TABLE 101.13 DMARDs USED IN THE TREATMENT OF JIA Drug Dosing schedule Side effects Methotrexate Weekly Nausea, hair loss, chemical hepatitis, hypersensitivity, pneumonitis Leflunomide Once a day Nausea, diarrhea, chemical hepatitis Sulfasalazine Twice a day Gastric irritation, photosensitivity, behavioral changes, hypersensitivity reaction, neutropenia Abdominal pain, diarrhea, retinitis Hydroxychloroquine Once a day DMARDs, disease-modifying antirheumatic drugs; JIA, juvenile rheumatoid arthritis Corticosteroids must be employed judiciously in JIA due to the significant toxicity associated with their use Systemic steroids are typically reserved for children with severe complications or time-limited flares, for example, in the setting of systemic symptoms, pericarditis, or pleuritis, during brief flare-ups of severe arthritis, or while waiting for slower-acting agents to take effect Intra-articular steroids may be used in patients with oligoarthritis, or in children with polyarticular disease in whom selected joints require particularly aggressive management Topical ophthalmologic steroids are the mainstay of therapy for iridocyclitis, though their use is limited by local toxicity, oftentimes necessitating the use of systemic immune modulatory therapy to treat eye inflammation even in the absence of joint inflammation Drug Toxicity Almost all drugs used for the treatment of JIA have the potential for serious toxicity If a child with JIA on treatment develops a new symptom, drug toxicity must always be considered as a possible cause Tables 101.12 and 101.13 list the common adverse reactions reported with NSAIDs and DMARDs typically used in the treatment of JIA Though new medications are more targeted in their effects on the immune system, most advanced therapies for arthritis cause at least some immunosuppression Accordingly, physicians caring for children with JIA should be particularly vigilant for evidence of infections For the nonsteroidal anti-inflammatory agents, GI toxicity is the most common side effect Nonetheless, significant NSAID gastropathy is unusual in children, and gastric or intestinal perforations, a significant problem in older adults, are rare NSAIDs may also cause various other side effects Reversible CNS complaints, particularly headaches, dizziness, and fatigue, occur in about 5% of children Hepatotoxicity, manifested primarily as elevation of transaminases, and nephrotoxicity, including proteinuria and renal papillary necrosis, are rare but potentially dangerous if overlooked Friability of the skin and a porphyria-like blistering of sun-exposed areas may be seen with these agents, especially naproxen when used in fair-skinned children Unlike salicylates, NSAIDs rarely cause tinnitus or hyperventilation Reye syndrome, although far less common than with salicylates, has been reported in children receiving NSAIDs; therefore, it is prudent to consider suspension of these agents in children with influenza or varicella Salicylates must be carefully avoided in children who are even exposed to these viruses In any child using salicylates or other NSAIDs, development of pernicious vomiting and/or alteration in mental status warrants consideration of Reye syndrome Each of the second-line agents used in the treatment of JIA also has the potential to cause specific forms of toxicity Despite its favorable therapeutic profile, methotrexate is an antimetabolite with the potential to cause oral ulcers, nausea, vomiting, and abdominal pain These adverse effects may be minimized by supplementation with folic acid Children must be monitored regularly for evidence of hepatic toxicity; persistent elevation of hepatic transaminases identifies those at risk for hepatic fibrosis or cirrhosis Methotrexate may also cause lymphopenia, especially with prolonged use, or even pancytopenia due to bone marrow suppression Ten percent of children receiving methotrexate for arthritis may develop mild hypogammaglobulinemia, but there is no evidence that this is clinically significant Concurrent use of other dihydrofolate reductase inhibitors, such as trimethoprim-sulfamethoxazole (Bactrim), potentiates these risks and should be avoided Rarely, use of methotrexate is associated with the development of pulmonary hypersensitivity This most commonly occurs during the first to 12 months of use and may be marked by dyspnea, cough, fever, and fluffy infiltrates on chest x-ray Although such symptoms may be conclusively distinguished from viral pneumonitis only by lung biopsy, suspicion of this complication necessitates discontinuation of methotrexate and institution of treatment with systemic corticosteroids Failure to stop the drug, or a second exposure to methotrexate, may cause fatal respiratory failure The biologics are generally well tolerated, but as with all medications that target the immune response as a way of controlling inflammation, biologics are immunosuppressive Although these effects are more limited than those of traditional cytotoxic agents, defenses against various infections are impaired The infectious risk appears to increase significantly with use of more than one biologic agent at a time Although most people note only an increased frequency of mild upper respiratory tract illnesses, treatment with TNF inhibitors also increases susceptibility to potentially serious mycobacterial, bacterial, fungal, and herpes viral infections The long-term effects of altering the immune response with anti-TNF medications are not yet known In adults, new autoantibodies may develop (including ANA and anti-ds DNA), and rarely patients may develop multiple sclerosis–like CNS abnormalities These associations should be kept in mind if a patient on anti-TNF therapy develops new neurologic or rheumatologic complaints Sulfasalazine is a sulfa drug, and its most severe side effects are typical of