Dose (mg/kg/day unless otherwise noted)
Maximal dose (mg/day)
Doses per day
Acetylsalicylic acid (ASA)
80–100 (<25 kg); 2500 mg/m2 (>25 kg)
3–5 mg/kg/day single dose
(OD for low dose)
Kawasaki disease: high dose for initial phase and low dose for subsequent treatment (stop ASA if LFT >3 times normal)
Association with Reye syndrome
Most frequently used; favorable efficacy and toxicity profile
Pseudoporphyria in fair skin patients
Most favorable efficacy/toxicity profile
Associated with aseptic meningitis in children with SLE
Indicated in spondyloarthropathies and treatment of fever/pericarditis in children with systemic onset JIA
Headache seen commonly at initial therapy may decrease with continuation
Less favorable toxicity profile
Potency akin to indomethacin
Extended-release tablets available at 400-, 500-, 600-mg strength
Least favorable efficacy/toxicity profile
Can mix tablet in water to create a slurry
>2 years and 10–25 kg: 50 mg twice daily
>2 years and 25–50 kg: 100 mg twice daily
Lowest effective dose for shortest time
Mechanism of Action
NSAIDs inhibit the cyclooxygenase (COX) enzyme which is required for the conversion of arachidonic acid to prostacyclin, prostaglandin, and thromboxane, the major mediators of inflammation. There are two isoforms of the COX enzyme: COX-1 and COX-2. Although they have 60 % sequence homology, they are coded by distinct genes and differ in their distribution and expression in the tissues. These enzymes catalyze the conversion of arachidonic acid to prostaglandin G2 and H2. COX-1 provides prostaglandins required for homeostatic function leading to vascular homeostasis, cytoprotection, maintenance of renal blood flow, and platelet aggregation. COX-2 is upregulated at the site of inflammation by pro-inflammatory mediators (e.g., interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), bacterial endotoxins, mitogenic and growth factors). COX-2 also plays a role in pathogenesis of fever and pain. Most NSAIDs preferentially inhibit COX-1, resulting in undesirable adverse effects while producing the desired anti-inflammatory effects by simultaneous inhibition of COX-2. NSAIDs that are more selective for COX-2 have a better adverse effect profile. Further it is observed that the doses of NSAIDS required to reduce inflammation are generally higher than the doses required to inhibit prostaglandin formation, suggesting the existence of other mechanisms for mediation of their anti-inflammatory effects. NSAIDs also inhibit specific proteinases that degrade collagen and proteoglycan, the generation of superoxide, release of bradykinin, lymphocyte response to antigen, and chemotaxis of monocytes and neutrophils. Indomethacin also blocks the action of phosphodiesterase leading to a decrease in the superoxide and hydroxyl radical generation and an increase in the intracellular cyclic adenosine monophosphate (anti-inflammatory).
NSAIDs are weakly acidic drugs that are rapidly absorbed after oral administration. Most of the absorption occurs in the stomach and upper small intestine. Circadian rhythms in gastric pH and intestinal motility may affect absorption. Hence there may be reduced absorption at night as compared to the morning. As most NSAIDs are protein bound, severe hypoalbuminemia may cause an increase in the unbound fraction of the drug and subject the patient to increased toxicity. Hepatic or renal disease may also reduce protein binding.
The kinetics of NSAIDs at the sites of action (e.g., synovial fluid) depends on the protein binding at that site and the half-life of the drug. As the synovial fluid albumin concentration is lower than the plasma concentration, the free fraction of NSAID in the synovial fluid is significantly higher, and this has been correlated to the clinical response .
Most NSAIDs are metabolized in the liver; thus baseline liver function tests should be done. If transaminase levels are more than three times normal, NSAIDs should be avoided. Sulindac and indomethacin also undergo enterohepatic recirculation . Most NSAIDs have first-order kinetics for their metabolism, whereas salicylates (ASA) are metabolized by zero-order kinetics. Hence dosage adjustments are frequently required with ASA therapy. There may be differences in the metabolic clearance of individual drugs among patients leading to a variation in their accumulation at different sites in the body. Children require more frequent doses for a sustained clinical response as they eliminate the NSAIDs more rapidly as compared to adults [5, 6].
