The principal drugs used in pediatric rheumatology are drugs that suppress the inflammatory and immune responses. This chapter outlines important general principles relating to these medications, 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) characterized mathematically by the pharmacokinetics of the drug as well as the multiple factors that contribute to the pharmacodynamics of drug response. In a simplistic sense, 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 (“ontogeny”) on the expression of drug metabolizing enzymes, transporters, receptors, and other gene products along the developmental continuum between birth and maturity. There has been considerable interest in the role of genetic variation (“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. GI absorption may be influenced by numerous factors, including the presence or absence of food in the gastric lumen, luminal pH, gastric emptying time, and coadministration of other drugs. Drug bioavailability, the net result of these factors, is usually determined by sequential measurement of plasma drug concentrations. Three parameters are routinely considered: (1) peak drug concentration, (2) the time necessary to reach peak concentration, and (3) the area under the time-concentration curve. The area under the curve (AUC) after intravenous administration is considered equivalent to complete absorption after oral administration. Because the effects of drugs that are administered repeatedly are cumulative—with the exception of drugs with extremely short half- lives that are given at infrequent intervals—bioavailability is best determined at the mean steady-state concentration of the drug, that is, the point at which drug intake is equal to drug elimination.
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 (e.g., penicillins) is increased and that of weakly acidic drugs (e.g., phenobarbital) 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 the apparent 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—considerably smaller than if the drug is distributed widely in tissues. Body composition changes dramatically between birth and adolescence. Water constitutes approximately 75% of total body mass in newborns and declines to the adult value of 55% by approximately 12 years of age. Body fat is approximately 16% in neonates and increases over the first 10 years of life, but also changes compositionally with age. The consequence of these changes is a decrease in the volume of distribution of hydrophilic drugs, such as aminoglycoside antibiotics.
Drugs in the body are either free or bound to plasma proteins or tissue lipids. The extent and nature of binding affect the volume of distribution of the drug, the rate of renal clearance (because only free drug is filtered by the glomerulus), the drug half-life, 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, although the extent of the decrease usually does not require any change in drug therapy.
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 from which a drug is removed per unit of time. Total body clearance represents the sum total of all clearance pathways and generally includes biotransformation to metabolites in the liver as well as elimination of unchanged drug by the kidney or in the bile. 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 . Salicylates obey capacity-limited kinetics: At low concentrations, first-order kinetics are observed, but at higher concentrations, the enzymes responsible for drug metabolism become saturated, and small increases in dose can lead to disproportionate increases in concentration. 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. Renal clearance changes with age and impacts drug elimination; thus, monitoring of drug levels and attention to the potential for drug toxicity becomes more critical in patients with significant renal disease.
The process of drug biotransformation is classified into phase I and phase II reactions, which occur sequentially and in most situations serve to terminate biological activity 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.
The changes related to ontogeny are critical to understanding the role of drug biotransformation in drug clearance from birth to adolescence. Most genes involved in drug biotransformation and transport are subject to genetic polymorphisms that also then can contribute to interindividual variability in drug disposition. By definition, a pharmacogenetic polymorphism is a heritable trait that involves a single gene locus occurring in more than one form, referred to as an allele, in a population, and results in a functional consequence in at least 1% of the population following drug exposure. The frequency of variant alleles, and therefore the prevalence of their functional consequences, differs among populations. 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.
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) provide symptomatic antiinflammatory relief; they are recommended for most patients with juvenile idiopathic arthritis (JIA) and are used in many other rheumatic disorders. NSAIDs that are commonly used in children are presented in eTable 12-1 .
|DRUG||DOSAGE (mg/kg/day UNLESS OTHERWISE NOTED)||MAX DOSE (mg/day)||DOSES PER DAY||COMMENTS|
|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|
|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|
|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|
Mechanism of Action
NSAIDs inhibit proinflammatory pathways that lead to chronic 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. Currently available NSAIDs (except diclofenac and indomethacin) have little effect on the lipoxygenase pathway, the other major pathway of arachidonic acid metabolism. Individual NSAIDs may have additional specific mechanisms of action.
There are two related but unique isoforms of the COX enzyme: COX-1 and COX-2, which are 60% identical in sequence but encoded by distinct genes and 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 widely distributed and constitutively expressed in most tissues. COX-1 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-α (TNF-α), bacterial endotoxins, and various mitogenic and growth factors. However, constitutive COX-2 expression is well recognized in brain, kidney, and the female reproductive tract. COX-2 also seems to have a role in the central mediation of pain and fever. The cardiotoxic effects of COX-2 inhibition also support a constitutive role of COX-2 in maintaining cardiovascular health.
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. NSAIDs differ in the degree of inhibition of COX-2, compared with COX-1. This difference has been found to correlate with their adverse-effect profiles: NSAIDs that are more selective for COX-2 seem to have more favorable adverse-effect profiles. Celecoxib is the only selective COX-2 inhibitor approved by the FDA for use in JIA.
The pharmacokinetic evaluation of NSAIDs in children with juvenile rheumatoid arthritis (JRA) or 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. Circadian rhythms in gastric pH and intestinal motility may lead to variability in NSAID absorption.
Most NSAIDs are strongly protein bound, primarily to albumin, leading to a potential for drug–disease and drug–drug interactions. Hypoalbuminemia may be one of the most important factors influencing the pharmacokinetics of NSAIDs in children. Because clinical effects are determined by unbound or free drug levels, states of severe hypoalbuminemia may be associated with a corresponding increase in the unbound fraction and with a potential for increased toxicity. Most studies of NSAID pharmacokinetics in children do not report the level of disease activity, however.
Although the strong plasma protein binding of NSAIDs also makes possible drug–drug interactions with other highly protein-bound drugs, significant clinical interactions are rare. NSAIDs may potentially interact with methotrexate (MTX) through several mechanisms, including displacement from plasma protein-binding sites, competition for renal secretion, and impairment of renal function. Although the impact of NSAIDs on MTX clearance varies widely and the potential for clinically significant interactions exists in some children, MTX–NSAID interactions are rarely of clinical significance.
The kinetics of NSAIDs at their antiinflammatory sites of action (e.g., synovial fluid) may be more clinically relevant than their kinetics in plasma. The comparative kinetics of NSAIDs in plasma and synovial fluid are related to the half-life of the drug and to differences in protein binding at these sites. This phenomenon may partially account for the fact that the dosage interval of these drugs is longer than their plasma half-life. In addition, because synovial fluid albumin concentrations are lower than plasma concentrations, the free fraction of NSAIDs in synovial fluid can be significantly higher, resulting in clinical effects observed with relatively low plasma drug levels. Except for naproxen and acetylsalicylic acid (ASA), plasma concentrations correlate poorly with antiinflammatory activity.
NSAIDs are eliminated predominantly by hepatic metabolism; only small amounts are excreted unchanged in urine. 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 salicylate 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. Naproxen may also show nonlinear pharmacokinetics at dosages greater than 500 mg/day in adults because of the saturation of plasma protein-binding sites and associated increase in clearance. In children (especially younger children), NSAIDs may be eliminated more rapidly than in adults; children may require more frequent doses to maintain a clinical response. Because hepatic metabolism plays a major role in NSAID elimination, it is necessary to assess hepatic function before institution of NSAID therapy; NSAIDs should not be initiated if there is significant elevation of transaminase levels (e.g., three times normal or higher).
General Principles of Nonsteroidal Antiinflammatory Drug Therapy
NSAIDs are generally good analgesic and antipyretic agents and weak antiinflammatory agents. They provide good symptomatic relief but have traditionally not been considered to influence the underlying disease process or to affect long-term outcomes significantly. Nevertheless, there is a suggestion that NSAIDs may change the course of ankylosing spondylitis by preventing syndesmophyte formation. 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 are relatively safe for long-term use. Although toxicities, especially GI side effects, are frequent, they are seldom serious. Given the wide variety of available NSAIDs, a few general principles can be applied in the selection of a particular NSAID for therapy in an individual patient. First, according to empirical evidence from clinical experience and some studies in adults, response to NSAIDs seems to have some disease specificity. Indomethacin may be more useful in treating manifestations of systemic JIA and in managing spondyloarthropathies. Second, individual patient response to NSAIDs is variable and often unpredictable: A child may fail to respond to one drug and yet respond to another, and some NSAIDs, such as ASA or indomethacin, seem to be more toxic than others. An adequate trial of any NSAID should be at least about 8 weeks, although about 50% of children who respond favorably to NSAID therapy do so by 2 weeks, and 25% may not respond until after approximately 12 weeks of therapy. Third, additional factors such as availability in liquid form, frequency of dosing, cost, and tolerability of any given NSAID may influence patient preference. A reasonable initial approach is to choose a drug that has a favorable toxicity and efficacy profile; can be taken on a convenient schedule (e.g., once or twice daily); is affordable; and, for young children, is available in a liquid formulation that is palatable. Use of multiple NSAIDs concurrently is not recommended because this approach has no documented benefit in terms of efficacy and can be associated with a greater potential for drug interactions and organ toxicity. The dose range and schedule of administration vary with the individual NSAID (see eTable 12-1 ). 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.
Serious toxicity associated with the use of NSAIDs seems to be rare in children. Generally, most toxicities are shared to a greater or lesser degree by all NSAIDs, although this can vary in individual patients.
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 not only led to the withdrawal of rofecoxib and valdecoxib from the market but also resulted in more restricted, similar product labels in the United States for celecoxib and traditional NSAIDs.
Meaningful data in children are scarce, so pediatric rheumatologists have traditionally relied on adult data. Consideration of the underlying cardiovascular risk of the patient, including the rheumatic disease being treated, is likely to enter into the calculation. In adults with rheumatoid arthritis (RA) and osteoarthritis, COX-2 inhibitors are recommended to be administered with low-dose aspirin in patients with cardiac risk factors. However, a recent multicenter, prospective, observational registry of 274 JIA patients receiving NSAIDs (55 receiving celecoxib) for a total of 410 patient-years (PY) of observation, revealed no difference in adverse events between nonselective NSAIDs and celecoxib. The two reported cardiovascular events were observed in the nonselective NSAID group.
GI toxicity is common to all NSAIDs. The pathogenesis of gastroduodenal mucosal injury involves multiple mechanisms and ranges from mild epigastric discomfort to symptomatic or asymptomatic peptic ulceration.
The average relative risk of developing a serious GI complication in adult patients exposed to NSAIDs is fivefold to sixfold that of patients not taking NSAIDs. Possible risk factors for GI complications during NSAID therapy include advanced age, past history of GI bleeding or peptic ulcer disease, and cardiovascular disease. Most patients who have a serious GI complication requiring hospitalization have not had prior GI side effects, however. Additional risk factors include longer disease duration, higher NSAID dose, use of more than one NSAID, longer duration of NSAID therapy, concomitant glucocorticoid or anticoagulant use, and serious underlying systemic disorders. Infection with Helicobacter pylori does not seem to play a major role.
