Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Therapeutics: Nonbiologics
The principal drugs used in pediatric rheumatology are drugs that suppress the inflammatory and immune responses. This chapter outlines important general principles relating to the nonbiological therapies, particularly as they apply to children. The treatment of specific rheumatic disorders is discussed in detail in the relevant chapters.
Concepts in Pharmacology
Optimizing the efficacy and safety of medications used to treat rheumatic disorders in children requires an understanding of the multiple factors involved in drug disposition and response. These include the processes of drug absorption, distribution, metabolism, and excretion (ADME) that characterize the movement of the drug within the body as a function of time (i.e., pharmacokinetics), as well as the multiple factors that contribute to the effect of the drug on the body (i.e., pharmacodynamics). Simplistically, pharmacokinetics describes what the body does to a drug, whereas pharmacodynamics represents what a drug does to the body. Adding to the complexity of drug disposition and response in children is the impact of growth and development (i.e., ontogeny) on the expression of drug metabolizing enzymes, transporters, receptors, and other proteins along the developmental continuum between birth and maturity. There has been considerable interest in the role of genetic variation (i.e., pharmacogenetics) as a determinant of interindividual variability in the clinical response to medications widely used in pediatric rheumatology. The following section provides a brief overview of the general principles of drug disposition and response and can be supplemented by referring to additional general pediatric texts.
Drug Absorption and Bioavailability
Drugs that are given by the oral route are absorbed through the mucosa of the gastrointestinal (GI) tract, primarily in the small intestine. Drug absorption across the GI tract may be influenced by numerous factors, including the presence or absence of food in the gastric lumen, luminal pH, gastric emptying time, coadministration of other drugs, and intestinal expression of drug transport proteins and drug metabolizing enzymes. Similarly, systemic absorption of drugs administered by routes other than direct intravenous (IV) administration (e.g., subcutaneous or intramuscular) are dependent on similar factors affecting drug dissolution and permeability at the site of administration, including hydration, vascularization, and pH. Drug bioavailability is commonly expressed as a percentage and represents the fractional cumulative exposure of the drug compared with when the drug is administered intravenously.
Several physiological processes that contribute to drug absorption undergo changes as children grow and develop. For example, gastric pH is relatively alkaline in neonates, and maturation to adult levels reflects the ontogeny of parietal cells and is not achieved until 3 years of age or older. As a consequence, the bioavailability of acid-labile drugs is increased and that of weakly acidic drugs is less than expected over this time period. , Other factors, such as gastric emptying time, intestinal motility, and intestinal surface area, are also important determinants of drug absorption and all mature over the first year of life.
Volume of Distribution
The volume of distribution is a theoretical volume that represents the volume of fluid into which a drug would need to be distributed to achieve a concentration equal to the concentration ultimately measured in plasma. If the drug stays in the plasma, its volume of distribution is essentially the plasma volume, which is considerably smaller than if the drug is distributed widely in tissues. Body composition changes dramatically between birth and adolescence. Water constitutes approximately 80% of total body mass in newborns and declines to the adult value of 60% within the first year of life. Body fat is approximately 16% in neonates and increases over the first year of life but also changes compositionally with age. The consequence of these changes is an increase in the volume of distribution of hydrophilic drugs and potential age-dependent changes in the volume of distribution of drugs that distribute into body fat and tissues.
Drugs in the body are either free or bound to plasma proteins or tissue lipids. The extent and nature of binding affects the volume of distribution of the drug, the rate of clearance (because only free drug is filtered by the glomerulus and/or metabolized by the liver), and the amount of free drug that reaches the target tissue or receptor. Most acidic drugs are bound to plasma albumin, whereas basic drugs are bound to lipoproteins, α 1 -acid glycoproteins, and globulins. In inflammatory states, plasma albumin concentration decreases and α 1 -acid glycoproteins increase.
Half-Life and Clearance
The half-life of a drug is the time necessary for the serum concentration to decrease by 50% during the elimination phase of the concentration-time curve. Clearance is the term used to describe the disappearance of a drug from the systemic circulation and is defined as the volume of body fluid, based on the apparent volume of distribution of the drug, from which a drug is removed per unit of time. Most drugs exhibit first-order kinetics whereby the rate of elimination is directly proportional to the concentration in the body. Drugs that are eliminated at a constant rate, independent of concentration, are said to follow zero-order kinetics. Drug clearance determines the relationship between dose administered and concentration achieved, and, in general, this relationship is best interpreted after at least five half-lives have passed and steady state has been achieved. Changes in renal and hepatic function can significantly impact drug elimination and are commonly associated with age and comorbidities; thus monitoring of drug levels and attention to the potential for drug toxicity become more critical in patients with significant renal or hepatic dysfunction.
