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Treatment of Rheumatic Diseases
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:
|
|
Social worker:
|
|
| Physical medicine and rehabilitation | Physical therapy:
|
Occupational therapy:
|
|
| Consultant team | Ophthalmology:
|
| Nephrology | |
| Orthopedics | |
| Dermatology | |
| Gastroenterology | |
| Physical and psychosocial growth and development | Nutrition:
|
School integration:
|
|
| 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 |
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| Naproxen a | 15 mg/kg/day PO in 2 divided doses Max 1,000 mg/day |
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| Celecoxib a | 10-25 kg: 50 mg PO bid >25 kg: 100 mg PO bid |
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| Meloxicam a | 0.125 mg/kg PO qd Max 7.5 mg |
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| Disease-modifying antirheumatic drugs (DMARDs) | Methotrexate a | 10-20 mg/m 2 /wk (0.35-0.65 mg/kg/wk) PO 20-30 mg/m 2 /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 |
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| Anti-CD20 (B-cell) antibody | Rituximab | 575 mg/m 2 , 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/m 2 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/m 2 /day PO (up to 2 g/day) divided bid Capsules: max 1,500 mg/day PO for BSA 1.25-1.5 m 2 , 2 g/day PO for BSA >1.5 m 2 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/m 2 /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 |
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| 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 |
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.
* 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: , JIA; , CAPS; , Kawasaki disease; , sarcoidosis; , SLE; , uveitis; , dermatomyositis.
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/m 2 ), 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/m 2 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/m 2 /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/m 2 /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.
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