General Principles of NSAID Therapy
NSAIDs have good antipyretic and analgesic effect but a weak anti-inflammatory effect.
Anti-inflammatory effect takes a longer time and requires almost double the analgesic dose.
They provide symptomatic relief, but do not influence the underlying disease process.
They are generally safe for prolonged use.
Toxicity is rarely serious; indomethacin and ASA are more toxic than the others.
There is variation in response to NSAIDs either related to disease or due to interindividual variability in metabolism.
An NSAID trial must be given for at least 6–8 weeks; 50 % respond favorably by 2 weeks. If there is inadequate response/toxicity, then another drug of the same class is tried.
Patient preference can be influenced by frequency of dosing, cost, availability in liquid form, and tolerability.
Therapy should begin with the lowest recommended dose and titrated to the clinical response for the shortest duration possible.
Avoid the use of multiple NSAIDs to minimize drug interactions and organ toxicity.
Gastrointestinal toxicity: It is common to all NSAIDs. Symptoms may range from mild epigastric discomfort to peptic ulceration. Ibuprofen and COX-2 inhibitors are associated with lower risk of serious GI complications; indomethacin, sulindac, naproxen, and aspirin have moderate risk; and ketoprofen, tolmetin, and piroxicam have the highest risk [7, 8].Toxicity can be reduced by giving the drug after food. Routine use of antacids in asymptomatic children on NSAIDs is not advised. Misoprostol which is a synthetic prostaglandin E1 analogue is effective in the treatment of GI toxicity [9, 10]. Studies in adults have shown that omeprazole (proton pump inhibitor – PPI) is superior to ranitidine and misoprostol for the prevention and treatment of NSAID-related gastroduodenal ulcers [11, 12].
Renal toxicity: Reversible renal insufficiency mediated due to decreased prostaglandins by NSAIDs is the most common renal toxicity. Acute interstitial nephritis with nephrotic syndrome is rarely reported and is thought to be a hypersensitivity reaction. It has an abrupt onset with proteinuria, hematuria, and flank pain and responds to glucocorticoids. Interstitial nephritis with or without nephrotic syndrome is reported with the use of naproxen, tolmetin, indomethacin, and sulindac. Papillary necrosis is seen with prolonged use of ibuprofen and mefenamic acid.
Central nervous system: Ibuprofen is commonly reported to cause aseptic meningitis. Indomethacin is implicated in inducing psychotic symptoms and seizures.
Dermatological: Pruritus, erythema multiforme, urticarial, and phototoxic reactions can occur. Pseudoporphyria in exposed areas has been described particularly in fair-skinned children on treatment with naproxen .
Cardiovascular: In adults, there is an increased risk of cardiovascular toxicity: myocardial infarction, hypertension, cerebrovascular ischemia, and exacerbation of congestive heart failure are associated with several NSAIDs and COX-2 inhibitors. Hence it is recommended that low-dose aspirin may be given with COX-2 inhibitors in the rare child with cardiac risk factors and a need for NSAID. Further, aspirin must be taken at least 2 h before NSAIDs or COX-2 inhibitors to minimize drug interaction.
Hematological toxicity: NSAIDs interfere with platelet prostaglandin synthesis and reduce platelet adhesiveness. Leukopenia, thrombocytopenia, agranulocytosis, and aplastic anemia have been rarely reported . Mild anemia can occur due to hemodilution, hemolysis, or occult GI bleed secondary to NSAID therapy .
Reye syndrome: This condition is associated with salicylate use in viral infections (chicken pox/influenza). It is rarely seen and its association with ASA is controversial .
Glucocorticoids (GCs) are the most potent anti-inflammatory drugs used in children with rheumatic diseases (Table 7.2).
Glucocorticoids – equivalent doses and relative inflammatory potency
Equivalent doses to 5 mg prednisolone (mg)
Relative anti-inflammatory potency
Pharmacology [1, 2] Glucocorticoids are 21-carbon molecules that have a hydroxyl group at C11 in their active form (prednisolone and hydrocortisone are the active forms of prednisone and cortisone, respectively).