Drug Biotransformation
The process of drug biotransformation is classified into phase I and phase II reactions, which commonly occur sequentially and, in most situations, serve to terminate biological activity, enhance aqueous solubility, and enhance elimination. Some drugs used to treat rheumatic diseases, such as sulindac, prednisone, leflunomide, azathioprine, mycophenolate mofetil (MMF), and cyclophosphamide, require biotransformation to their therapeutically active forms before they exert their principal effects. Phase I biotransformations are most commonly performed by a family of enzymes highly expressed in the liver known as cytochrome P450 (CYPs) that have broad substrate specificity and are responsible for metabolism of over 70% of drugs used in humans. Subsequent to initial chemical modification by phase I enzymes, many drugs will undergo a second conjugation reaction through which a polar compound is conjugated to the drug resulting in a more hydrophilic molecule that is then excreted in the urine or the bile.
Changes related to ontogeny are critical to understanding the role of drug biotransformation in drug clearance from birth to adolescence. Most proteins involved in drug biotransformation and transport are subject to genetic polymorphisms that also can contribute to interindividual variability in drug disposition. In pediatrics, ontogeny factors into the interpretation of pharmacogenetic information as genotype–phenotype associations observed in adults will not occur in children until the gene is fully expressed.
Precision Medicine and Individualized Drug Therapy
Precision medicine represents the goal of getting the right drug to the right patient at the right dose, and at the right time to maximize drug efficacy and minimize drug-related toxicities and ultimately improve patient outcomes. Omics-based technologies that were ushered in through the completion of the human genome project have enabled major advances that are expected to allow the rapid advancement and translation of these technologies to improve patient care. At this point in time the clinical applications of these tools remain in their infancy, especially within the pediatric rheumatology patient population, but examples such as pretreatment genotyping and phenotyping of thiopurine S-methyltransferase (TPMT) to individualize azathioprine dosing and prevent serious drug-related toxicity (i.e., myelosuppression) demonstrate what the future may have in store.
Antirheumatic Drugs
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) provide symptomatic antiinflammatory relief. NSAIDs that are commonly used in children are presented in eTable 13.1 .
Mechanism of Action
NSAIDs inhibit proinflammatory pathways that lead to inflammation. The major antiinflammatory effect of NSAIDs is mediated by inhibition of the cyclooxygenase (COX) enzyme in the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins.
There are two related but unique isoforms of the COX enzyme: COX-1 and COX-2. These isoforms are 60% identical in sequence and encoded by distinct genes; they differ in their distribution and expression in tissues. COX enzymes catalyze the conversion of arachidonic acid to prostaglandins G 2 and H 2 . COX-1 enzyme production is constitutively expressed in most tissues and provides prostaglandins that are required for “housekeeping” or homeostatic function, resulting in cytoprotection, platelet aggregation, vascular homeostasis, and maintenance of renal blood flow. In contrast, COX-2 is an inducible enzyme that is upregulated at sites of inflammation by various proinflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor (TNF), bacterial endotoxins, and various mitogenic and growth factors.
Currently available NSAIDs inhibit both isoforms of COX, but most inhibit COX-1 preferentially, resulting in undesirable adverse effects such as GI toxicity while producing desirable antiinflammatory effects through concurrent inhibition of COX-2. An NSAID’s degree of inhibition of COX-2, compared with COX-1, correlates with its adverse-effect profiles. Celecoxib is the only selective COX-2 inhibitor approved by the U.S. Food and Drug Administration (FDA) for use in juvenile idiopathic arthritis (JIA).
Pharmacology
The pharmacokinetic evaluation of NSAIDs in children with JIA has been variable, ranging from extensive for salicylates to minimal or none with newer agents; the interested reader is referred to reviews on the subject. , They are weakly acidic drugs that are rapidly absorbed after oral administration, with most absorption occurring in the stomach and upper small intestine.
Most NSAIDs are strongly protein bound, primarily to albumin, leading to a potential for drug–disease and drug–drug interactions, although significant clinical interactions are rare. , NSAIDs may potentially interact with methotrexate (MTX) through displacement from plasma protein-binding sites, competition for renal secretion, and impairment of renal function. However, MTX–NSAID interactions are rarely of clinical significance and do not deter coadministration in routine clinical care. Hypoalbuminemia may be one of the most important factors influencing the pharmacokinetics of NSAIDs in children, by allowing an increase in the unbound fraction of drug, which increases the potential for toxicity.