The magnitude of this problem in children is poorly documented but has traditionally been thought to be considerably less than in adults, partly because of the absence of the associated risk factors identified in adults. H. pylori has not been reported to be an important pathogen in children with JRA treated with NSAIDs. 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. A retrospective study of a cohort of 702 children receiving NSAID therapy for JRA who were monitored for at least 1 year found 5 children (0.7%) with clinically significant gastropathy defined as esophagitis, gastritis, or peptic ulcer disease. The retrospective nature of this study may have resulted in underestimation of the prevalence of NSAID-associated gastropathy. A prospective study of a cohort of 203 children found that although 135 children (66.5%) had documented GI symptoms at some point during NSAID therapy, only 9 (4.4%) had endoscopically detected ulcers or erosions. A prospective study reported 45 children (24 of whom who were symptomatic with abdominal pain) who underwent routine endoscopy (in association with general anesthesia for joint injections). Of these children, 19 (42%) had normal gastric and duodenal mucosa, and 20 had histologically mild gastritis. A clear association was seen between abdominal pain and gastroduodenal pathology, but the severity of gastric inflammation did not correlate with the duration of NSAID therapy. 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.
Studies have shown differences in rates of serious GI complications associated with different NSAIDs. Systematic reviews have found ibuprofen to be associated with the lowest risk; indomethacin, naproxen, sulindac, and aspirin with moderate risk; and tolmetin, ketoprofen, and piroxicam with the highest risk. GI symptoms can be minimized further by ensuring that NSAIDs are always given with food. The utility of antacids and histamine 2 -receptor antagonists for prophylaxis against serious NSAID-induced GI complications is controversial. Although these medications suppress symptoms, they do not prevent significant GI events such as endoscopically documented gastric ulcers. Asymptomatic patients on acid-reduction therapies seem to be at greater risk for serious GI complications than patients not taking these medications, so their routine use in asymptomatic patients receiving NSAIDs cannot be recommended. Misoprostol, a synthetic prostaglandin E 1 analogue, has been shown in adults to be effective in prophylaxis and treatment of NSAID-induced gastroduodenal damage, thereby allowing continuation of NSAID therapy while achieving the healing of an ulcer. Studies of misoprostol cotherapy in children are limited, but they 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 but has most commonly been reported in children with JRA receiving ASA. In one retrospective study, transaminase levels were increased in 6% of children receiving naproxen. Elevated transaminase levels are rarely of clinical significance and often resolve spontaneously. However, when they are greater than twice the upper limit of normal, or when present for prolonged periods of time without resolution, it may be necessary to reduce the dose or temporarily stop NSAID therapy. Rarely, hepatotoxicity is severe; NSAIDs have been associated with macrophage activation syndrome (MAS). Liver function should be monitored in children taking daily NSAIDs for extended periods, particularly children with systemic JIA.
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. Although more common in adults, cases have been described in children. A 4-year prospective study of 226 children with JRA treated with NSAIDs found the prevalence of renal and urinary abnormalities attributable to NSAID therapy to be only 0.4% ; an even lower prevalence of 0.2% was reported in another cohort of 433 children.
Central nervous system effects.
Three general categories of central nervous system (CNS) side effects have been reported in association with NSAID therapy in adults: (1) aseptic meningitis, (2) psychosis, and (3) cognitive dysfunction. The NSAID most commonly reported to cause aseptic meningitis has been ibuprofen; susceptibility seems to be greater in patients with SLE. Indomethacin and sulindac have been reported to induce psychotic symptoms, including paranoid delusions, depersonalization, and hallucinations, in a few patients. More subtle CNS effects, such as cognitive dysfunction and depression, can also occur and are probably underrecognized and underreported. Tinnitus may occur with any NSAID, but particularly with ASA. A prospective study of 203 children with JRA found that CNS symptoms occurred in 55% of patients receiving NSAIDs; the most common symptom was headache, which occurred in about one third of children. Other reported symptoms included fatigue, sleep disturbance, and hyperactivity.
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 JRA is a distinctive photodermatitis marked by erythema, vesiculation, and increased skin fragility characterized by easy scarring of sun-exposed skin ( Fig. 12-1 ). 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. Children with fair skin and blue eyes are particularly susceptible; one study reported a relative risk of 2.96 if the child had blue-gray eyes and was taking naproxen. In one retrospective and parallel prospective study, young age, JIA itself, duration of therapy, evidence of systemic inflammation, and concurrent antimalarial therapy seemed to be additional risk factors for naproxen-induced pseudoporphyria. It is also rarely reported with other NSAIDs.
Effects of coagulation.
NSAIDs decrease platelet adhesiveness by interfering with platelet prostaglandin synthesis. This inhibition is reversible in the case of all NSAIDs except ASA, which irreversibly acetylates and inactivates COX, an effect that persists for the life of the platelet; bleeding time returns to normal only as new platelets are released into the circulation. NSAIDs also displace anticoagulants from protein-binding sites, potentiating their pharmacological effect.
Hypersensitivity and miscellaneous effects.
The precipitation of asthma or anaphylaxis with NSAIDs has been reported in adults as a unique syndrome associated with nasal polyps. Although this syndrome can theoretically be provoked by any NSAID, it has most commonly been reported with ASA or tolmetin. True hypersensitivity to ASA is exceedingly rare in childhood. ASA hypersensitivity occurs in about 0.3% to 0.9% of the general population, in 20% of patients with chronic urticaria, and in 3% to 4% of patients with chronic asthma and nasal polyps.
Hematological toxicity, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia, has been reported but is uncommon. Mild anemia occurs in about 2% to 14% of children and may be due partly to hemodilution, hemolysis, or occult GI blood loss secondary to NSAID therapy.
ASA is the oldest NSAID and continues to have a primary role in the management of Kawasaki disease (see eTable 12-1 ), acute rheumatic fever, and in the treatment of patients who are predisposed to thromboses. The general principles of NSAID mechanism of action and pharmacology and the principles of therapy and the spectrum of known adverse effects have already been addressed with reference to salicylates where relevant.
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. Salicylic acid is found in most body fluids (including cerebrospinal fluid, saliva, synovial fluid, and breast milk), and it crosses the placenta.
ASA is quickly absorbed from the stomach and proximal small intestine. The systemic antiinflammatory effects of ASA are maximal, and in most cases they are achieved only if serum steady-state levels are 15 to 25 mg/dL (1.09 to 1.81 mmol/L). At levels greater than 30 mg/dL (2.17 mmol/L), it is 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.
Therapeutic levels are not reliably attained before 2 to 5 days of administration, and most patients with Kawasaki disease have by this point been decreased to low-dose ASA therapy. If prolonged high-dose ASA is required (e.g., for acute rheumatic fever management), serum salicylate and serum liver enzyme levels should be checked 5 days after initiation of therapy or after any dose adjustment.
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 due to 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 certain other rheumatic diseases exert their beneficial effects weeks to months after initiation of therapy. These compounds—disease – modifying antirheumatic drugs (DMARDs)—currently include MTX, hydroxychloroquine, sulfasalazine, and leflunomide, among others. Recent evidence and experience suggest that early institution of DMARDs for the treatment of JIA is safe and effective, and may likely result in improved outcomes.
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 the first-choice second-line agent in childhood arthritis, and in some cases arguably a first-line agent. It is also used in many other chronic inflammatory disorders.
Mechanism of action.
MTX ( Fig. 12-2 ) is a folic acid analogue and a potent competitive inhibitor of several enzymes in the folate pathway ( Fig. 12-3 ). MTX is absorbed via the proton-coupled folate transporter ( PCFT / SLC46A1 ) in the gut and enters the cells primarily through the reduced folate carrier ( RFC/SLC19A1 ) and folate receptors (FOLR) 1 and 2. Intracellularly, MTX is bioactivated to a polyglutamated (MTXGlu n ) form by folylpolyglutamyl synthase (FPGS), which enhances the pharmacological activity and intracellular retention of MTX. The first MTX target to be identified was dihydrofolate reductase (DHFR), the enzyme responsible for reducing dietary folates and dihydrofolate to the biologically active tetrahydrofolate. Tetrahydrofolate is the source of one carbon donors supporting the synthesis of thymidylate, purines, and serine, as well as the remethylation of homocysteine to form methionine and subsequently S- adenosylmethionine (SAM), the one-carbon donor for multiple methyltransferase enzymes. Additionally, MTX inhibits thymidylate synthetase (TYMS) directly and indirectly via depletion of tetrahydrofolate, leading to inhibition of pyrimidine (thymidylate) biosynthesis with a resultant antiproliferative effect. Importantly, MTX targets aminoimidazole carboxamide ribonucleotide (AICAR) transformylase (gene name, ATIC ), which inhibits de novo purine synthesis and promotes the accumulation of extracellular adenosine. Extracellular adenosine is thought to be a large contributor to the site-specific antiinflammatory effects of MTX through inhibition of neutrophil adherence. Pharmacogenomic studies in RA and JIA have provided additional support for the involvement of the purine synthesis and adenosine pathways in mediating MTX response. Glutamate residues are removed from MTXGlu n by gamma-glutamyl hydrolase (GGH), allowing efflux of MTX from the cell by the ATP-binding cassette (ABC) family of transporters.
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-α, 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. In addition, adenosine inhibits adherence of stimulated neutrophils to endothelial cells, protecting the vascular endothelium from neutrophil-induced damage. MTX may also have more direct effects in inflamed joints by inhibiting the proliferation of synovial cells and synovial collagenase gene expression.
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 intravenous dosing) and highly variable, ranging from 0.25 to 1.49, with 25% of subjects in one study absorbing less than half their dose. In adults with RA, factors such as age, body weight, creatinine clearance, sex, dose, and fed-versus-fasted state significantly influenced MTX disposition. The bioavailability of MTX has also been shown to be greater in the fasting state in children with JIA. Oral bioavailability is generally about 15% less than after intramuscular or subcutaneous administration, and oral absorption is saturable ( eFig. 12-5 ).
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. 12-4 ). 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. Circulating levels diminish rapidly as the drug is distributed into tissue and eliminated. The predominant route of elimination is renal, with more than 80% of the drug eliminated unchanged via glomerular filtration and tubular secretion within 8 to 48 hours. 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 because of slow release from tissues, tubular reabsorption, and enterohepatic recirculation; the third phase is flat, reflecting the gradual release of tissue MTX.
Plasma drug levels do not correlate well with clinical effects and are not useful in routine monitoring of MTX therapy. 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 higher doses of MTX than adults to obtain similar therapeutic effects. As MTX is cleared rapidly from serum, 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 concentration of MTXGlu n have been shown to correlate with drug efficacy in patients with RA, although similar conclusions have not been consistently seen in children with JIA. MTXGlu n concentrations have been shown to be quite variable in JIA and are associated with drug dose, route, and duration of MTX therapy. Accumulation of long-chain MTXGlu n have been shown to be higher in children who experience GI side effects with the drug, and although cross-sectional studies have found no association with drug effectiveness, a recent prospective report has shown that responders to MTX had higher concentrations of long-chain MTXGlu n .