Glucocorticoids have both a physiological and a pharmacological role. They enter cells passively and bind to mineralocorticoid (type I) and glucocorticoid (type II) receptors (GRs). Type I receptors which have highest affinity for aldosterone are present on epithelial cells of the colon, kidney, and salivary glands and on non-epithelial cells in the heart and brain. Activation of mineralocorticoid receptors causes sodium retention and hypertension by inducing activity of epithelial sodium channels.
Type II receptors have the highest affinity for dexamethasone and are present in almost all cells. The receptors are present in the cytoplasm and consist of a DNA-binding domain, a hormone-binding portion, and an immunogenic region. Binding of the hormone to the receptor leads to translocation of the complex to the nucleus. The DNA-binding portion attaches to glucocorticoid-responsive elements of the DNA in the promoter or enhancer region of the responsive genes. This causes mRNA transcription of genes that encode for proteins required in inflammatory and immune responses, such as phospholipase A2 inhibitory protein, and results in reduced prostaglandin production. Gene transcription may be repressed by binding to negative glucocorticoid-responsive elements. Thus genomic action mediates both activation and repression of gene transcription. The modular hypothesis for the therapeutic effects of these drugs postulates the following three steps [1, 3, 18]:
Module 1: Low-dose glucocorticoids, genomic effects occur. Classic receptor-mediated actions result in increased transcription of some genes (lipocortin-coding genes) and reduced transcription of some genes (cytokine-coding genes). These effects are seen 30 min after drug administration due to binding to cytosolic receptors and result in the net anti-inflammatory and immunosuppressive effects.
Module 2: Specific non-genomic effects occur as the dose is increased to approximately 200–300 mg of prednisone equivalent per day, due to a greater occupation of receptors. These receptor-mediated actions occur within minutes after drug administration. The behavioral changes, negative feedback of ACTH production, and apoptosis (programmed cell death) may be the clinical correlation of this function.
Module 3: Nonspecific non-genomic mechanisms, mediated by membrane-bound receptors, occur by the assumed additional therapeutic effects of higher dosages by even more rapid effects (within seconds) by physicochemical interactions within cellular membranes, e.g., the antianaphylactic actions of glucocorticoids.
Thus, this hypothesis provides a modular system whereby increasing dosage increases the therapeutic effect, by recruitment of numerous non-genomic actions, with increasingly more rapid onset of effect than the classic genomic actions of glucocorticoids.
Indications for Systemic Glucocorticoid Therapy
It is important to set a clear therapeutic target and plan for duration of therapy. The benefit/risk ratio must be considered especially when prescribing systemic GCs. The aim is to limit the dose and duration of steroid therapy to the lowest possible level while achieving optimum disease control. Single morning dose and alternate-day regimen have been shown to minimize toxicity and suppression of linear growth in children . The indications for the use of steroids are dealt with in the specific chapters.
Most adverse effects of corticosteroids are due to the prolonged use of high dose of drug or because of abrupt withdrawal of therapy.
Cushing syndrome is characterized by truncal obesity, hirsutism, hypertension, striae, osteoporosis, and increased appetite.
Osteoporosis: The diagnosis of osteoporosis in children necessitates a history of clinical fracture (at least one fracture of a long bone in the lower limbs, at least two fractures in the upper limbs, or one compression vertebral fracture) associated with lowered bone densitometry . This consequence of long-term therapy could be due to inadequate dietary intake of calcium and vitamin D, reduced physical activity, high disease activity, low body weight, poor exposure to sunlight, and finally on the dose and duration of treatment with steroids.
Immunosuppression: Corticosteroids (CS) reduce the resistance to viral and bacterial infections as they suppress humoral and cellular immune response. In addition CS may mask the signs and symptoms of infection. Risk of tuberculosis is also increased. Thus, Mantoux test may be done before starting CS. Bacterial infections must be treated aggressively while on steroid therapy.
Cardiovascular system: Steroid-induced hypertension and premature atherosclerosis are seen in a few patients.