NSAIDs are eliminated predominantly by hepatic metabolism. Some NSAIDs, such as sulindac or indomethacin, are also secreted in significant amounts in bile and undergo enterohepatic recirculation. Most NSAIDs are metabolized by first-order or linear kinetics, whereas acetylsalicylic acid (ASA) is metabolized by zero-order or nonlinear kinetics. For this reason, dosage adjustments are frequently required with ASA therapy, and small changes in dose may lead to large fluctuations in serum levels of ASA at the higher end of the therapeutic range.
General Principles of Nonsteroidal Antiinflammatory Drug Therapy
NSAIDs are generally good analgesic and antipyretic agents and weak antiinflammatory agents. The analgesic effect of NSAIDs is rapid, but the antiinflammatory effect takes longer and can require doses twice as large as those needed for analgesia. , NSAIDs provide good symptomatic relief but have traditionally not been considered to influence the underlying disease process. However, there is a suggestion that NSAIDs can change the course of ankylosing spondylitis (AS) by preventing syndesmophyte formation. The biological basis is hypothesized to be a result of the inhibition of prostaglandins, which have an effect on osteoblast formation and osteoclast differentiation factor and may have a genetic link with AS through PTGER 4. In further studies, new bone formation has been slowed in patients on higher continuous doses of NSAIDs and with higher inflammatory states. , Formal recommendations for the treatment of AS have endorsed a short trial of NSAIDs as first-line therapy before escalation to TNF-inhibitor therapy. Patients who receive long-term daily NSAID therapy should have a complete blood count and liver and renal function tests, including a urinalysis, performed at baseline and every 6 to 12 months.
Safety/Toxicity
Serious toxicity associated with the use of NSAIDs is rare in children, and generally, most toxicities are shared to a greater or lesser degree by all NSAIDs.
Cardiovascular toxicity
Data from several clinical trials and observational studies in adults have suggested that there is an increased risk of cardiovascular toxicity associated with several NSAIDs and COX-2 inhibitors. Cardiovascular toxicity led to the withdrawal of rofecoxib and valdecoxib from the market and also resulted in more restricted, similar product labels in the United States for celecoxib and traditional NSAIDs. This risk has been shown to be variable by NSAID , and higher in the first month of use, with higher drug doses and in patients who had previous cardiovascular disease or risk factors for cardiovascular events. Meaningful data in children are scarce; however, cardiovascular risk factors in children remain low compared with adults.
Gastrointestinal toxicity
GI toxicity is common to all NSAIDs. The pathogenesis of gastroduodenal mucosal injury involves multiple mechanisms, and symptoms range from mild epigastric discomfort to symptomatic or asymptomatic peptic ulceration.
Studies in children confirm that although mild GI disturbances are frequently associated with NSAID therapy, the number of children who develop clinically significant gastropathy is low, but tolmetin, ketoprofen, and piroxicam exhibit the highest risk. , The phase IV safety registry of celecoxib and nonselective NSAIDs revealed no evidence of GI ulcer and one report of gastritis in the nonselective NSAID group.
GI symptoms can be minimized by ensuring that NSAIDs are always given with food. The use of antacids and histamine 2 -receptor antagonists for prophylaxis against serious NSAID-induced GI complications is not recommended because of lack of evidence for the prevention of endoscopically documented gastric ulcers. , Misoprostol, a synthetic prostaglandin E 1 analog, has been shown in adults to be effective in prophylaxis, and studies of misoprostol cotherapy in children also suggest that misoprostol may be effective in the treatment of GI toxicity symptoms in children receiving NSAIDs. , Omeprazole, a proton pump inhibitor, has been shown to be superior to ranitidine and misoprostol for the prevention and treatment of NSAID-related gastroduodenal ulcers in adults.
Hepatitis with elevation of transaminase levels can occur with any NSAID. , NSAIDs have been associated with macrophage activation syndrome (MAS). , Thus liver function should be monitored in children taking daily NSAIDs for extended periods, particularly children with systemic JIA.
Cutaneous toxicity
A diverse group of skin reactions, including pruritus, urticaria, morbilliform rashes, erythema multiforme, and phototoxic reactions, have been described. , The syndrome of pseudoporphyria that occurs in association with naproxen therapy in children with juvenile rheumatoid arthritis (JRA) is a distinctive photodermatitis marked by erythema, vesiculation, and increased skin fragility characterized by easy scarring of sun-exposed skin ( Fig. 13.1 ). Naproxen is the most commonly reported NSAID to trigger this phenomenon, but other classes of NSAIDs have been reported , in addition to a variety of other medications. In spite of the name, porphyrin metabolism is normal. All findings except scarring resolve with discontinuation of naproxen, but the vesiculation may persist for several months and even years. , Children with fair skin and blue eyes are particularly susceptible.