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 is not clinically significant. Several studies in children have shown an interaction between MTX and NSAIDs that may be clinically significant, particularly in patients with renal dysfunction. The combination of MTX and trimethoprim-sulfamethoxazole should be avoided because it may lead to hematological toxicity through the synergistic effects of these drugs on dihydrofolate reductase within the folate pathway.
The effect of genetic variation within the folate pathway upon drug response has been a focus in adult RA, and several review papers have discussed the vast work for the interested reader. However, there has been a lack of reproducibility of results, likely a consequence of several factors including variability in MTX treatment regimens, outcome measurements, and folate supplementation between studies; small sample sizes; the under characterized role of MTXGlu and folate on drug metabolism; and the unknown functional impact of the genetic polymorphisms. In children, recent work has identified clinical outcomes associated with genetic variation in the folate pathway, specifically in genes involved in the purine synthesis portion of the pathway as well as cellular transporters of MTX and folate ; however, these findings have not yet been replicated in larger cohorts.
The efficacy of MTX in controlling the signs and symptoms of JIA is now well established. Benefits reported in countless initial retrospective and uncontrolled studies were subsequently confirmed in a randomized, placebo-controlled clinical trial.
There have been various attempts at identifying the 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. Although there have been studies to support its effectiveness in systemic JIA, there are have been others that show no effect, or even worsening in patients on MTX therapy in this subtype of JIA. The utilization of MTX also differs by subtype in clinical practice. In a recent report from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, JIA patients with oligoarticular JIA (53%) and enthesitis-related arthritis (ERA) (63%) were the least likely to ever receive nonbiologic DMARDS such as MTX, compared to RF+ polyarticular (91%) or extended oligoarticular JIA patients (89%). Recently published American College of Rheumatology (ACR) recommendations for treatment of JIA utilize MTX differently by JIA subtype as well. Although in most subtypes a “ step-up”/escalation approach is recommended, in patients with high disease activity, poor prognostic, or systemic features, MTX (or biological therapy for systemic JIA) is recommended to be used earlier, and some advocate using it as first-line therapy. In fact, with newer cytokine-targeting therapies now available, the most recently updated ACR recommendations for the treatment of systemic JIA suggest MTX primarily for the treatment of mild or moderate arthritis in systemic JIA rather than for the treatment of systemic features or MAS where it has been shown to be less effective.
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 12-2 ). Improvement is generally seen by about 6 to 8 weeks on effective doses, but 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.
|DMARD||DOSAGE AND ROUTE||CLINICAL MONITORING||LABORATORY MONITORING|
|Hydroxychloroquine||≤6.5 mg/kg/day to a maximum of 400 mg/day, oral||Baseline ophthalmological exam and yearly screening for visual acuity, color vision, visual field, and retinoscopy||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, 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|
Many pediatric rheumatologists advocate using parenteral MTX at initiation of treatment to ensure complete absorption and achievement of early disease remission ; the 2011 ACR recommendations 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. F or example, approximately one quarter of the MTX users in the CARRA registry received MTX vial the oral route, and in the German Methotrexate Registry over half of patients (63%) received oral MTX exclusively for the first 6 months. Patients in the German registry reported similar rates of ACR Pediatric 30,50, and 70 response, as well as toxicity between routes of MTX administered. It remains agreed upon that parenteral MTX administration should be considered in children who (1) have a poor clinical response to orally administered MTX (this may be due to 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) ( eFig. 12-5 ) ; or (3) develop significant GI toxicity with orally administered MTX. Studies in adult patients with rheumatoid arthritis suggest that oral absorption of MTX is considerably reduced at doses of 15 mg or more, and MTX should be administered parenterally. Bypassing the enterohepatic circulation may also reduce hepatotoxicity.
The issue of when, how, and by what criteria to consider withdrawing MTX therapy in JIA remains unclear. However, the criteria for “remission” or “relapse” have usually not been well defined or standardized among various studies, and the assessment of outcomes has not been the subject of blind studies. Given these limitations, no firm conclusions can be drawn about the optimal time and mode of MTX discontinuation in children with JIA. 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) secreted by activated phagocytes at local sites of inflammation may be viable biomarkers to determine the appropriate time to discontinue MTX. Levels of MRP8/14 at the time of MTX discontinuation were significantly higher in patients who subsequently developed flares, compared to those who remained in stable remission.
Although MTX is associated with many potential toxicities, the documented overall frequency and severity of adverse effects in children with arthritis have been low. Most side effects are mild and reversible and can be treated conservatively. Although the precise mechanism of all MTX-related toxicities is not clearly understood, at least some of MTX’s adverse effects are directly related to its folate antagonism and its cytostatic effects. This relationship is especially evident in tissues with a high cell turnover rate, such as the GI tract and bone marrow, that have a high requirement for purines, thymidine, and methionine, which may explain why supplementation with folic or folinic acid may diminish these symptoms.
Abdominal discomfort and nausea, the most frequently reported symptoms, have traditionally been thought to occur in about 12-20% of children with JRA who receive MTX. However, in addition to the physical GI symptoms, in recent years 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 and nonadherence, leading to untimely interruption or termination of therapy. Stomatitis or oral ulcers are reported in about 3% of children. 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 only anecdotal.
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 JRA who were treated with MTX ; and the majority of these elevations are less than twice normal values. These elevations are usually transient and resolve without intervention, with 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 differ, however, from the risk in adults who have comorbidities that may include heavy alcohol consumption, preexisting liver disease, obesity, insulin-dependent diabetes mellitus, and renal insufficiency.
In many small studies in children, liver biopsies were performed after cumulative doses of 3000 mg had been reached; none showed cirrhosis. A cross-sectional study in children exposed to even higher cumulative doses of MTX (>3000 mg or >4000 mg/1.73 m 2 over a mean of 6 years), found no significant fibrosis or cirrhosis on liver histology; however, 13 (93%) of 14 biopsy specimens showed some histological abnormality (with only 1 graded as Roenigk grade II). In addition, higher weekly dosages of MTX (20 mg/m 2 /week or more) were not associated with significant hepatic fibrosis in 10 patients who underwent liver biopsy. Only the frequency of biochemical abnormalities and body mass index correlated with the Roenigk grade.
Although these data are encouraging, their interpretation requires some caution. The sample size in these studies is small, and thus the statistical power for detection of infrequent events, such as cirrhosis, is low. Selection bias may have occurred, as not all eligible patients receiving MTX treatment underwent biopsy. There were no control biopsy specimens to help distinguish the effects of disease or concomitant medications on liver histology, and the long-term clinical significance, if any, of the minor histological abnormalities is unknown. Further long-term, prospective studies using greater numbers of children are needed to define more accurately the risk of MTX-related liver fibrosis or cirrhosis and aid in the development of guidelines for monitoring therapy in JIA.
The ACR has suggested guidelines developed by consensus for laboratory monitoring of patients with RA, and traditionally children with JRA/JIA have been monitored via similar guidelines. ( Table 12-2 ). 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 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.
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. There have been reports of hypogammaglobulinemia resulting from MTX use in children. A recent study that investigated rates of bacterial infections in hospitalized patients by 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-α therapy. Furthermore, the infection rate in children receiving MTX alone (2,646 person-years of observation) compared with children with JIA without current use of MTX or anti–TNF-α agents (adjusting for age, sex, race, prior bacterial infections, comorbid conditions, and glucocorticoid dose at the start of the study) was similar (adjusted hazard ratio 1.2 [95% CI, 0.9-1.7 ]). There are no standard guidelines on if 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 vaccine administration without increased risk of flare.
Hematological toxicity includes macrocytic anemia, leukopenia, thrombocytopenia, and pancytopenia. In adults with rheumatoid arthritis, pancytopenia has been reported in about 1% to 2%, but it has not been reported in children. In patients with mild bone marrow suppression, spontaneous recovery is usually within 2 weeks after withdrawal of MTX. Patients with moderate to severe bone marrow suppression may require folinic acid rescue and supportive therapy (e.g., colony-stimulating factors).
The issue of whether low-dose MTX treatment is an independent risk factor for various malignancies is controversial and remains unresolved. Although in vitro studies have shown that MTX has mutagenic and carcinogenic potential, in vivo studies in animal models (mice, rats, hamsters) have failed to show any carcinogenicity. In humans, low-dose weekly MTX therapy has not been convincingly linked to malignancy. There have been case reports of an association between MTX treatment and lymphoproliferative diseases in adults with RA, and several cases of Hodgkin lymphoma and non-Hodgkin lymphoma have been reported in children with JRA who were treated with MTX ; however, in some of these cases, Epstein–Barr virus (EBV) was implicated.
It has not been possible to determine whether the development of malignancy while a patient is receiving MTX is merely coincidental or causally linked to MTX or the underlying inflammatory disease process. RA is known to be associated with an increased risk of hematological malignancy, and there have been varying reports of an increased incidence of malignancy in JIA, with some reports supporting an increased baseline risk in JIA, whereas others do not. Using a large U.S. Medicaid claims database from 2000-2005, nearly 8000 JIA patients were compared with large cohorts of children with attention deficit hyperactivity disorder and asthma, and an increased incidence of malignancy was found in children with JIA compared with the control groups, but there was no increased risk of cancer based on MTX or anti–TNF-α use.
Other rare adverse effects
Central nervous system.
Various CNS symptoms, including headaches, mood alterations, change in sleep patterns, irritability, fatigue, and impaired academic performance, have been reported to occur transiently in the 12 to 48 hours after the weekly dose of MTX.
MTX therapy is associated with spontaneous abortions and congenital abnormalities. Women of childbearing age should be counseled to practice effective contraception during the course of treatment. They should discontinue MTX therapy at least one ovulatory cycle before trying to conceive. There have not been any reports of azoospermia caused by low-dose MTX treatment of JRA, and a recent study in adult men taking MTX who fathered 113 pregnancies did not show a higher risk of birth defects or spontaneous abortions. MTX is excreted in breast milk in low concentrations, and women taking MTX should be advised not to breast-feed.
Rare side effects such as pulmonary toxicity, accelerated nodulosis, and osteopathy have also been reported with MTX.
