity observed among adults with rheumatoid arthritis (RA) treated with MTX has raised concern about similar problems in children. Analysis of liver biopsy specimens in children with JIA undergoing long-term MTX treatment has revealed occasional mild fibrosis but no evidence of even moderate liver damage. Children receiving MTX should be counseled to avoid alcohol, smoking, and pregnancy. Folic acid (1 mg daily) is given as an adjunct to minimize adverse effects. Lymphoproliferative disorders have been reported in adults treated with MTX, primarily in association with Epstein-Barr virus (EBV) infection. Regression of lymphoma may follow withdrawal of MTX.

Monitoring laboratory tests for MTX toxicity include CBC and LFTs at regular intervals, initially every 4 wk for the 1st 3 mo of treatment, then every 8-12 wk, with more frequent intervals after dosing adjustments or in response to abnormal values.

Hydroxychloroquine

Hydroxychloroquine sulfate is an antimalarial drug important in the treatment of SLE and dermatomyositis, particularly cutaneous manifestations of disease and to reduce lupus flares. It is not indicated to treat JIA because of lack of efficacy. The most significant potential adverse effect is retinal toxicity, which occurs rarely but results in irreversible color blindness or loss of central vision. Complete ophthalmologic examinations, including assessment of peripheral vision and color fields, are conducted at baseline and every 6-12 mo to screen for retinal toxicity. Retinal toxicity is rare (1/5,000 patients) and is associated with weight-based dosing exceeding 6.5 mg/kg/day; therefore recommended dosing is <6.5 mg/kg/day, not to exceed 400 mg/day. Other potential adverse effects include rash, skin discoloration, gastric irritation, bone marrow suppression, central nervous system (CNS) stimulation, and myositis.

Leflunomide

Leflunomide is a DMARD approved for treatment of RA that offers an alternative to MTX for treatment of JIA. MTX outperformed leflunomide for treatment of JIA in a randomized trial (at 16 wk, 89% of patients receiving MTX achieved a 30% response rate vs 68% of those receiving leflunomide), although both drugs were effective. Dosing is oral, once daily, and weight based: 10 mg for children 10 to <20 kg, 15 mg for children 20-40 kg, and 20 mg for children >40 kg. Adverse reactions include paresthesias and peripheral neuropathy, GI intolerance, elevated liver transaminases and hepatic failure, cytopenias, alopecia, and teratogenesis. Leflunomide has a long half-life, and in cases in which discontinuation of the agent is required, a drug elimination protocol with cholestyramine may be indicated. Avoidance of pregnancy is essential. Laboratory tests (e.g., CBC, LFTs) are monitored every 4 wk for the 1st 6 mo of treatment, then every 8-12 wk.

Sulfasalazine

Sulfasalazine is used to treat children with polyarticular JIA, oligoarticular JIA, and the peripheral arthritis and enthesitis associated with juvenile ankylosing spondylitis . In JIA, sulfasalazine, 50 mg/kg/day (adult maximum: 3,000 mg/day), achieves greater improvement in joint inflammation, global assessment parameters, and laboratory parameters than placebo. More than 30% of sulfasalazine-treated patients withdraw from the treatment because of adverse effects, primarily GI irritation and skin rashes. Sulfasalazine is associated with severe systemic hypersensitivity reactions, including Stevens-Johnson syndrome. Sulfasalazine is generally considered contraindicated in children with active systemic JIA because of increased hypersensitivity reactions. Sulfasalazine should not be used in patients with sulfa or salicylate hypersensitivity or porphyria.

Monitoring laboratory tests for sulfasalazine toxicity include CBC, LFTs, serum creatinine/blood urea nitrogen (BUN), and urinalysis, every other week for the 1st 3 mo of treatment, monthly for 3 mo, every 3 mo for 1 yr, then every 6 mo.

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) is an immunosuppressive drug approved by the FDA for organ transplant rejection. In rheumatology, MMF is used primarily for treatment of lupus, uveitis, and autoimmune skin manifestations. In adult clinical trials, MMF was noninferior to cyclophosphamide for induction therapy of lupus nephritis, with a potential for less adverse effects (infection, gonadal toxicity). Dosing is based on body surface area (BSA): 600 mg/m² orally twice daily, with maximum dosage limits varying by formulation and BSA. The most common adverse reaction is GI intolerance; infections, cytopenias, and secondary malignancies are also reported.