Miscellaneous toxicities
Several types of renal complications have been associated with NSAID therapy, including reversible renal insufficiency and acute renal failure; acute interstitial nephritis; nephrotic syndrome; papillary necrosis; and sodium, potassium, and water retention, but renal toxicity is rare in children, specifically reported in less than 1% in two prospective JRA cohorts. Central nervous system (CNS) side effects have been reported in adults to include the following: (1) aseptic meningitis, (2) psychosis, and (3) cognitive dysfunction. The NSAID most commonly reported to cause aseptic meningitis has been ibuprofen. Indomethacin and sulindac have been reported to induce psychotic symptoms. More subtle CNS effects, such as cognitive dysfunction, depression, and headaches, can also occur. Tinnitus may occur with any NSAID, but particularly with ASA. NSAIDs decrease platelet adhesiveness by interfering with platelet prostaglandin synthesis, and ASA irreversibly acetylates and inactivates COX, an effect that persists for the life of the platelet. The precipitation of asthma or anaphylaxis with NSAIDs has been reported in adults as a unique syndrome associated with nasal polyps, , most commonly reported with ASA or tolmetin.
Salicylates
ASA is the oldest NSAID and continues to have a primary role in the management of Kawasaki disease (see eTable 13.1 ).The general principles of NSAID mechanisms of action, pharmacology, principles of therapy, and the spectrum of known adverse effects have already been addressed with reference to salicylates where relevant. FLOAT NOT FOUND
eTable 13.1
Nonsteroidal Antiinflammatory Drugs (NSAIDS) Commonly Used in Children
| Drug | Dosage (mg/kg/day unless otherwise noted) | Max Dose (mg/day) | Doses Per Day | Comments |
|---|---|---|---|---|
| Salicylates | ||||
| Acetylsalicylic acid (ASA) | Antiinflammatory dose: 80–100 (<25 kg); 2500 mg/m 2 (>25 kg) Antiplatelet dose: 5 |
4900 | 2–4 | Kawasaki disease: high dose for initial and low dose for subsequent treatment |
| Therapeutic serum levels (for antiinflammatory therapy): 16–25 mg/dL (measure 5 days after initiation of therapy or dose alteration, watch for salicylism, Reye syndrome) | ||||
| Propionic Acid Group | ||||
| Naproxyn ∗ | 10–20 | 1000 | 2 | Overall favorable toxicity/efficacy (T/E) profile |
| Pseudoporphyria in fair-skinned children (see text) | ||||
| Ibuprofen ∗ | 30–40 | 2400 | 3–4 | Most favorable T/E profile |
| Association with aseptic meningitis in SLE patients | ||||
| Ketoprofen | 2–4 | 300 | 3–4 | Least favorable T/E profile |
| Fenoprofen | 35 | 3200 | 4 | Risk of nephrotoxicity |
| Oxaprozin | 10–20 | 1200 | 1 | Available only in 600 mg tablets |
| Acetic Acid Derivatives | ||||
| Indomethacin ∗ | 1.5–3 | 150 | 3 | Useful in spondyloarthropathies and treatment of fever or serositis in sJIA |
| Less favorable T/E profile | ||||
| Tolmentin | 20–30 | 1800 | 3–4 | Least favorable T/E profile |
| May cause false-positive result for urinary protein | ||||
| Sulindac | 4–6 | 400 | 2 | Absorbed as a prodrug and converted to active metabolite |
| Significant enterohepatic recirculation | ||||
| May be less nephrotoxic | ||||
| Diclofenac | 2–3 | 150 | 3 | Similar potency to indomethacin |
| Reports of hepatotoxicity | ||||
| Etodolac | 10–20 | 1000 | 1 | Extended release tabs in 400-, 500-, 600-mg doses |
| Oxicams | ||||
| Meloxicam ∗ | 0.25 | 15 | 1 | Once daily dosing |
| Piroxicam | 0.2–0.3 | 20 | 1 | Least favorable T/E profile |
| Less experience in young children | ||||
| Nabumetone | 30 | 2000 | 1 | Tablets can be mixed in water to create a slurry |
| Pyrazole Derivative | ||||
| Celecoxib | 100 mg/day (50 mg twice a day) (>2 years old, 10–25 kg) 200 mg/day (100 mg twice a day) (>2 years old, 25–50 kg) |
200 | 2 | Use lowest effective dose, shortest effective treatment |
| Capsules can be opened and sprinkled on applesauce | ||||
LFT, Liver function test; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus.