As a potent antifolate drug, the side effects of MTX are also consistent with symptoms of folate deficiency, and it is rational to question how the folate pathway and folic acid supplementation may impact drug efficacy at the expense of minimizing toxicity. Baseline plasma and erythrocyte folate concentrations have been shown to negatively correlate with MTX toxicity scores in RA, and children with historical intolerance to MTX have shown significantly lower cellular folate concentrations in a cross-sectional study. Numerous studies have examined the issue of minimizing MTX toxicities with the use of concurrent folic or folinic acid (leucovorin) supplementation in adults with rheumatoid arthritis. A Cochrane review of all trials on “ low-dose” folic acid (≤7 mg/week) or folinic acid in adults with RA from 1999 through March 2012 revealed a 26% relative risk reduction in the incidence of GI side effects, a 76.9% relative risk reduction in transaminase elevation, and a 60.5% relative risk reduction in MTX withdrawal for any reason, with no observed effect upon efficacy.
However, the effect of folate supplementation upon drug effectiveness is far from clear. Some studies have shown that concurrent folate supplementation may worsen disease activity in psoriasis and RA. A small number of clinical studies that investigated supplemented folic acid in JRA have suggested no substantial effect upon MTX efficacy, but higher doses of folinic acid were associated with disease flares. Baseline variability in the endogenous target folate pathway may also be important for drug outcomes, as preliminary data suggest that initiating MTX in a folate replete state may be associated with improved outcomes on MTX, as enhanced cellular folate uptake may also represent enhanced cellular MTX uptake.
Based on the data from adult studies and the small trial in children with JRA, it seems that daily (1 mg/day) folic acid supplementation confers a beneficial effect in terms of GI and mucosal toxicities associated with low-dose weekly MTX treatment and does not have any significant detrimental effect on disease control. Without firm data to direct otherwise, folic acid supplementation should be considered at least in symptomatic patients. High-dose folinic acid rescue should be reserved for patients with severe, life-threatening toxicity (e.g., aplastic anemia).
Hydroxychloroquine sulfate is the first-line antimalarial to treat pediatric rheumatic diseases.
Mechanism of action.
The exact mechanism of action of hydroxychloroquine remains unknown, although several physiological effects have been attributed to this drug class that may be pertinent to rheumatic disease. These include the inhibition of neutrophil chemotaxis, nitric oxide production, and phagocytosis. Hydroxychloroquine may also antagonize the action of prostaglandins, interfere with IL-1 release by monocytes ; interfere with production of TNF-α, IL-6, and IFN-γ ; inhibit natural killer activity ; and induce apoptosis. It has antiplatelet and antihyperlipidemic effects extremely important in patients with SLE, and antagonistic effects upon Toll-like receptor 7/9.
Hydroxychloroquine is rapidly absorbed from the intestine. Equilibrium concentrations are reached after 2 to 6 months of a constant daily dose, and the half-life exceeds 40 days. Tissue levels are much greater than plasma concentrations, and there is increased affinity of the drug for the liver, pituitary, spleen, kidney, lung, adrenals, and specifically for melanin. Excretion is primarily via the kidney.
The recommended dosage for hydroxychloroquine is less than or equal to 6.5 mg/kg/day to a maximum dosage of 400 mg/day ( Table 12-2 ). Early studies have not shown hydroxychloroquine to be an extremely effective disease-modifying agent in JRA ; however, it is used commonly in pediatric SLE and cutaneous LE in children, as well as for juvenile dermatomyositis. Although this medication is commonly used, like many older DMARDs, it has been inadequately studied in children. It is used mostly in combination with other medications, or in mild or well- controlled disease. Data from adults has shown an increased risk of lupus flare once their hydroxychloroquine was withdrawn, and utilizing hydroxychloroquine in addition to MTX and sulfasalazine has been shown to be superior than single or double therapy in adults with RA. Recent data support a protective effect against fetal heart block in neonatal lupus.
When used at recommended doses, antimalarials are considered extremely safe. At least four young children have died of respiratory failure after accidental ingestion of large doses (1 to 3 g) of chloroquine, however, as there is no antidote.
GI intolerance occurs in 10% of adults, and skin hyperpigmentation, myasthenia, and muscle weakness have been described. CNS side effects that include headache, light-headedness, tinnitus, insomnia, and anxiety are common. These side effects may be reversible with dose reduction and may remit spontaneously.
The major concerning side effect is retinal toxicity. Retinal toxicity, although rare, can cause blindness, even after the medication has been stopped. Antimalarials accumulate in the pigmented cells of the retina and persist; however, retinitis is sometimes, but not always, reversible. Evidence in adults suggests that retinal toxicity does not occur if the dosage of hydroxychloroquine is maintained at less than 6. 5 mg/kg/day, even for up to 7 years. Routine ophthalmological monitoring can lead to early detection of premaculopathy; vision loss can be prevented if the medication is discontinued. Newly revised recommendations in adults suggest a baseline exam and then annual screening starting after 5 years on therapy. Each examination should include visual acuity, color vision testing, visual field examination, and retinoscopy. In addition, newer objective tests including multifocal electroretinogram, spectral domain optical coherence tomography, and fundus autofluorescence have been shown to be more sensitive than visual fields, and at least one is recommended to be performed, if available, in addition to standard testing. Retinal abnormalities or interference with vision, especially with foveal recognition of red, is an absolute indication for discontinuation of hydroxychloroquine. Use of hydroxychloroquine in children younger than 7 years may be limited by difficulty in obtaining satisfactory evaluation of color vision in this age group, and the standard of care in children remains an annual exam until definitive studies in children suggest increasing the frequency of monitoring.
Hydroxychloroquine crosses the placenta but is considered safe to use during pregnancy. Hydroxychloroquine does appear in breast milk, but the amount ingested per day by a breast-feeding infant would be very low.
Sulfasalazine is an analogue of 5-aminosalicylic acid linked by an azo bond to sulfapyridine, a sulfonamide. Its development was based on the concept that RA might be an infectious disease and would respond to combination therapy with an antibacterial agent and an antiinflammatory drug. Sulfasalazine is used in the treatment of mild to moderate inflammatory bowel disease, and it has been reported to be beneficial in the management of childhood arthritis, particularly oligoarthritis, psoriatic arthritis, and reactive arthritis. Its role in ankylosing spondylitis is controversial, although it does seem to be effective for the peripheral arthritis associated with this condition.
Mechanisms of action.
Several mechanisms of action may explain the antiinflammatory effect of sulfasalazine. Bacterial growth is reduced by sulfasalazine and sulfapyridine, and the bacterial antigenic load delivered to the gut-associated lymphoid tissue may be reduced. This mechanism may be important for patients with spondyloarthropathies, in whom bacteria may gain access through inflamed gut mucosa and stimulate the immune system. Sulfasalazine interferes with many enzymes that are important in inflammation in the formation of leukotrienes and prostaglandins, and it is a potent inhibitor of AICAR transformylase, resulting in an accumulation of extracellular adenosine. There are several additional pharmacological effects reported in the literature.
Sulfasalazine is poorly absorbed from the GI tract. Peak serum concentrations are reached after 5 days of therapy. The half-life of the drug is 10 hours. Approximately one third of the dose is absorbed in the small intestine and excreted unchanged in the bile. The remaining 70% enters the colon intact, where the azo linkage is split by bacterial enzymes to sulfapyridine, which is absorbed and excreted in the urine, and 5-aminosalicylate, which reaches high concentrations in the feces. Approximately 90% of sulfapyridine is absorbed from the colon. Sulfapyridine is tightly protein bound and acetylated, hydroxylated, and conjugated with glucuronic acid in the liver. Sulfasalazine and sulfapyridine reach synovial fluid in concentrations comparable with those in serum. About one third of 5-aminosalicylic acid is absorbed, acetylated, and excreted in the urine. The rest is eliminated unchanged in the stool. The small amount of salicylate absorbed is insufficient to reach antiinflammatory levels in the plasma.
Sulfasalazine is a recommended treatment for ERA following a trial of NSAIDs and/or intraarticular steroid injections. The suggested dosage in children is 30 to 50 mg/kg/day in two to three divided doses, usually taken with food or milk. Treatment is initiated at a lower dosage (10 to 15 mg/kg/day) and increased weekly over 4 weeks to achieve maintenance levels. A satisfactory clinical response may occur within 4 to 8 weeks ( Table 12-2 ).
Several studies have investigated sulfasalazine use in children and results have been mixed. A double-blind, randomized, placebo-controlled study of 69 Dutch children with oligoarticular or polyarticular juvenile chronic arthritis showed significant improvement in overall articular severity score, global, and laboratory parameters. A follow-up study showed sustained benefits in these same individuals 7 to 10 years later. Alternatively, in a small, 26-week, randomized, double-blind, placebo-controlled study, no significant differences in active joint count, tender entheses count, pain visual analogue scale, or spinal flexion were seen with sulfasalazine compared with placebo.
Intolerance and toxic reactions occur in approximately 20% of sulfasalazine-treated adults with rheumatoid arthritis (range 5% to 55%). In a placebo-controlled study of 35 children with JRA, 29% developed adverse effects that led to discontinuation of the drug. Rashes occur in 1% to 5% of patients. A maculopapular rash occurring within 2 days after institution of therapy, especially on sun-exposed skin, is the most common dermatological complication.
Oral ulcers and Stevens–Johnson syndrome are uncommon but important complications. The drug should not be used in infants or in patients with known hypersensitivity to sulfa drugs or salicylates, impaired renal or hepatic function, or specific disease contraindications (e.g., porphyria, glucose-6-phosphate dehydrogenase deficiency). Other rare side effects have been reported and include cytopenias, drug-induced SLE, Raynaud phenomenon, interstitial pneumonitis, fibrosis, alveolitis, pulmonary syndromes, hepatitis, hypogammaglobulinemia, and IgA deficiency. Serious infections have not been reported, however. Most authors also consider sulfasalazine to be contraindicated in patients with systemic JIA because of an apparent increased risk of toxicity reported in patients with adult-onset Still disease.
A reversible decrease in sperm count has been observed, but there are no reports of teratogenicity, and it can be safely used in pregnancy. Sulfasalazine enters breast milk in negligible amounts and thus is not an absolute contraindication to breast-feeding. However, caution should be exercised because its metabolite, sulfapyridine, is present at significant levels in breast milk, and there has been a single case report of bloody diarrhea in an infant exposed to sulfasalazine through lactation. In addition, as sulfapyridine can displace bilirubin, this medication should be avoided in nursing mothers of premature infants, infants who are ill or suffering from hyperbilirubinemia, or glucose-6-phosphate dehydrogenase deficiency.
Mechanisms of action.
Leflunomide is an immunomodulatory agent that, through its active plasma metabolite, A77-1726, inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydroorotate dehydrogenase. As a result of the inhibition, p53 in the cytoplasm translocates to the nucleus and initiates cellular arrest in the G 1 phase of the cell cycle. It also inhibits tyrosine kinase, inhibits leukocyte-endothelial adhesion, affects cytokine production, and decreases serum metalloproteinase activity similarly to MTX. In vitro, leflunomide inhibits the production of prostaglandin E 2 , matrix metalloproteinase (MMP)-1, and IL-6, and modulates various tyrosine kinases and growth factor receptors.