Glucocorticoids

Glucocorticoids are given through oral, intravenous (IV), ocular, topical, and intraarticular administration as part of treatment of rheumatic disease. Oral corticosteroids are foundational treatment for moderate to severe lupus, dermatomyositis, and most forms of vasculitis; their long-term use is associated with many well-described, dose-dependent complications, including linear growth suppression, Cushingoid features, osteoporosis, avascular necrosis, hypertension, impaired glucose tolerance, mood disturbance, and increased infection risk. Glucocorticoids should be tapered to the lowest effective dose over time and DMARDs introduced as steroid-sparing agents.

Intravenous corticosteroids have been used to treat severe, acute manifestations of systemic rheumatic diseases such as SLE, dermatomyositis, and vasculitis. The IV route allows for higher doses to obtain an immediate, profound antiinflammatory effect. Methylprednisolone, 10-30 mg/kg/dose up to a maximum of 1 g, given over 1 hr daily for 1-5 days, is the IV preparation of choice. Although generally associated with fewer adverse effects than oral corticosteroids, IV steroids are associated with significant and occasionally life-threatening toxicities, such as cardiac arrhythmia, acute hypertension, hypotension, hyperglycemia, shock, pancreatitis, and avascular necrosis.

Ocular corticosteroids are prescribed by ophthalmologists as ophthalmologic drops or injections into the soft tissue surrounding the globe (sub–Tenon capsule injection) for active uveitis . Long-term ocular corticosteroid use leads to cataract formation and glaucoma. Current ophthalmologic management has significantly decreased the frequency of blindness as a complication of JIA-associated uveitis.

Intraarticular corticosteroids are being used with increasing frequency as initial therapy for children with oligoarticular JIA or as bridge therapy while awaiting efficacy of a DMARD in polyarticular disease. Most patients have significant clinical improvement within 3 days. Duration of response depends on steroid preparation used, joint affected, and arthritis subtype; the anticipated response rate to knee injection is 60–80% at 6 mo. Intraarticular administration may result in subcutaneous atrophy and hypopigmentation of the skin at the injection site, as well as subcutaneous calcifications along the needle track.

Biologic Agents

Biologic agents are proteins that have been engineered to target and modulate specific components of the immune system, with the goal of decreasing the inflammatory response. Antibodies have been developed to target specific cytokines such as IL-1 and IL-6 or to interfere with specific immune cell function through depletion of B cells or suppression of T-cell activation (Table 179.3 ). The availability of biologic agents has dramatically increased the therapeutic options for treating rheumatic disease recalcitrant to nonbiologic therapies, and in some cases biologics are becoming first-line interventions. A primary concern is the increased risk of malignancy when biologics are combined with other immunosuppressants.

Table 179.3

Method of Action of Biologic Therapies Studied in Juvenile Idiopathic Arthritis

DRUG	METHOD OF ACTION
Etanercept	Soluble TNF p75 receptor fusion protein that binds to and inactivates TNF-α
Infliximab	Chimeric human/mouse monoclonal antibody that binds to soluble TNF-α and its membrane-bound precursor, neutralizing its action
Adalimumab	A humanized IgG1 monoclonal antibody that binds to TNF-α
Abatacept	Soluble, fully human fusion protein of the extracellular domain of (CTLA-4, linked to a modified Fc portion of the human IgG1 . It acts as a co-stimulatory signal inhibitor by binding competitively to CD80 or CD86, where it selectively inhibits T-cell activation
Tocilizumab	A humanized anti–human IL-6 receptor monoclonal antibody
Anakinra	An IL-1 receptor antagonist (IL-1RA)

CTLA, Cytotoxic T lymphocyte–associated antigen; IL, interleukin; TNF, tumor necrosis factor.

From Beresford MW, Baildam EM: New advances in the management of juvenile idiopathic arthritis. Part 2. The era of biologicals, Arch Dis Child Educ Pract Ed 94:151–156, 2009.