Central nervous system: These may include mood and behavioral changes, euphoria, aggression, and even psychosis. Psychosis, though less common in iatrogenic Cushing syndrome than the idiopathic variety, has an acute onset and is related to high doses of the drug. Reversible posterior leukoencephalopathy syndrome (RPLS) or posterior reversible encephalopathy syndrome (PRES) is a complication characterized by confusion, headache, convulsions, and visual loss due to a combination in different degrees of immunosuppression, nephropathy, hypertension, and inflammation .
Eye: Risk of developing subcapsular cataracts is seen when the dose of prednisone is equal or greater than 9 mg/m2/day and is taken for more than a year. This rarely affects vision. These children should also be monitored for glaucoma.
Muscle disease: High-dose therapy is associated with atrophy of muscle fiber especially type II B fiber. Steroid myopathy is seldom painful, usually affects the proximal muscles, has normal muscle enzymes, and has amyopathic electromyogram. Muscle biopsy can differentiate active myositis from steroid-induced myopathy. Muscular weakness and fatigue may also be attributed to steroid-induced hypokalemia and vitamin D deficiency. Recovery may be incomplete and delayed .
Endocrine: Children with genetic predisposition to diabetes mellitus may develop glycosuria and glucose intolerance after exposure to large doses for an extended period.
Avascular necrosis of the bone (AVN): Exact mechanism of AVN with high-dose glucocorticoids is not known. Accelerated glucocorticoid-induced osteocyte apoptosis may cause intramedullary vascular compromise.
It is imperative to curtail toxicity of steroids as most of the rheumatologic diseases in children persist as they transit to adulthood [24, 25].
Prednisone has the best risk/benefit ratio due to its minimal mineralocorticoid and enhanced glucocorticoid action. Deflazacort may have a bone-sparing effect when compared to prednisone but is not frequently prescribed in rheumatic diseases in children. The anti-inflammatory efficacy and drug toxicity are dose and frequency dependent. Short-acting glucocorticoids may be given in the morning to reduce suppression of the pituitary axis.
Tapering of CS is individualized for the disease and the patient. Dose can be reduced by 10 mg if the child is on high dose, e.g., 60 mg/day. At lower doses, e.g., 10 mg/day, a decrease of 1 or 2 mg may be better tolerated. Alternate-day therapy may be well tolerated but may not be as efficacious. Steroid pseudo-rheumatism and pseudotumor cerebri may occur in some patients with rapid reduction of the drug .
Calcium and vitamin D supplementation can help to maintain bone health in children treated with CS. Bisphosphonates may be needed for glucocorticoid-induced osteoporosis. The most frequently used drug is alendronate 5 mg/day in children weighing less than 20 kg and 10 mg for children weighing more than 20 kg given on an empty stomach .
Glucocorticoids given for about 2 weeks in pharmacological doses can cause transient suppression of endogenous cortisol production. Prolonged treatment can suppress the hypothalamo-pituitary-adrenal axis. The time lag in returning to normal may predispose the child to adrenal insufficiency which may be life threatening (adrenal crisis, vascular collapse). Additional CS must be prescribed when these children are under stress, e.g., with surgery, trauma, and infection. GC must be supplemented in any child undergoing surgery that has been given glucocorticoids in the past 36 months. In an elective procedure, “steroid preparation” may consist of dexamethasone 0.10–0.15 mg/kg/day every 6 h for 24 h prior the surgery and continuous intravenous infusion of hydrocortisone at 1.5–4 mg/kg/day during the surgery and 24 h postoperative till the child is able to take prednisone by mouth. These doses can be modified according to the degree of stress and the magnitude of the suppression of the axis .
High-Dose Intravenous Glucocorticoid Therapy
“Pulse therapy” is used to treat severe systemic connective diseases such as vasculitis, SLE, JDM, and macrophage activation syndrome. The aim is to achieve instant profound anti-inflammatory effect, minimize toxicity, and have a rapid clinical improvement. Methylprednisolone in a dose of 10–30 mg/kg/day up to a maximum of 1 g for 1–5 days has been the drug of choice. Abnormal behavior may be observed in 10 % of children (e.g., hyperactivity, psychosis, disorientation, and sleep disturbances). Other adverse effects seen are hypertension, hypotension, tachycardia, hyperglycemia, vomiting, hives, pruritus, bone pain, and avascular necrosis (AVN) of the bone .