Leflunomide is rapidly converted to A77-1726, which is highly protein bound and has a prolonged half-life of up to 18 days. As a result, loading doses have been recommended for the first 3 days of administration to achieve steady state rapidly in RA, although it may increase the frequency of GI toxicity ; however, a loading dose has not been adopted consistently in children with JIA.
Dosing guidelines for children are limited and based on studies by Silverman and colleagues ( Table 12-2 ) that compared the safety and efficacy of leflunomide to MTX in patients with polyarticular course JIA. Pharmacokinetic studies were performed. At week 16, 68% of patients receiving leflunomide showed an improvement according to the ACR Pediatric 30 versus 89% of patients treated with MTX; the improvements achieved were maintained at a similar rate in a 32-week extension study. The median time to ACR Pediatric 30 did not differ between the two groups. Body weight was a significant determinant of response, and patients weighing less than 20 kg showed the greatest discrepancy, with the clinically active metabolite notably lower in this group. The incidence of treatment-related adverse events was similar in both groups, although there was an increased frequency of liver transaminase elevations in the MTX group. Furthermore, in a long-term open label study of leflunomide in polyarticular JIA patients who were MTX intolerant or refractory, 52% of patients met ACR Pediatric 30 by 12 weeks, with 65% of those who entered the extension phase maintaining ACR Pediatric 30 status up to 2 years.
An additional retrospective review of 58 German JIA patients treated with leflunomide either alone (n = 48) or in conjunction with MTX (n = 10) were examined over a mean of 1.5 years and found that leflunomide was well tolerated and effective; approximately 30% of patients on leflunomide attained remission.
Mild and dose- related side effects in adults include GI side effects (abdominal pain, dyspepsia, anorexia, diarrhea, gastritis), allergic rash, reversible alopecia, mild weight loss, and elevated hepatic transaminases. Side effects in children have included transiently elevated liver enzymes, abdominal pain and nausea, diarrhea, headaches, mouth ulcers, and alopecia; these symptoms tend to be dose related.
Leflunomide is teratogenic. Because of the very long half-life of this drug, it has been recommended that cholestyramine be administered, and that drug levels less than 0. 02 mg/L be verified on two separate tests at least 2 weeks apart in men and women before attempting to conceive. Breast-feeding is contraindicated.
Other Disease-Modifying Drugs
The primary use of colchicine in pediatric patients is for treatment of familial Mediterranean fever (FMF), where it has been shown to reduce not only the frequency of attacks, but also prevent the development of amyloidosis. Colchicine is also occasionally used for recurrent aphthous stomatitis, Behçet disease, and cutaneous vasculitis.
Mechanism of action
Colchicine’s action is thought to depend on binding of two of its rings to cellular microtubules, inhibiting the movement of intracellular granules and preventing secretion of various components to the cell exterior. Interaction between endothelial cells and neutrophils is inhibited by reducing the expression of adhesion molecules on the neutrophil membrane. The drug is present in granulocytes to a much greater extent than in lymphocytes or monocytes.
Peak plasma levels are reached 1 to 3 hours after oral administration. Colchicine’s bioavailability is less than 50%, and its half-life after oral administration is 9 ± 4 hours. It is predominantly eliminated by biliary excretion through the stool. The multidrug transporter molecule ABCB1 (also known as P-glycoprotein and multidrug transporter 1) mediates the extrusion of colchicine into the GI tract, and polymorphisms in ABCB1 may explain some of the differences in treatment response in patients with FMF. Enteric and hepatic cytochrome P-450 3A4 (CYP3A4) is also important in colchicine metabolism. Drug interactions may also occur either at the level of the transporter or through the cytochrome P-450 system, and thus inhibition or competition for CYP3A4 may lead to colchicine accumulation and toxicity. Dose reduction algorithms have been proposed for adults.
The therapeutic dose of colchicine ranges from 0.5 to 2 mg/day as needed to prevent or reduce significantly the frequency of FMF attacks and is administered once or twice daily. Toxicity is extremely rare with oral administration and is generally limited to the GI tract (nausea, vomiting, abdominal pain, diarrhea); this can be helped by administering colchicine in two divided doses and reducing dietary lactose intake. In the case of serious overdose, treatment with colchicine-specific Fab could be considered. Severe toxicity can result in dehydration, multiorgan failure, and a disseminated intravascular coagulation–like syndrome. Colchicine is safe to take during pregnancy and while breast-feeding. Concerns about chromosomal and gonadal aberrations resulting from its effect upon microtubules have not been supported.
Thalidomide and Lenalidomide
Thalidomide (N-α-phthalimidoglutarimide), a major teratogen, has been shown to be effective in various immune-mediated disorders. Its immunosuppressive effects include inhibition of neutrophil chemotaxis, decreased monocyte phagocytosis, decrease in the ratio of T-helper cells to T-suppressor cells, inhibition of expression of TNF-α and IL-6 messenger RNA (mRNA), and inhibition of angiogenesis. Mean peak plasma concentrations occur 4.39 ± 1.27 hours after a 200-mg dose. It is metabolized primarily by spontaneous hydrolysis and has an elimination half-life of 3 to 7.3 hours.
Controlled trials have shown the benefits of thalidomide compared with placebo in recurrent aphthous ulcers and in recurrent oral ulceration in men with Behçet syndrome. Several recent small series of children with systemic-onset JIA who have benefited from thalidomide treatment have also been described. There are several case reports of its successful use in various other disorders.
The dosage of thalidomide ranges from 100 to 400 mg/day administered once or twice daily. Dosages of 2.5 to 5 mg/kg/day have been suggested for children with SLE or systemic-onset JRA.
Birth control must be practiced due to thalidomide’s well-known teratogenic effects. Excellent control is maintained in a postmarketing surveillance program and a restricted distribution program, the System for Thalidomide Education and Prescribing Safety program (STEPS), monitored by Boston University, Celgene Corporation, and the U.S. Food and Drug Administration (FDA). In addition to embryopathy, the major side effects of thalidomide include peripheral neuropathy and drowsiness. Neuropathy is predominantly sensory and manifests as painful paresthesias in a glove-and-stocking distribution. Neuropathy can progress despite discontinuation of thalidomide and may or may not be dose related. Baseline and routine follow-up electrophysiological testing should be performed, and the dose should be reduced or discontinued on detection of abnormalities.
A promising immunomodulatory analogue to thalidomide—lenalidomide—has a better safety profile than thalidomide, with similar immunomodulatory effects. Although there are no published reports on its effects on JIA, there has been a report of successful use in a pediatric patient with refractory complex aphthosis. A risk evaluation and mitigation strategy (REMS) program for lenalidomide has also been developed in conjunction with Celgene and the FDA to prevent the risk for embryo-fetal exposure. Tight regulation requires licensure for prescribers and provides for patient education and monitoring. A recent FDA warning reported an increased risk of secondary malignancies in patients who were treated with lenalidomide to treat multiple myeloma compared to placebo, making a clear risk /benefit analysis imperative prior to prescribing.
Glucocorticoid drugs are the most potent antiinflammatory agents used the treatment of rheumatic diseases. Specific aspects of therapy are discussed in the chapters on individual diseases and in reviews.
Glucocorticoid drugs are structural variants of the naturally occurring glucocorticoid, cortisol. Synthetic compounds, such as prednisone and cortisone, must be hydroxylated to form therapeutically active prednisolone and hydrocortisone. Topical glucocorticoids, such as dexamethasone, or those administered by intraarticular injection (e.g., triamcinolone hexacetonide) already have a hydroxyl group at C11 and are thus in active form. The different relative potencies and durations of biological action of the various synthetic analogues are outlined in Table 12-3 .
|GLUCOCORTICOID *||EQUIVALENT DOSE † (mg)||RELATIVE ANTI-INFLAMMATORY POTENCY||RELATIVE SODIUM RETAINING POTENCY|
Orally administered glucocorticoids (prednisone, prednisolone) are rapidly absorbed. Prednisone is converted to prednisolone in the liver and reaches a peak plasma concentration within 2 hours. Hydrocortisone and prednisolone bind to the serum proteins transcortin (high affinity) and albumin (low affinity). Methylprednisolone and dexamethasone are bound primarily to albumin. Prednisolone has a large volume of distribution; about two thirds is taken up by muscle. After metabolism in the liver, excretion occurs principally via the bile.
Physiological and pharmacological effects.
Glucocorticoids are unique among pharmacological agents used to treat rheumatic diseases because they are synthetic analogues of endogenous molecules that are produced by the body that perform important physiological and pharmacological functions through glucocorticoid receptors (GRs) and genomic and nongenomic mechanisms.
Antiinflammatory and immunosuppressive actions.
Glucocorticoids have antiinflammatory and immunosuppressive effects. Steroids inhibit the early stages of inflammation (e.g., edema, fibrin deposition, capillary dilation, migration of lymphocytes into inflamed areas, phagocytic activity) and the later manifestations (e.g., proliferation of capillaries and fibroblasts, deposition of collagen). Many of these effects are mediated by inhibition of numerous chemokines and cytokines, including arachidonic acid and its metabolites, platelet-activating factor, TNF, IL-1, mitogen-activated protein kinase (MAPK) phosphatase 1, and NF-κB.
Glucocorticoid effects on the immune system are mediated principally through T lymphocytes. Acute administration of hydrocortisone produces a 70% decline in circulating lymphocytes. T lymphocytes are affected more than B lymphocytes, and T-helper cells are affected more than T-suppressor cells. Lymphopenia is probably a result of sequestration of cells in the bone marrow rather than cell lysis, although drug-induced apoptotic cell death may also be involved. Corticosteroids have been shown to result in a profound and transient lymphocytopenia, maximal at 4 hours after the dose and resolved by 24 hours, due to a redistribution of these cells to the bone marrow. There is also a 90% decline in circulating monocytes within the initial 6 hours. Proliferative T-cell responses to antigens (streptodornase-streptokinase), mitogens (concanavalin A), and cell surface antigens (as in the mixed leukocyte reaction) are reduced by glucocorticoids. IL-2 production by T cells in vitro is also reduced. Glucocorticoids cause an increase in the numbers of blood neutrophils by increasing the release of cells from the marginated neutrophil pool, prolonging their stay in the circulation, and reducing chemotaxis of neutrophils to sites of inflammation.
Intravenous glucocorticoid causes a decrease in circulating IgG but has little discernible effect on the serum titer of specific antibodies. The protein catabolic effects of long-term administration may have consequences on the humoral immune system. Endothelial secretion of C3 and factor B of the complement cascade are also inhibited.
Indications for systemic glucocorticoid therapy.
When considering glucocorticoid use in children with rheumatic diseases, the risk/benefit ratio must be carefully weighed because these agents are associated with substantial toxicity when used systemically in the long term ( eBox 12-1 ). The overall aim is to limit the dose and duration of steroid therapy as much as possible while achieving disease control.