this class of medications Headache and GI upset—especially with preparations that are not enterically coated—occur most commonly Although rare, more concerning are bone marrow suppression, agranulocytosis, photosensitive eruptions, and hypersensitivity reactions, including Stevens–Johnson syndrome Antimalarial agents such as hydroxychloroquine must be administered judiciously because of their ability to cause irreversible ocular toxicity at high doses Even at lower doses, children may develop rashes, gastric upset, or reversible visual disturbances secondary to altered accommodation Finally, children with glucose-6-phosphate deficiency who receive hydroxychloroquine may develop hemolytic anemia, especially during intercurrent infections The long list of potential side effects of systemic corticosteroids is enumerated elsewhere In the acute setting, immunosuppressive effects of systemic steroids are most salient It is important to remember that these agents dramatically increase susceptibility to herpes viruses (especially disseminated varicella) and intracellular pathogens, such as mycobacteria and listeria Although they have little effect on susceptibility to other bacterial pathogens, their anti-inflammatory effects tend to mask clinical signs of infection, accentuating the need for attentiveness on the part of clinicians In addition, patients receiving chronic corticosteroid therapy are at risk for adrenal insufficiency, and treatment with stress dose steroids may be necessary in the setting of acute illness or injury Management of Complications and Emergencies Patients with all subtypes of JIA may have extra-articular complications either due to their underlying disease or as a result of treatment with immunosuppressive medications It should be noted, however, that children with sJIA are at higher risk for more severe complications of disease, including life-threatening cardiopulmonary manifestations of disease as well as MAS, a cytokine storm syndrome As such, extra care to evaluate for such complications should be taken when children with sJIA present to the ED Fever Marked elevation of body temperature is characteristic of sJIA, whereas a lowergrade fever often accompanies polyarticular disease The diagnosis of sJIA is one of exclusion and fever is a common symptom, so diligent efforts should be made to rule out infections and malignancies This may require hospitalization for a diagnostic evaluation, particularly in infants and young children A bone marrow examination to rule out malignancy may be necessary in patients who have or are suspected to have sJIA because acute lymphoblastic leukemia may cause joint pain and swelling, fever, lymphadenopathy, and HSM that are indistinguishable from findings in sJIA In a patient being treated for known sJIA, fever may represent recurrence of JIA, or it may be because of an intercurrent infection Fevers in sJIA typically follow the classic twice daily pattern, with two peaks above 39°C daily, as well as periods at or below normal without use of antipyretic medications If there are no localizing signs of infection, the CBC shows the leukocytosis, thrombocytosis, and anemia typical of JIA, and the urinalysis is normal, the child may be treated for a presumed JIA flare Notably, an acute infection can cause a flare of disease and both entities may coexist Children being treated with immunosuppressive medications may require empiric antibiotics or observation in the hospital until negative culture results allow infection to be excluded If the patient has received more than 20 mg of prednisone daily for more than weeks within the previous 12 months, appropriate coverage with stress doses of steroids (three times the physiologic dose) is indicated while the infection is being treated Fever in sJIA, especially within months of disease onset, occasionally may be caused by MAS, also known as reactive hemophagocytic lymphohistiocytosis (HLH) This spectrum of disease will be discussed in greater detail below This life-threatening complication is characterized by systemic inflammation with disseminated intravascular coagulopathy with diffuse microthromboses, cytopenias, hepatic inflammation, SIRS-type physiology, and CNS changes progressing to seizures or coma The cause of MAS is unknown, but it does occur more commonly during viral illnesses, as well as in children receiving NSAIDs or DMARDs (particularly sulfasalazine) as treatment A subset of children with sJIA likely have a genetic predisposition to MAS as they carry mutations in genes associated with HLH Differentiation from sepsis or a flare of JIA may be difficult, although a sudden rise in hepatic enzymes, ferritin, and triglycerides or a sudden drop in platelets, red blood cells, or ESR (due to consumption of cellular elements and fibrinogen) is suggestive Early diagnosis and a high level of suspicion are essential Treatment with anakinra, pulse-dose methylprednisolone (30 mg/kg, maximum g), and/or cyclosporine, as well as general support measures for DIC, often lead to full recovery Delayed diagnosis, in contrast, is accompanied by a reported mortality rate of 20% to 50% Cardiac Complications Cardiac involvement is an important feature of sJIA but is uncommon in other subtypes of juvenile arthritis Pericarditis, like other systemic manifestations of Still disease, most often occurs during the first years of the illness Fortunately, pericardial effusions in JIA rarely lead to cardiac tamponade Valvulitis is not typical of JIA and should suggest the possibility of acute rheumatic fever or bacterial endocarditis Myocarditis is rare but may be seen Bed rest and therapy with an NSAID should be adequate for the treatment of mild to moderate pericarditis due to JIA Corticosteroids (prednisone to mg/kg/day, maximum 60 to 80 mg) are indicated for the treatment of noninfectious myocarditis,