Pharmacology
The plasma level of salicylate (ASA and salicylate ion) peaks 1 to 2 hours after a single dose, and the drug is virtually undetectable at 6 hours. ASA itself is bound very little to plasma protein, but salicylic acid binds extensively to albumin and erythrocytes, is found in most body fluids, and crosses the placenta. ASA is quickly absorbed from the stomach and proximal small intestine. , The systemic antiinflammatory effects of ASA are maximal if serum steady-state levels are 15 to 25 mg/dL (1.09 to 1.81 mmol/L). , Levels greater than 30 mg/dL (2.17 mmol/L) are likely to be toxic. The dosage necessary to reach these concentrations is the dose used to treat the early acute febrile phase of Kawasaki disease (75 to 90 mg/kg/day divided into four doses). However, this high-dose regimen is only continued until fever is absent for 24 to 48 hours, then a low dose is initiated (3 to 5 mg/kg/day) for antiplatelet effects. If prolonged high-dose ASA is required, serum salicylate and serum liver enzyme levels should be checked 5 days after initiation of therapy or after any dose adjustment.
Salicylism
Symptoms of salicylism include tinnitus, deafness, nausea, and vomiting. Early on, there is CNS stimulation (hyperkinetic agitation, excitement, maniacal behavior, slurred speech, disorientation, delirium, convulsions). Later, CNS depression (stupor and coma) supervenes. There is a narrow margin between therapeutic and toxic levels. , In Kawasaki disease, hypoalbuminemia may predispose children to salicylate toxicity as a result of increased free levels of drug. The reader is referred to the recommendations of Mofenson and Caraccio for details of the management of severe salicylate poisoning.
Disease-Modifying Antirheumatic Drugs
Numerous drugs used to treat JIA and other rheumatic diseases exert their beneficial effects weeks to months after initiation of therapy. These compounds, termed disease-modifying antirheumatic drugs (DMARDs) , changed the landscape of treatment for JIA and are now often used first line and in conjunction with biological therapies for the treatment of JIA. ,
Methotrexate
Low-dose weekly MTX has emerged as one of the most useful agents in the treatment of rheumatic diseases in children, and it has become in many cases a first-line agent. It is also used in many other chronic inflammatory disorders.
Mechanism of action
MTX is a folic acid analog and a potent competitive inhibitor of several enzymes in the folate pathway ( Fig. 13.2 ). Intracellularly, MTX is bioactivated to a polyglutamated (MTXGlu n ) form, which enhances both the pharmacological activity at the target enzymes and intracellular retention of MTX. Known intracellular targets of MTX include dihydrofolate reductase (DHFR), thymidylate synthetase (TYMS) targeted directly and indirectly via depletion of tetrahydrofolate formation through DHFR inhibition, and aminoimidazole carboxamide ribonucleotide (AICAR) transformylase (gene name ATIC ), which inhibits de novo purine synthesis and promotes the accumulation of extracellular adenosine. Adenosine accumulation is thought to be a contributor to the site-specific antiinflammatory effects of MTX through inhibition of neutrophil adherence. The downstream inhibition of purine and pyrimidine synthesis and the subsequent impact upon DNA synthesis, repair, and replication is thought to interfere with actively proliferating tissues, such as malignant cells.
MTX also modulates the function of many of the cells involved in inflammation and affects the production of various cytokines, including the reduction of TNF, interferon-γ (IFN-γ), IL-1, IL-6, and IL-8 production, thereby acting as a potent inhibitor of cell-mediated immunity. , By reducing the expression of adhesion molecules on endothelial cells, MTX may reduce the permeability of the vascular endothelium. , MTX may also have more direct effects in inflamed joints by inhibiting the proliferation of synovial cells and synovial collagenase gene expression, and there is evidence of inhibition of the effects of mitogens upon cell cycle regulators in fibroblast-like synoviocytes in rheumatoid arthritis (RA).
Pharmacology
There is significant intraindividual and interindividual variability in the absorption and pharmacokinetics of MTX after oral administration. On average, oral bioavailability is about 0.70 (compared with IV dosing) and highly variable, ranging from 0.25 to 1.49, with 25% of subjects in one study absorbing less than half their dose. The pharmacokinetics of oral MTX in JIA seem to be age dependent, with more extensive metabolism of MTX in younger children. This difference may account for the observation that children require relatively higher doses of MTX than adults to obtain similar therapeutic effects. , Oral bioavailability is generally about 15% less than after intramuscular or subcutaneous administration, and oral absorption is greater in the fasting state and is saturable.