Adverse Effects of Glucocorticoid Drugs
Effects on bone: osteoporosis, avascular necrosis
Lymphopenia and neutrophilia
Central nervous system effects: psychosis, mood and behavioral disturbances
Cataracts and glaucoma
Metabolic effects: Impaired carbohydrate tolerance, protein wasting, metabolic alkalosis
Two broad categories of adverse effects are associated with the therapeutic use of systemic glucocorticoids: effects resulting from prolonged use of large doses and effects resulting from withdrawal of therapy. The mechanisms involved in the development of these adverse events are reviewed in detail elsewhere.
Cushing syndrome, a term used originally to identify the effects of idiopathic hypercorticism, may also be induced by prolonged glucocorticoid administration. It is characterized biochemically by high plasma glucocorticoid levels and suppression of the hypothalamic–pituitary–adrenal axis. It is characterized clinically by many features, including truncal obesity ( Fig. 12-6 ), osteoporosis, thinning of the subcutaneous tissues, and hypertension. The distribution of fat in Cushing syndrome is predominantly in the subcutaneous tissue of the abdomen and upper back (buffalo hump) and in the face (moon facies). Weight gain reflects fluid retention and increased caloric intake. Skin changes, in addition to the characteristic purple striae, include hirsutism and acne. Hypertension is usually mild but occasionally requires treatment or reduction of the glucocorticoid dose. With the exception of skin striae, all of these physical features are reversible after cessation of glucocorticoid therapy.
Growth suppression is one of the most worrisome long-term adverse effects of glucocorticoids. It occurs in young children who receive prolonged therapy in dosages equivalent to 3 mg/day of prednisone, and increases with higher dosages. The mechanism of glucocorticoid-associated growth suppression in children with arthritis is controversial. Glucocorticoids have been shown to inhibit cell growth and cell division as well as inhibit production of insulin-like growth factor I (somatomedin C), resulting in decreased chondrocyte proliferation, Alternate-day dosing regimens have been shown to minimize this adverse effect. Although early studies showed that growth hormone did not always improve growth failure in children with glucocorticoid-induced inhibition of growth, more recent reports have shown increased height velocity, and catch-up growth in patients who received growth hormone. In fact, achievement of their genetically determined target height was observed in JIA patients randomized to receive growth hormone, with normalization of total bone and muscle cross-sectional area in the treated group. However, the optimal time to initiate growth hormone and the optimal dose to use have yet to be determined. Although considered generally safe, the potential for metabolic complications requires routine monitoring.
Effects on bone: osteoporosis and avascular necrosis.
Osteoporosis is one of the most troublesome consequences of long-term, high-dose glucocorticoid therapy, although there are multiple other contributing factors to consider, including inadequate dietary intake of calcium and vitamin D, underlying disease activity, reduced physical activity, and low body weight.
Glucocorticoids are associated with a reduction in bone formation and an increase in bone resorption; the reduction in bone formation seems to be more important and is caused by a direct inhibitory effect on, and apoptosis of, osteoblasts. Glucocorticoids also directly inhibit gut absorption of calcium and cause increased urinary calcium excretion, potentially resulting in secondary hyperparathyroidism and increased bone resorption. Additional mechanisms by which glucocorticoids result in bone loss are depicted and detailed in eFig. 12-7 . These mechanisms include effects on the production of local growth factors, reduction of matrix proteins, increase in the production of enzymes that break down matrix, increase in apoptosis of osteoblasts and osteocytes, increase in osteoclastogenesis secondary to decreased production of osteoprotegerin, and an increased production of receptor-associated NF-κB ligand (RANK ligand).
The extent of bone loss seems to be related to the dose and duration of glucocorticoid therapy, although these factors do not have a consistent relationship with fracture risk. Significant bone loss occurs with dosages of 7.5 mg/day or greater in most adults. In adults, bone loss is predominantly trabecular (e.g., spine and ribs) rather than cortical, whereas in children the osteoporotic effects of glucocorticoids are more generalized. Bone loss seems to occur rapidly within the first 6 to 12 months of therapy and then reaches a plateau. Alternate-day glucocorticoid therapy may not be protective. Not all patients exposed to long-term glucocorticoid therapy develop bone loss ; there are, however, no reliable biochemical predictive markers. Bone densitometry may be used to screen children who are at high risk for osteoporosis, although there are challenges with misinterpretation due to adult norms. There are limited guidelines on what frequency to perform densitometry and also controversy on the utility of other types of imaging modalities.
High-dose glucocorticoids have also been associated with avascular necrosis of bone (AVN), although the exact mechanism is unknown. Intramedullary vascular compromise may result from increased osteocyte apoptosis induced by glucocorticoids. In the absence of the clearance of these apoptotic osteocytes, reduced blood flow and bony ischemia may result. Glucocorticoids induce adipocyte differentiation via the increased production of PPAR-γ 2 , which may result in increased fat in the marrow. Finally, glucocorticoids also increase the expression of endothelin-I, which may also lead to reduced intramedullary blood flow. The most common and clinically significant location for AVN is the femoral head, and the underlying disease process (such as in SLE) can be a contributing factor as well as age.
Infection and immunity.
Glucocorticoids interfere with the ability to resist infection through two main mechanisms. They act as immunosuppressives and unpredictably decrease the patient’s resistance to viral and bacterial infections. They are also antiinflammatory agents and may mask the signs and symptoms of infection. The minimal dose and duration of systemic steroids that result in immunosuppression in an otherwise healthy child are not well defined. Additional factors that may affect the overall extent of immunosuppression in children with rheumatic diseases include the effects of the underlying disease and concurrent immunosuppressive therapies.
Patients receiving high doses of glucocorticoids for a prolonged period are prone to infections that are associated with defects of delayed hypersensitivity (e.g., tuberculosis). Thus if possible, the Mantoux test (purified protein derivative [PPD], 5 tuberculin units) should be performed before glucocorticoid initiation. The risk of complications of varicella infection must also be considered. A susceptible child being treated with glucocorticoids who is exposed to chickenpox should receive varicella- zoster immune globulin (VariZIG) as soon as possible, but can be given up to 10 days after exposure (this is only effective in prevention or modification of the disease course if administered before the disease is established; therefore, the sooner it is administered the better). If VariZIG is unavailable, intravenous immunoglobulin (IVIG) can also be used at a dose of 400 mg/kg IV up to 10 days after exposure. If acutely infected, IV acyclovir should be used to prevent dissemination, as oral acyclovir has poor oral bioavailability.
Central nervous system.
The effect of glucocorticoids on the CNS results from changes in the concentration of plasma glucose, circulatory dynamics, and electrolyte balance, reflected by changes in mood, behavior, and electroencephalographic studies. Most glucocorticoid-induced psychoses have an acute onset, are related to high doses, and occur within 96 hours after initiation of medication. Early on, there may be euphoria and mania; later, depression tends to predominate. Anxiety and insomnia may occur. Pseudotumor cerebri is rare but may occur after rapid dose reduction. A prospective cohort study of the adverse effects of high-dose intermittent intravenous glucocorticoids in 213 children with rheumatic diseases found behavioral changes in 21 (10%). These abnormalities included altered mood, hyperactivity, sleep disturbance, and psychosis.
The major effects of glucocorticoids on the cardiovascular system result in hypertension and dyslipidemia. The mechanisms by which these undesirable side effects occur are complex, but in part they are thought to be related to the regulation of renal sodium excretion, induction of angiotensin II receptors, increased plasma renin or antidiuretic hormone activity, and glucocorticoid effects upon capillaries, arterioles, and the myocardium. Dyslipoproteinemia and accelerated coronary atherosclerosis have been observed in patients, especially those with SLE, after prolonged administration of glucocorticoids. However, the pathogenesis of coronary artery disease in these patients is multifactorial, as uncontrolled disease activity likely also plays a role.
Cataracts and glaucoma.
Subcapsular cataracts can occur with glucocorticoid therapy. The risk of cataract development becomes significant when a dosage of prednisone equal to or greater than 9 mg/m 2 /day has been maintained for longer than 1 year. These cataracts often do not progress and rarely affect vision. Children should also be monitored for glaucoma.
Muscle wasting on high-dose glucocorticoid administration is associated with atrophy of muscle fibers, especially type IIB fibers. Myopathy induced by glucocorticoids usually affects proximal muscles, is seldom painful, and is usually associated with normal serum levels of muscle enzymes and an electromyogram suggestive of myopathy. Glucocorticoid-induced hypokalemia may also lead to muscular weakness and fatigue. Recovery from steroid myopathy may be slow and incomplete.
Glucocorticoids decrease the number of circulating lymphocytes, monocytes, basophils, and eosinophils, but increase the number of circulating neutrophils. Excess glucocorticoid may also cause polycythemia.
Other glucocorticoid side effects include glucose intolerance and glycosuria, and peptic ulceration.
The deleterious effects of glucocorticoids can be minimized by choosing a drug with a short half-life (see Table 12-3 ). Prednisone is the drug most often given for oral therapy, as its prominent glucocorticoid and minimal mineralocorticoid actions give it the lowest risk/benefit ratio of any of the analogues in general use.
The antiinflammatory effect and the toxicity of glucocorticoids increase with larger doses and more frequent administration ( Table 12-4 ). Short-acting glucocorticoids given in the morning do not suppress the pituitary as much as glucocorticoids given later in the day (which suppress the normal surge of adrenocorticotropic hormone [ACTH] that occurs during sleep) so once daily administration should always be in the morning.
|Divided daily doses||Optimal disease control||More side effects|
|Single daily dose||Good disease control; fewer side effects||May not control severe disease|
|Alternate-day dose||Fewer side effects, less chance of developing Cushing syndrome or pituitary suppression||Less disease control|
|Intravenous pulse therapy||Less long-term toxicity, rapid onset of action||Acute toxicities|
Reduction in glucocorticoid dose must be individualized for the child and the disease, and is often fraught with difficulty because of the adaptation of the patient’s metabolism to chronic steroid excess. At high dosages (e.g., 60 mg/day), reductions of 10 mg are usually well tolerated; at lower dosages (e.g., 10 mg/day), reductions of only 1 or 2 mg may be possible. An alternate-day regimen should be the goal to minimize toxicity, although some patients do not tolerate this regimen. In some children, steroid pseudorheumatism may result from a rapid dose decrease. These withdrawal effects gradually resolve over 1 or 2 weeks and are minimized if each decrement in daily prednisone is 1 mg or less per week (at the lower dose levels).