Tumor Necrosis Factor-α Antagonists

Two TNF antagonists have an FDA indication for treatment of children with moderate to severe polyarticular JIA (etanercept and adalimumab). Etanercept is a genetically engineered fusion protein consisting of 2 identical chains of the recombinant extracellular TNF receptor monomer fused with the Fc domain of human immunoglobulin G₁ . Etanercept binds both TNF-α and lymphotoxin-α (formerly called TNF-β) and inhibits their activity. Three fourths of children with active polyarticular JIA that fails to respond to MTX demonstrate response to etanercept after 3 mo of therapy. Dosing is 0.8 mg/kg subcutaneously weekly (max 50 mg/dose) or 0.4 mg/kg SC twice weekly (max 25 mg/dose). Adalimumab is a fully human anti-TNF monoclonal antibody (mAb) used alone or in combination with MTX. In a placebo-controlled withdrawal-design study, children continuing to receive adalimumab were less likely to experience disease flares (43% vs. 71%) even if they were also taking MTX (37% vs 65%). Adalimumab is administered subcutaneously every other week at a dose of 10 mg for children weighing 10 to <15 kg, 20 mg for children weighing 15 to <30 kg and 40 mg for those weighing ≥30 kg.

Infliximab, a chimeric mouse-human mAb, was tested in an RCT for use in JIA but did not achieve study end-points. However, it is FDA approved for pediatric inflammatory bowel disease and has been used “off label” for treatment of polyarticular JIA, uveitis, Behçet syndrome, and sarcoidosis. Two additional anti-TNF agents—golimumab , a human mAb against TNF, and certolizumab pegol , a pegylated humanized antibody against TNF—have been approved by the FDA for RA in adults and are currently in pediatric trials.

The most common adverse effects are injection site reactions that diminish over time. TNF blockade is associated with an increased frequency of serious systemic infections, including sepsis, dissemination of latent tuberculosis (TB), and invasive fungal infections in endemic areas. TNF blockade should not be initiated in patients with a history of chronic or frequent recurrent infections. TB testing should be done before initiation of therapy with TNF antagonists. If test results are positive, antitubercular treatment must be administered before anti-TNF treatment can be started. Theoretically, risk of malignancy increases with TNF-α antagonists. Case reports describe the development of lupus-like syndromes, leukocytoclastic vasculitis, interstitial lung disease, demyelinating syndromes, antibody formation to the drug, rashes, cytopenias, anaphylaxis, serum sickness, and other reactions. The benefit/risk profile appears favorable after a decade of experience with this therapeutic class; the safety of longer-term suppression of TNF function is unknown.

Modulator of T-Cell Activation

Abatacept is a selective inhibitor of T-cell co-stimulation resulting in T-cell anergy. It is FDA approved for treatment of moderate to severe polyarticular JIA. In a double-blind withdrawal RCT in children whose disease had not responded to DMARDs, 53% of placebo-treated patients vs 20% of abatacept-treated patients experienced disease flares during the withdrawal period. The frequency of adverse events did not differ between the groups. Abatacept is administered IV every other week for 3 doses (<75 kg: 10 mg/kg/dose; 75-100 kg: 750 mg/dose; >100 kg: 1,000 mg/dose; maximum 1,000 mg/dose at 0, 2, and 4 wk) and then monthly thereafter. Abatacept administered by SC injection was given FDA approval in March 2017 for children ≥4 yr old for treatment of polyarticular JIA, at doses given weekly: 50 mg for 10-25 kg, 87.5 mg for ≥25 to <50 kg, and 125 mg for ≥50 kg.

B-Cell Depletion

Rituximab is a chimeric mAb to the antigen CD20, a transmembrane protein on the surface of B-cell precursors and mature B lymphocytes. This antibody induces B-cell apoptosis and causes depletion of circulating and tissue-based B cells. Antibody production is not completely abrogated because plasma cells are not removed. Rituximab is licensed for treatment of B-cell non-Hodgkin lymphoma and is FDA approved for use in adult RA and idiopathic thrombocytopenic purpura but does not have a pediatric indication. Rituximab may also have a role in treatment of SLE, particularly its hematologic manifestations. Adverse events include serious infusion reactions, cytopenias, hepatitis B virus reactivation, hypogammaglobulinemia, infections, serum sickness, vasculitis, and a rare but fatal side effect, progressive multifocal leukoencephalopathy . Resistance to rituximab may develop over time in patients being treated for lymphoma.