After a single dose of MTX, the drug is present in the circulation for a short period before it is redistributed to the tissues ( Fig. 13.3 ). Peak serum levels are reached in approximately 1.5 hours (range 0.25 to 6 hours), with elimination half-life being approximately 7 hours in subjects with normal renal function. The predominant route of elimination is renal. A smaller but significant route of elimination is the biliary tract. The pharmacokinetics of MTX are triphasic. The initial rapid phase represents tissue distribution and renal clearance; the second phase is prolonged, slow release from tissues, tubular reabsorption, and enterohepatic recirculation; the third phase is flat, reflecting the gradual release of tissue MTX.
Plasma drug levels are cleared rapidly from the serum and do not correlate well with clinical effects, and thus are not useful in routine monitoring of MTX therapy. Attention has turned to measurement of intracellular concentrations of the therapeutically active polyglutamated forms of MTX (MTXGlu n ) as more stable and reliable biomarkers of the effect of MTX. , , Higher concentrations of MTXGlu n have been shown to correlate with drug efficacy in patients with RA and JIA.
At low doses, MTX is only moderately protein bound (11% to 57%), so the potential for interactions with other protein-bound drugs is small and usually not clinically significant, except in patients with renal impairment. , , The combination of MTX and trimethoprim-sulfamethoxazole should be avoided because it may lead to hematological toxicity through synergistic effects of these drugs on dihydrofolate reductase.
The effect of genetic variation within the folate pathway upon drug response has been a focus in adult RA, , and this work has expanded to children as well. Many genetic associations in adults and children have lacked reproducibility, due in part to relatively small study sample sizes and variability in the defined clinical response phenotypes between studies. However, with continued attempts to achieve precision medicine, efforts to assess genetic predictors of drug response continue. In children, clinical outcomes have been shown to be associated with genetic variation in the folate pathway in genes involved in purine synthesis, , cellular transport of MTX and folate, and MTX excretion, all with a plausible physiological rationale for their effect. However, broader genome-wide approaches have also aimed to study an unbiased survey of the genome and have found novel pathways associated with MTX effect in both JIA and RA. Gene expression profiling has also been explored and showed a difference in gene transcripts in monocytes of MTX nonresponders. Pharmacodynamic associations are also being explored for clues to mechanistic effects of MTX. For example, a decrease in erythrocyte inosine triphosphate pyrophosphatase (ITPA) enzyme activity has been associated with poor response to MTX, and increased nicotinamide phosphoribosyltransferase (NAMPT) expression has been shown to attenuate MTX response in vitro and in patients.
Efficacy
There have been various attempts at identifying clinical predictors of response to MTX in children with JIA, with regards to the specific JIA subtype. There are data to support MTX as an effective therapy in extended oligoarticular JIA more than several other JIA subtypes, but overall it is used extensively in JIA when assessed through worldwide registries. The utilization of MTX differs by subtype in clinical practice, as reflected in data derived from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, where RF+ polyarticular (91%) or extended oligoarticular JIA patients (89%) were most likely to receive MTX compared with other subtypes. American College of Rheumatology (ACR) recommendations for treatment of JIA utilize a “step-up”/escalation approach in some JIA subtypes. However, in patients with high disease activity or poor prognostic features, MTX is recommended to be used as first-line therapy with or without a biological agent in addition. , , This recommendation was reinforced globally by the Methotrexate Advice and RecommendAtions on Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting held by the Italian Pediatric Rheumatology Study Group. In systemic JIA, MTX is recommended only for the treatment of mild or moderate arthritis in systemic JIA rather than for the treatment of systemic features or MAS. , Studies such as TREAT and BeSt for Kids have shown that combination MTX+TNF inhibition for first-line treatment of polyarthritis results in a higher percentage of subjects achieving a rapid optimal clinical response (ACR Pediatric 70 at approximately 3 months) compared with MTX alone; however, in both studies, there remained a subset of patients on MTX alone who achieved these same outcomes. Therefore in the future, identification of which patients require combination therapy with MTX and a biological therapy at the onset of treatment will be important to judiciously personalize therapy in JIA.