Long-acting intra-articular steroids (IAS) can be injected into almost every joint in the human body. IAS therapy has a role as an alternative to NSAID therapy in oligoarticular disease. In polyarticular disease, IAS therapy in multiple joints can temporarily relieve symptoms while awaiting the response of the second-line agents. IAS treatment can reduce NSAID dosage, joint deformity, growth deformity, and muscle wasting. About two thirds of children achieve remission for about 12 months after a single dose. The duration of remission is better in oligoarticular disease when compared to polyarticular disease.
Triamcinolone hexacetonide (THA) and triamcinolone acetonide (TA) are examples of the long-acting and least soluble forms of steroids. These are absorbed from the sites of injection within 2–3 weeks. Intra-articular THA is superior in efficacy when compared to TA, hydrocortisone, and methylprednisolone in equivalent doses .Triamcinolone hexacetonide is unavailable currently in many countries including India. The doses though not standardized is usually 20 mg THA in the large joints in children weighing less than 20 kg; 30–40 mg in children weighing more than 20 kg in the knees, hips, and shoulders; 10–20 mg in the elbows and ankles; 10 mg in the wrist, subtalar, midtarsal, and other smaller joints. 0.25–0.50 ml of methylprednisolone and preservative-free 1 % lignocaine (1:1 dilution) can be injected into the tendon sheaths and small joints of feet and hands. Joint injections can be given not more than three times per year in the same joint . IAS is a very safe procedure, and septic arthritis can be avoided by using proper aseptic precautions. Atrophic skin changes at injection sites are due to leakage of drug into the subcutaneous tissues, which can be minimized by injecting saline or local anesthetic while withdrawing the needle from the track. Some children may have transient suppression of endogenous cortisol suppression.
Disease-Modifying Antirheumatic Drugs (DMARDs)
Traditional DMARDs exert their beneficial effects a few weeks after initiation of therapy. These include methotrexate, hydroxychloroquine, leflunomide, and sulfasalazine. They are prescribed early in the course of the disease to achieve quick disease control, reduce damage, and improve the health-related quality of life. These drugs also help in reducing the need for NSAIDs and steroids.
MTX has multiple actions such as anti-inflammatory, immunomodulatory, and antimetabolite actions. It modulates the function of several cells involved in inflammation and influences production of various cytokines. The biologic effects of this drug may account for its use in a wide variety of illnesses such as cancer, psoriasis, sarcoidosis, JIA, uveitis, dermatomyositis, Crohn’s disease, vasculitis, and other rheumatic and chronic inflammatory diseases [1, 27–29].
MTX is a folate antagonist. It should be administered on an empty stomach with water or clear beverages. Bioavailability with intramuscular injection is 15 % better than the oral bioavailability. Bioavailability of the subcutaneous and intramuscular route of drug administration is similar with the former being more acceptable for children requiring parenteral therapy.
It is a potent competitive inhibitor of dihydrofolate reductase (DHFR). It may also interfere with the metabolic transfer of single carbon units in the methylation reaction, especially those involving thymidylate and purine deoxynucleoside synthesis. These processes are required for DNA synthesis.
MTX may also interfere with de novo purine biosynthesis by inhibition of an enzyme in the purine biosynthetic pathway [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase].
It is postulated that intracellular MTX-glutamate derivatives are the true active anti-inflammatory agents as there is a latent period of weeks before the MTX effect is observed in children with JIA. MTX-glutamate binds with DHFR and has high affinity for enzymes requiring folate cofactor including thymidylate synthetase (TS) and AICAR transformylase. The inhibition of TS, induced by MTX, impedes the DNA synthesis in actively dividing cells, and the increase of AICAR enzyme system enhances release of adenosine into the blood. The anti-inflammatory effect of MTX may be due to the extracellular adenosine release at site of inflamed tissues and its interaction with specific cell surface receptors.
Practical Issues with MTX
Route of administration: Oral treatment is satisfactory in most patients as a single weekly dose given on an empty stomach with water, carbonated, or citrus beverage. For dose more than 15 mg/m2/week, the parenteral route is preferred because of the reduced oral bioavailability of the drug at high doses. Subcutaneous administration of MTX has a 10–12 % increased absorption compared with the oral tablet . Parenteral MTX at initiation of treatment may ensure complete absorption and early disease remission.