Belimumab is a human mAb to B-lymphocyte stimulator that negatively affects B-cell proliferation, differentiation, and long-term survival. It is approved for treatment of SLE in adults, and studies of long-term safety and efficacy are ongoing. Belimumab is not FDA approved for use in pediatric SLE.

Interleukin-1 Antagonists

Anakinra, a recombinant form of the human IL-1 receptor antagonist, competitively inhibits binding of IL-1α and IL-1β to the natural receptor, interrupting the cytokine proinflammatory cascade. Anakinra has been approved for RA in adults. In meta-analyses of treatments for RA, anakinra was outperformed by TNF-α antagonists but has a special niche in pediatric rheumatology for treatment of systemic JIA (sJIA) and other autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome (CAPS) . The medication is dosed SC, 1-2 mg/kg, once daily. An IL-1β mAb, canakinumab, is FDA approved for use in CAPS, dosed SC every 8 wk, and sJIA, dosed SC every 4 wk. Adverse reactions include significant injection site reactions and increased bacterial infections.

Interleukin-6 Receptor Antagonist

Tocilizumab is an anti–IL-6 receptor antibody binding to both soluble as well as membrane-associated receptors. Tocilizumab has FDA approval for treatment of sJIA and polyarticular JIA. Adverse reactions include transaminase and lipid elevations. Tocilizumab is given as an IV infusion every 2 wk (sJIA) to 4 wk (polyarticular JIA), and SC for polyarticular JIA 162 mg every 3 wk for those <30 kg and every 2 wk for ≥30 kg.

Intravenous Immune Globulin

IVIG is thought to be beneficial in various clinical conditions. IVIG significantly improves the short- and long-term natural history of Kawasaki disease . Open studies have supported benefit for juvenile dermatomyositis, lupus-associated thrombocytopenia, and polyarticular JIA. IVIG is given as 1-2 g/kg/dose, administered once monthly. It has been occasionally associated with severe, systemic allergy–like reactions and postinfusion aseptic meningitis (headache, stiff neck).

Cytotoxics

Cyclophosphamide

Cyclophosphamide requires metabolic conversion in the liver to its active metabolites, which alkylate the guanine in DNA, leading to immunosuppression by inhibition of the S2 phase of mitosis. The subsequent decrease in numbers of T and B lymphocytes results in diminished humoral and cellular immune responses. Cyclophosphamide infusions (500-1,000 mg/m² ) given monthly for 6 mo, then every 3 mo for 12-18 mo, have been shown to reduce the frequency of renal failure in patients with lupus and diffuse proliferative glomerulonephritis. Open trials suggest efficacy in severe CNS lupus. Oral cyclophosphamide (1-2 mg/kg/day) is effective as induction treatment of severe antineutrophilic cytoplasmic antibody (ANCA)–associated vasculitis and other forms of systemic vasculitis, as well as interstitial lung disease or pulmonary hemorrhage associated with rheumatic disease.

Cyclophosphamide is a potent cytotoxic drug associated with significant toxicities. Potential short-term adverse effects include nausea, vomiting, anorexia, alopecia, mucositis, hemorrhagic cystitis, and bone marrow suppression. Long-term complications include an increased risk for sterility and cancer, especially leukemia, lymphoma, and bladder cancer. In adult women with lupus treated with IV cyclophosphamide, 30–40% become infertile; the risk of ovarian failure appears to be significantly lower in adolescent and premenarchal girls. Ovarian suppression with an inhibitor of gonadotropin-releasing hormone to preserve fertility is currently being studied.

Other Drugs

Azathioprine is sometimes used to treat ANCA-associated vasculitis following induction therapy or to treat SLE. Cyclosporine has been used occasionally in the treatment of dermatomyositis on the basis of uncontrolled studies and is helpful in the treatment of macrophage activation syndrome complicating sJIA (see Chapter 155 ). Case reports describe the successful use of thalidomide , or its analog lenalidomide, as treatment for sJIA, inflammatory skin disorders, and Behçet disease.

Several drugs commonly used in the past to treat arthritis are no longer part of standard treatment, including salicylates, gold compounds, and D -penicillamine.

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