Many approaches for the prevention and treatment of corticosteroid-associated osteoporosis have been studied in adults, and several guidelines have addressed these issues. Vitamin D and its analogues, calcitonin, and various bisphosphonates have been used. Calcitriol (vitamin D 3 ) or cholecalciferol (vitamin D), with or without calcitonin, were shown to prevent bone loss from the lumbar spine better than calcium alone in several randomized controlled clinical trials of adults who started long-term glucocorticoid therapy. Treatment with calcium and vitamin D in adults who receive glucocorticoids effectively slows lumbar and forearm bone loss, and treatment with calcium and vitamin D supplementation has become standard practice in most centers for children with rheumatic disease who receive glucocorticoids.
Bisphosphonates have also been studied as a potential treatment for glucocorticoid-induced osteoporosis. Etidronate, pamidronate, alendronate, and risedronate have been shown in randomized controlled trials to increase lumbar spine bone mineral density in adults receiving long-term glucocorticoids for various diseases These trials did not include children, however, and did not show any significant reduction in fracture incidence, which is the most clinically relevant outcome. Bisphosphonates have been studied in children with osteogenesis imperfecta and seem to be beneficial in reducing bone resorption, increasing bone density, and reducing the chronic bone pain associated with this condition. In addition, although there are concerns regarding their effects on growth and remodeling, bisphosphonates have been found to be useful and safe in open-label studies of children with idiopathic juvenile osteoporosis, or osteoporosis associated with connective tissue diseases or induced by glucorticoids. Binding to bone and prolonged renal excretion (mean 7 years) continues to concern clinicians for long-term safety of these agents in children. This concern necessitates larger, prospective trials to evaluate bisphophonates for the prevention and treatment of glucocorticoid-induced osteoporosis in children.
Preventing acute adrenal insufficiency (addisonian crisis).
The use of pharmacological doses of glucocorticoids for a 2-week period may result in transient suppression of endogenous cortisol production, and prolonged therapy may lead to suppression of pituitary–adrenal function that can be slow in returning to normal. This is potentially the most serious and life-threatening adverse effect associated with glucocorticoid therapy. The actual doses and duration of therapy that are associated with suppression and the length of the recovery period after cessation of therapy are not well defined. The recovery period may even be affected by the underlying inflammatory process.
If not recognized, suppression of the hypothalamic–pituitary–adrenal axis places a child at risk for vascular collapse, adrenal crisis, and death in situations that demand increased availability of cortisol. Under conditions of stress (e.g., serious infection, trauma, surgery), all children who may be at risk for hypothalamic–pituitary–adrenal axis suppression require additional glucocorticoids.
The “stress dose” regimen is based on the body’s requirements for hydrocortisone during stress. Hydrocortisone (6 to 9 mg/m 2 /day divided three times daily) is needed for physiological maintenance. For febrile or severe illnesses, hydrocortisone requirements increase to 40 mg/m 2 /day. With induction of anesthesia or in a resuscitation situation, 100 mg/m 2 IV of hydrocortisone is required initially, and then 25 mg/m 2 IV every 6 hours for the following 24 to 48 hours.
If the patient is currently receiving glucocorticoids such as prednisone or prednisolone at a dosage equivalent to or greater than 40 mg/m 2 /day of hydrocortisone (see Table 12-3 for conversion), then the current glucocorticoid dose prescribed for disease management may be enough for febrile or severe illnesses. However, as steroids are weaned or discontinued after prolonged use, glucocorticoid replacement may be required to prevent adrenal crisis if the body’s corticosteroid needs exceed the dose prescribed for disease management.
High-dose intravenous glucocorticoid therapy.
Intravenous glucocorticoid “pulse” therapy is sometimes used to treat more severe, acute, systemic connective tissue diseases. The rationale of this approach is to achieve an immediate, profound antiinflammatory effect and to minimize toxicity related to long-term continuous therapy in moderate to high daily doses. Pulse methylprednisolone has been shown to inhibit cytokine generation and dissolve in cell membranes, altering membrane-associated proteins. Differences are seen in the alpha-interferon gene expression signature in pediatric lupus patients receiving pulse methylprednisolone therapy as compared with oral glucocorticoid therapy, which may explain an advantage this dosing regimen may have over oral doses. However, this observation will need further validation, and additional investigation is needed to optimize efficacy and minimize toxicity with this therapeutic modality.
Although oral pulse regimens have been reported, IV methylprednisolone has been the drug of choice, given in a dosage of 10 to 30 mg/kg/pulse up to a maximum dose of 1 g, administered according to various protocols ( eBox 12-2 ): a single administration as clinical circumstances warrant, a pulse each day for 3 to 5 days, or alternate-day pulses for three doses. Intravenous glucocorticoid pulse therapy may be associated with potentially serious complications ( eBox 12-2 ).
Methylprednisolone up to 30 mg/kg (maximum 1 g)
Prepare drug with diluent provided with package
Calculated dose is added to 100 mL normal saline and infused over 1 to 3 hours
Temperature, pulse rate, respiratory rate, blood pressure before beginning infusion
Pulse and blood pressure every 15 min for first hour, every 30 min thereafter
Slow rate or discontinue infusion, and increase frequency of monitoring, if there are significant changes in blood pressure or pulse rate
Side Effects/Potential Acute Toxicities
Hypertension or hypotension, tachycardia, bradycardia, cardiac arrhythmia secondary to potassium depletion, blurring of vision, hyperglycemia with or without ketosis, flushing, sweating, metallic taste in mouth, acute psychosis, behavioral changes, convulsions, anaphylaxis
Injection of long-acting glucocorticoids directly into inflamed joints has emerged as a major advance in the management of various types of arthritis. Although intraarticular steroid (IAS) therapy has not been studied in randomized controlled clinical trials, multiple reports have documented its efficacy and safety in children.
IAS therapy has been used most often in children with oligoarticular disease; indications for use have included lack of response to NSAIDs; significant NSAID toxicity; and the presence of joint deformity, growth disturbance, or muscle wasting, or as an alternative to NSAID therapy in children with oligoarticular disease. In polyarticular disease, multiple IAS injections at one time can be used as a temporizing measure while awaiting response to second-line systemic agents to take effect. IAS may also be useful as an alternative to increasing systemic therapy in children with polyarticular disease who have significant inflammation in only a few joints.
Virtually all patients experience rapid resolution of symptoms and signs of joint inflammation within a few days after injection, resulting in improved physical function. About two thirds achieve remission for at least 12 months after a single injection. A longer duration of response has been described in children with oligoarticular JIA, and in those who are younger, with shorter disease duration, and with higher mean erythrocyte sedimentation rates. Early use of IAS injections have been associated with less leg-length discrepancies in patients with asymmetrical pauciarticular JRA. More recent data suggest the effectiveness of using radiographic assistance to guide IAS injections into involved temporomandibular and subtalar joints.
Type of steroid, dosage, and frequency of injection.
Various preparations are available for IAS injection. The most frequently studied agents in children are triamcinolone hexacetonide (THA) and triamcinolone acetonide. These agents are completely absorbed from the site of injection over 2 to 3 weeks. Because of its lower solubility, THA is absorbed more slowly than triamcinolone acetonide, thereby maintaining synovial levels for a longer period and resulting in lower systemic glucocorticoid levels, and it is preferred by most pediatric rheumatologists. In comparative studies in patients with JIA, at equivalent doses, THA was found to be more effective than triamcinolone acetonide, betamethasone, and methylprednisolone.
The dose of THA used in clinical studies has varied: Some data indicate that higher doses (about 1 mg/kg) may be associated with a better response. Generally, children who weigh less than 20 kg receive 20 mg of THA in large joints. Children weighing more than 20 kg receive 30 to 40 mg THA in the hips, knees, and shoulders, and 10 to 20 mg in the ankles and elbows. In smaller joints such as the wrist, midtarsal, and subtalar joints, 10 mg is used. For injections into tendon sheaths and small joints of the hands and feet, 0.25 to 0.50 mL of a combination of methylprednisolone acetate mixed 1 : 1 with preservative-free 1% lidocaine (Xylocaine) is recommended. The shorter acting steroid is associated with less risk of damage to tendon sheaths or local soft tissue atrophy.
Repeated injections into the same joint are not performed more than three times per year, although there are few data on which to base this recommendation. There are also no controlled studies in children that examine whether postinjection rest has a role. Although full immobilization of the injected joint is common practice in some clinics, the authors’ recommendation is to limit ambulation and strenuous activity for the first 24 hours after a joint injection.
Despite initial reservations about the safety of IAS therapy in children, clinical studies indicate an overall favorable adverse-effect profile. Iatrogenic septic arthritis is always a potential risk, yet it occurs very rarely and can be avoided with appropriate aseptic precautions. Transient crystal synovitis occurs rarely but is self-limited within 3 to 5 days in most cases without any intervention. The most frequent adverse effects are atrophic skin changes at the site of injection, particularly of smaller joints such as wrists, ankles, and interphalangeal joints in young children, and asymptomatic calcifications on radiographs in joints after multiple injections. The frequency of these skin changes differs by joint, and most eventually resolve. The skin changes are attributed to leakage of long-acting steroids into subcutaneous tissues and can be minimized by clearing the needle track with injection of saline or local anesthetic as the needle is withdrawn from the joint. Radiographic reviews have shown usually asymptomatic joint calcifications in 6% to 50% of injected joints. Nonspecific cartilage changes have been seen in children with multiple IAS injections after long-term monitoring. Systemic steroid effects can occur in rare instances.
Cytotoxic, Antimetabolic, and Immunomodulatory Agents
Cytotoxic drugs prevent cell division or cause cell death. They act primarily on rapidly dividing cells such as cells of the immune system, particularly T lymphocytes, and are immunosuppressive. The cell cycle consists of the G 1 presynthetic phase, the S phase (synthesis of DNA), the G 2 resting (or postsynthetic) phase, and mitosis. Cytotoxic drugs act during various stages of the cell cycle. These agents are maximally effective in inhibiting immunological responses when their administration coincides with the period of proliferation of the specific immunologically competent cells.
Azathioprine, a purine analogue, is inactive until it is metabolized to 6-mercaptopurine (6MP) by the liver and erythrocytes. After that, 6MP is transported into cells via nucleoside transporters and undergoes intracellular activation: first to thioinosinic acid by hypoxanthine phosphoribosyl transferase and then through several additional steps, which results in the formation of thioguanine monophosphate, which inhibits de novo purine synthesis. Azathioprine’s immunosuppressive effects are related primarily to inhibition of T-cell growth during the S phase of cell division. A measurable decrease in antibody synthesis occurs with long-term administration. Oral bioavailability of azathioprine is approximately 50%, and about one third of absorbed drug is protein bound. The plasma half-life is approximately 75 minutes, with renal excretion being the primary route of elimination for 6MP and its metabolites. Therefore, proportional dosage adjustment for glomerular filtration rate (GFR) of 50 mL/min/1.73 m 2 or lower is recommended.