Baseline information before drug initiation: Weight, height, body surface area, complete blood count, ESR and/or C-reactive protein, transaminases, renal function tests, and urine analysis must be done. Varicella and MMR titers may be measured if facilities are available. Vaccination should be administered if child’s titers are negative .
Duration for therapeutic effect: At the standard dose regime, 60–75 % of patients with JIA benefit from MTX therapy, with improvement seen by 6–12 weeks; the maximum therapeutic effect usually becomes apparent 4–6 months after commencing the treatment. A multinational, randomized controlled study coordinated by the Pediatric Rheumatology International Trials Organization (PRINTO) compared 30 mg/m2/week MTX dose with 15 mg/m2/week dose in children with polyarticular JIA who failed to improve significantly on the conventional dose regimen (8–12.5 mg/m2). Seventy-two percent improved significantly with the conventional dose, and when the dose was increased to 15 mg/m2, there was a significant improvement in the nonresponders. However, no added benefit of the 30 mg/m2 dose over the 15 mg/m2 dose was observed .The subgroup of children with polyarticular JIA of the above cohort with prolonged disease duration, higher disability, ANA negativity, and presence of wrist activity had poorer response to a 6-month MTX course . In a more recent study, minimal response as defined by the American College of Rheumatology pediatric (PedACR) 30 was achieved in 3 months in 77.4 % children with JIA treated with MTX .
Laboratory monitoring: CBC with WBC count, differential and platelet count, ALT, AST, and albumin every 4–8 weeks initially then every 12–16 weeks. Therapy must be withheld if the AST (or ALT) is >2 times above upper level of the normal range, hemoglobin < 8 g %, platelets <50,000/mm3, white cell count <3000/mm3, and creatinine clearance < 30 ml per minor if the patient has hepatitis B or C infection .
Drug interactions and combination treatment: Rarely significant at the low doses and NSAIDs can be safely used with MTX. It can also be co-prescribed with biologic response modifiers ..
Patient education and support groups: Education and creating support organizations for parents and children that have regular interactions with health-care providers are essential to facilitate adherence, optimize efficacy, and monitor MTX safety.
Immunization: Guidelines on immunizing the immunocompromised child should be followed. Live-attenuated vaccines should be avoided including the use of live polio vaccine in family members. Varicella zoster nonimmune patients may be at risk of severe chicken pox infection and may require zoster immune globulin if in close contact or treatment with oral or intravenous acyclovir if they acquire chicken pox infection. Inactivated vaccines should be given.
Folate supplementation: Prescribe 1 mg folic acid once daily, for all children begun on oral or subcutaneous MTX and skip the drug on the day before or the day of MTX administration. There are no clinical trials in pediatrics to support any specific regimen, and the least frequent dose is often preferred for reasons of patient compliance. Folic acid deficiency is rare in children as they have an adequate intake of folic acid in their diet, through enriched foods such as breakfast cereals or vitamin supplements [27, 28].
Withdrawal of MTX therapy: This is an area of uncertainty as there is lack of evidence to support the time of withdrawal and also the method of dose reduction. A longer duration of MTX, after drug-induced remission has been obtained, does not prolong the time to flare. A recent study has confirmed that there was no difference in the relapse rates when MTX therapy was discontinued either 6 or 12 months after the patient had attained remission .
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Toxicity: MTX has the best toxicity/efficacy profile for treating rheumatologic illnesses. Most side effects are mild and reversible. The two areas of greatest concern are the potentially increased risk of hepatic cirrhosis and malignancy. These toxicities may be directly related to the folate antagonism and its cytotoxic effects. Monitoring MTX toxicity was included in the pediatric rheumatology top five list as part of the American Board of Internal Medicine Foundation’s Choosing Wisely campaign .
Gastrointestinal toxicity: Abdominal discomfort and nausea are the most common symptoms with MTX. These symptoms or mouth ulcers are seen 24–36 h after administration of the weekly dose and can be reduced by adding folic acid, by dose reduction, or by converting to the subcutaneous route.
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