MTX is also used in many other rheumatic disorders, including systemic lupus erythematosus (SLE), some vasculitides, , sarcoidosis, systemic sclerosis, localized scleroderma, and uveitis. ,
Dosage, route of administration, and duration of methotrexate therapy
Standard effective dosing regimens of MTX in children with JIA are 10 to 15 mg/m 2 /week or 0.3 to 0.6 mg/kg/week ( Table 13.2 ). Improvement is generally seen by about 6 to 8 weeks on effective doses, but it may take up to 6 months to see the full effect. Children seem to tolerate much higher doses than adults, and some series have described using 20 to 25 mg/m 2 /week or 1.1 mg/kg/week in children with resistant disease, with relative safety in the short term. Early reports supporting the efficacy of higher dosing regimens (25 to 30 mg/m 2 /week) for JIA have been followed with studies that do not support additional gains with higher doses. , However, higher dosages of MTX (1 mg/kg/dose up to 40 mg weekly) have been used in other disease processes, such as juvenile dermatomyositis and juvenile localized scleroderma. ,
Table 13.2
Dosage and Monitoring of Commonly Use Disease-Modifying Antirheumatic Drugs (DMARDs)
| DMARD | Dosage and Route | Clinical Monitoring | Laboratory Monitoring |
|---|---|---|---|
| Hydroxychloroquine | ≤5 mg/kg/day to a maximum of 400 mg/day, oral | Baseline ophthalmological exam and yearly screening for subjective (e.g., visual field) and objective (e.g., SD-OCT) testing | None |
| Methotrexate | 10–15 mg/m 2 , once weekly, oral (preferably on empty stomach) or subcutaneous Administer with folic acid or folinic acid (see text) |
Improvement seen in 6–12 weeks Initial evaluation in 2–4 weeks, then monitor every 3–6 months |
CBC with WBC count, differential and platelets; MCV; AST, ALT, creatinine, albumin, (+/− urine pregnancy screening, if appropriate) baseline and in 4–8 weeks initially and with dose adjustments, then every 12 weeks once clinically stable |
| Sulfasalazine | Initial: 10–15 mg/kg/day (max 500 mg) in two to three divided doses, oral Increase over course of 4 weeks to 30–50 mg/kg/day in two divided doses (maximum dose 2 g/day) |
Improvement seen in 4–8 weeks Initial evaluation in 2–4 weeks, then every 2–4 months Discontinue if rash appears |
CBC with WBC count, differential and platelets; AST, ALT, creatinine, UA, (consider testing for G6PD deficiency), baseline and every 1–2 weeks with dose increases, then every 3 months while on maintenance doses Follow immunoglobulins every 6 months |
| Leflunomide | <20 kg: 10 mg every other day 20–40 kg: 10 mg daily >40 kg: 20 mg daily, oral |
Improvement seen in 6–12 weeks Initial evaluation in 2–4 weeks then every 3–6 months |
CBC with WBC count, differential and platelets; AST, ALT, creatinine (+/− urine pregnancy screening, if appropriate) baseline and in 2–4 weeks with dose adjustments, then every 3 months while on maintenance doses |
ALT , Alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; MCV, mean corpuscular volume; SD-OCT, spectral domain optical coherence tomography; UA, urinalysis; WBC, white blood cell count.
Many pediatric rheumatologists advocate using parenteral MTX at initiation of treatment to ensure complete absorption and increased bioavailability to achieve early disease remission , , ; the 2011 ACR recommendation for treatment of JIA assumes MTX dosing to be 15 mg/m 2 /week administered via the parenteral route. However, there remains variability in clinical practice, , and reported rates of ACR Pediatric 30, 50, and 70 response, as well as toxicity, are similar between routes of MTX administration. There is general agreement that parenteral MTX administration should be considered in children who (1) have a poor clinical response to orally administered MTX (this may be the result of poor compliance or to reduced oral bioavailability for various reasons); (2) need dosages greater than about 10 to 15 mg/m 2 /week to achieve maximum clinical response (oral MTX absorption is a saturable process, whereas subcutaneous administration is not) , ; or (3) develop significant GI toxicity with orally administered MTX. ,
The approach to when, how, and by what criteria to consider withdrawing MTX therapy in JIA remains unclear. , , MTX withdrawal may result in disease flare in more than 50% of patients; this rate may be even higher in younger children. , Cellular biomarkers such as myeloid-related protein (MRP) 8 (S100A8) and MRP 14 (S100A9) heterocomplex (calprotectin, or MRP8/14) have been shown to be significantly higher in patients who subsequently developed flares compared with those who remained in stable remission. In one randomized controlled trial, there appeared to be no difference in relapse rates when MTX was discontinued after 6 months versus 12 months of remission, prompting some to recommend discontinuation of MTX after 6 months of stable remission. However, the criteria for “remission” or “relapse” have not been well defined or standardized among various studies, and the assessment of outcomes has not been the subject of blinded studies. Given these limitations, no firm conclusions can be drawn about the optimal time and mode of MTX discontinuation in children with JIA.