The use of azathioprine has been reported anecdotally in many pediatric rheumatic diseases and in series of patients with JRA or SLE. Starting dosages should be 1 to 1.5 mg/kg/day, increasing as needed and as tolerated to 2 to 2.5 mg/kg/day, with a maximum dose of 150 mg daily ( eTable 12-5 ).
|DRUG||DOSAGE AND ROUTE||CLINICAL MONITORING||LABORATORY MONITORING|
|Azathioprine||0.5-2.5 mg/kg/day in a single dose, max 150 mg daily, oral (taken with food)||Initial evaluation in 1-2 months and then every 3 months||CBC with WBC count, differential and platelets every 1-2 weeks until stable dose, then every 4-12 weeks |
AST, ALT, BUN, creatinine every 4 weeks until stable dose achieved, then every 12 weeks
Consider testing TPMT genotype and/or activity at baseline
Adjust dosing (may have to discontinue) for WBC <3,500/mm 3 , platelets <100,000/mm 3 , or elevated AST/ALT
|Mycophenolate Mofetil||Initial: 300 mg/m 2 /dose given twice daily, oral |
Increase in 2 weeks to 600 mg/m 2 /dose twice daily
Maximum dose 2-3 g/day depending on indication
|Initial evaluation in 1-2 months and then every 3 months||CBC with WBC count, differential and platelets; urine pregnancy screening, if appropriate every 4-12 weeks |
Adjust dosing (may have to discontinue) for WBC <3,500/mm 3 , platelets <100,000/mm 3 , or falling hemoglobin not related to disease activity
|Cyclophosphamide||Daily: 0.5-2 mg/kg/day, oral or IV |
IV pulse: 0.5-1.0 g/m 2 every 2-4 weeks (see eBox 12-3 )
|Evaluation monthly |
Encourage fluid intake to minimize risk of hemorrhagic cystitis
Encourage frequent emptying of bladder
|CBC with WBC count, differential and platelets and UA every week until stable dose, then every 4 weeks |
AST, ALT, BUN, creatinine and urine pregnancy screening, if appropriate, every 4 weeks
Adjust dosing (may have to discontinue) for WBC <1,500/mm 3 , platelets <100,000/mm 3 , or hematuria
|Cyclosporine||3-5 mg/kg/day divided twice a day, oral |
If using liquid neoral, use glass dropper; may be mixed with milk, apple juice, or orange juice
|Blood pressure every week for first month, then monthly||CBC with WBC count, differential and platelets; AST, ALT, BUN, creatinine, UA and urine pregnancy screening, if appropriate, at baseline and every 4 weeks |
Maintain 12-hour whole-blood trough drug levels between 125 and 175 ng/mL (RIA method)
Reduce dose if creatinine increases by 30%
0.5-1.0 g/m 2 cyclophosphamide
IV 0.9% sodium chloride 20 ml/kg (max 1 liter) bolus
Cyclophosphamide is mixed with D5 1/2 normal saline to infuse over 6 hours
Three mesna doses equaling the total cyclophosphamide dose are administered intravenously in D5W: one third of the dose is given 30 min before the infusion, one third midway through the dose, and one third at the end of the infusion. (Alternatively, the last dose of mesna can be given by mouth but at double the IV dose [i.e., two thirds of the total cyclophosphamide dose].)
Ondansetron (0.15 mg/kg/dose diluted in 0.9% sodium chloride) IV or by mouth 30 min before cyclophosphamide and every 8 hours until infusion is complete. Ondansetron by mouth every 8 hours times 2 doses at home
Pulse, blood pressure, and respiratory rate every 30 min during infusion, then every 4 hours for next 24 hours
Urinalysis before and after infusion
Monitor urinary output: Empty bladder every 2-4 hours; if urinary output falls to less than 50% of IV input over any 4-hour period, give furosemide 1 mg/kg IV. Repeat at 2-4 mg/kg in 2 hours, if necessary
Toxicity to the GI tract (oral ulcers, nausea, vomiting, diarrhea, epigastric pain) is common. Toxicity to the liver, lung (interstitial pneumonitis), pancreas, bone marrow (cytopenias), or skin (maculopapular rash) is uncommonly associated with azathioprine therapy. Use of azathioprine is accompanied by the known risk of idiosyncratic arrest of granulocyte maturation that occurs shortly after initiation of therapy. This bone marrow toxicity has been attributed to genetic variation in thiopurine S-methyltransferase (TPMT), the enzyme normally responsible for conversion of the active metabolite 6MP to the inactive metabolite 6-methylmercaptopurine. The most common genetic variants ( TPMT*2, *3A, and *3C ) account for 98% of low activity phenotypes in Caucasians and are associated with reduced activity of the enzyme, resulting in higher than expected intracellular levels of active 6-thioguanine nucleotide metabolites and subsequent myelosuppression. Approximately 90% of the population possesses two fully active copies of the gene, approximately 10% of the population has one variant allele (heterozygous genotype) and intermediate activity, and approximately 0.03% of the population possess a homozygous variant genotype and are considered to be “TPMT deficient” at highest risk for myelotoxicity with standard azathioprine doses. Lower levels of enzymatic activity have been observed in African Americans, and ontogeny does not appear to contribute to changes in enzyme activity. Testing of thiopurine methyltransferase levels, as well as TPMT genotype, is available commercially; however, there remains variation in utilization of these tests prior to azathioprine administration across subspecialties. Additional enzymes in the thiopurine metabolic pathway have recently been shown to have an effect on myelotoxicity.
The bone marrow suppressive effects of azathioprine can be increased by concomitant use of trimethoprim. Although the risk of malignancy theoretically increases in patients treated with azathioprine, the long-term data are inconclusive, and in adults with RA treated with azathioprine, there was no increased risk. The combination of azathioprine with infliximab is associated with increased hepatosplenic T-cell lymphoma.
Azathioprine crosses the placenta but the fetal liver lacks the enzyme inosinate pyrophosphorylase, which is necessary to convert azathioprine and 6MP to active metabolites, so the fetus should be protected from teratogenic effects. Clinical studies have revealed no association with poor pregnancy outcomes in inflammatory bowel disease patients treated with 6MP. Breast-feeding is contraindicated because the drug is transferred into breast milk.
Mycophenolate mofetil (MMF) is an ester prodrug form of mycophenolic acid (MPA) and has been found to be effective in various autoimmune diseases as a selective noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key rate-limiting step in the de novo synthesis of guanine nucleotide—a pathway in which T and B lymphocytes are primarily dependent. IMPDH exists in two forms: IMPDH1 is ubiquitously expressed in most cell types, whereas IMPDH2 is expressed in activated T cells. MPA exerts more potent cytostatic effects on T cells due to four- to five fold greater inhibition of IMPDH2 relative to IMPDH1.
MMF is rapidly absorbed after oral administration with a bioavailability of approximately 94%. Peak plasma levels occur 1 to 3 hours after a single dose, with a second peak at 6 to 12 hours as a result of enterohepatic circulation. Upon absorption, MMF is hydrolyzed by carboxylesterases in the liver to biologically active MPA. MPA is 97% albumin bound, and because of its extensive binding to albumin, MMF may interact with other albumin-bound drugs. MMF can also be hydrolyzed in the acidic environment of the stomach, and coadministration of proton pump inhibitors that suppress acid production and gastric pH has been reported to result in decreased potency of MMF. Antacids containing aluminum and magnesium decrease absorption and should also not be administered simultaneously. The elimination half-life of MPA is approximately up to 17 hours after oral administration. The major route of elimination is formation of MPA-glucuronide (MPAG) and UDP-glucuronosyltransferases in the liver (UGT 1A9) and intestine (UGT 1A8 and UGT 1A10). Allelic variations in these enzymes have been investigated.
The carboxyl group of MPA can also be glucuronidated by UGT2B7 to form an acyl glucuronide metabolite (AcMPAG), and although a minor pathway, it may contribute to MPA toxicity. MPAG is excreted into bile by the MRP2 (ABCC2) transporter, converted back to MPA by bacterial glucuronidases, and subsequently reabsorbed, giving rise to the secondary peak observed in pharmacokinetic studies. Most MPA (87%) is recovered in the urine as MPAG.
The effective adult dosage in solid organ transplantation is 2 to 3 g/day in two divided doses. The recommended dosage used to prevent solid organ transplant rejection in children 13 months to 18 years of age is 600 mg/m 2 /dose twice daily. Cyclosporine and, to a lesser extent, tacrolimus alter the kinetics of MMF so that higher doses may be required when coadministering. In children with autoimmune diseases, initial dosing is recommended at approximately 300 mg/m 2 /dose twice daily and then increased to 600 mg/m 2 /dose twice day with a maximum daily dose range of 2000 to 3000 mg/day ( eTable 12-5 ).
Individual pharmacokinetic profiling is available and can be especially helpful in determining the lowest effective dose in patients who experience side effects, and pharmacokinetic and pharmacodynamic (PK/PD) measurements have even been explored to guide dosing in pediatric SLE. Sagcal-Gironella and colleagues reported only a moderate relationship between weight-adjusted MMF dosing and MPA exposure with a large interindividual variability in the AUC. This high interindividual variability in MPA AUC was also seen in adult patients treated with MMF for SLE. Single nucleotide polymorphisms in genes that encode enzymes important in MMF biotransformation are being explored.
Adverse effects of MMF include GI toxicity, hematological effects (leukopenia, anemia, thrombocytopenia, pancytopenia), and opportunistic infections. GI side effects are usually improved by giving the dose three or four times a day instead of twice a day or by reducing it. Hematological toxicity usually responds to therapy cessation within 1 week. Pure red blood cell aplasia has been reported in patients treated with MMF, mostly when combined with other immunosuppressing agents after transplantation. A large prospective registry of 6751 transplant patients receiving MMF compared with an equal number of matched controls revealed no increased risk of malignancy with MMF.
Several cases of structural malformations have been seen with MMF exposure during pregnancy in renal transplant recipients and others. In fact, the FDA has approved a single shared REMS for medications that contain mycophenolate. Breast-feeding is not recommended.
Cyclophosphamide, an alkylating agent, is a nitrogen mustard derivative. It is well absorbed after oral administration and is also given intravenously ( eTable 12-5 and eBox 12-3 ). It is inactive until metabolized, principally in the liver, by cytochrome P-450 enzymes to inactive intermediates and the active metabolite phosphoramide mustard. Phosphoramide mustard covalently binds to guanine in DNA, destroying the purine ring and preventing cell replication. Cyclophosphamide potentially acts on all cells, including cells that are mitotically inactive (G 0 interphase) at the time of administration (e.g., memory T cells). Excretion of the drug is primarily by the kidney, and the dose must be reduced in patients with renal impairment ( eTable 12-6 ). As cyclophosphamide is dialyzable, it is important to delay hemodialysis until at least 12 hours after intravenous administration of the drug. The half-life of cyclophosphamide is approximately 7 hours.