Safety/toxicity
Although MTX is associated with many potential toxicities, the documented overall frequency and severity of adverse effects in children with arthritis have been low. , , Although the precise mechanisms of all MTX-related toxicities are not clearly understood, at least some of MTX’s adverse effects are directly related to folate antagonism and cytostatic effects. This relationship is especially evident in tissues with a high cell turnover rate and a high requirement for purines, thymidine, and methionine, such as the GI tract and bone marrow.
Gastrointestinal toxicity
Abdominal discomfort and nausea, the most frequently reported symptoms, have traditionally been thought to occur in about 12% to 20% of children with JIA who receive MTX. Stomatitis or oral ulcers are reported in about 3% of children. However, in addition to the physical GI symptoms, conditioned responses that result in anticipatory and associative GI symptoms with MTX have been recognized and termed MTX intolerance. These symptoms have been reported to occur at much higher frequencies (50%), and although previously underreported, they certainly can contribute to MTX dose adjustment, nonadherence, and a negative impact on health-related quality of life, leading to untimely interruption or termination of therapy. There have been attempts to develop prediction tools and identify clinical, genetic, or cellular biomarkers to predict MTX intolerance, although none have been validated, nor are they widely used in clinical practice to date. MTX-related abdominal discomfort, anorexia, nausea, or oral ulcers usually occur within 24 to 36 hours after administration of the weekly dose and can be diminished by the addition of folic acid supplementation, by dose reduction, or by conversion to subcutaneous MTX administration, although the evidence for the effectiveness of these strategies is minimal or mostly anecdotal. Further studies have evaluated the use of antiemetics or behavioral strategies , to prevent or treat MTX-induced nausea and intolerance, although the data supporting these interventions are minimal and still contradictory.
The effect of MTX on liver function and the development of hepatic fibrosis has been extensively reviewed. Mild acute toxicity, with elevations of transaminases, is common, occurring in about 9% to 17% of children with JIA who were treated with MTX ; the majority of these elevations are less than twice normal values. , , These elevations are usually transient and resolve without intervention, with a lowered dose, or after a brief interval off treatment. , , In some of these cases, concurrent administration of NSAIDs may contribute to the elevation in transaminases. The issue of greatest concern with the long-term use of low-dose MTX in children has been the potential for significant liver fibrosis or cirrhosis. The risk of this complication in children with JIA appears to be minimal, , compared with the risk in adults with additional comorbidities. , , ,
The ACR has suggested guidelines developed by consensus for laboratory monitoring of patients with RA, and traditionally children with JIA have been monitored via similar guidelines. (see Table 13.2 ). However, based on fewer comorbidities, minimal risk for liver fibrosis, and the low frequency of significantly elevated transaminases, it has been suggested that screening low-risk children for MTX toxicity can be less frequent than for adults. In the 2011 ACR recommendations for treatment of JIA and the ACR Top Five for pediatric rheumatology, measurement of serum creatinine, complete cell blood count, and liver enzymes is recommended prior to initiation of MTX, repeated approximately 1 month after MTX initiation or any subsequent increase in MTX dose and every 3 to 4 months in children receiving stable doses of MTX who do not have recent history of abnormal laboratory monitoring. ,
Infection
Infections reported in patients treated with MTX are usually common bacterial infections (e.g., of the lungs or skin) or herpes zoster. Opportunistic infections associated with MTX treatment are rare, unless there is concurrent treatment with high-dose glucocorticoids. , , A study that investigated rates of bacterial infections in hospitalized patients using U.S. Medicaid administrative claims data revealed a doubling of the background rate of infections in children with JIA, even in the absence of MTX or anti–TNF therapy. The infection rate in children receiving MTX alone was comparable to children with JIA without current use of MTX or anti–TNF agents. , There are no standard guidelines addressing whether and when to withhold MTX administration during a concurrent infection and antibiotic administration. It has been recommended to withhold MTX until a course of antibiotics is completed and perioperatively—specifically 1 week prior and 2 weeks after major surgery. MTX is recommended to be continued uninterrupted for dental work.
Immunization with inactivated vaccines is not contraindicated in children receiving MTX treatment, but immunization with live attenuated vaccines is not currently recommended. However, there are data emerging that support the safety and effectiveness of live booster vaccine administration without increased risk of flare.
Hematological toxicity
Hematological toxicity includes macrocytic anemia, leukopenia, thrombocytopenia, and pancytopenia. In patients with mild bone marrow suppression, spontaneous recovery usually occurs within 2 weeks after MTX withdrawal. Patients with moderate to severe bone marrow suppression may require folinic acid rescue and supportive therapy (e.g., colony-stimulating factors).
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here