Table A3.

Use of Corticosteroid-Sparing Agents in Pediatric Acute-Onset Neuropsychiatric Syndrome

	Description/benefit	Adverse effects	Dosing
IVIG	IVIG is derived from pooled plasma from human donors and processed using rigorous purification steps.	Common infusion-related side effects include nausea, myalgia, fever, chills, rigors, chest discomfort, and hypotension (often dose related or because of rapid administration).	Induction: 1.5–2 g/kg, maximum dose 70 g/dose. If patient has clear improvement and then recrudesces, subsequent doses should be dosed at 1 g/kg. Second and third doses have been given at 4–6-week intervals by PANS Consortium members.
	Several potential immunomodulatory roles including effects on Fc receptor activity (saturating FcR) and F(ab)2 activity (anti-idiotypic antibodies) and other mechanisms.	Postinfusion headaches (HA)a are common including aseptic-like meningitis. Aggressive hydration pre/post and half way through IVIG infusion can help minimize HA. Use of OTC NSAIDs or corticosteroids during and after IVIG can also help prevent/manage HA.	Some patients are treated with rheumatology protocols that utilize 2 g/kg monthly (maximum dose 70 g/dose).
	Benefit: Broadly impacts immune function and autoimmune responses and may help moderate the autoantibody responses.	A transient fever can be seen in the first 24 hours. Rarely, symptomatic hemolysis can occur and manifest up to 1-week postinfusion. Anaphylaxis can occur, especially in patients with IgA deficiency (if IgA deficient, use formulation that does not contain IgA). Other rare side effects include renal failure, thrombosis (including sinus venous thrombosis), dermatological reactions, hemolytic reactions, neutropenia, transfusion-related lung injury, and seizures.	If patient becomes dependent on IVIG to maintain good baseline, consider adding in or replacing with rituximab or MMF.
	Caution: The authors report rare cases of worsening PANS symptoms after IVIG when IVIG is given around the time of a new viral illness.
TPE	Removes autoantibodies triggering immune responses leading to brain inflammation.	TPE often requires an intensive care admission and this may be psychiatrically traumatizing to some children.	1 volume therapeutic exchanges every other day for 10–12 days (5–6 runs) (Perlmutter et al. 1999).
	TPE is a process of separating blood components using centrifugation and a semipermeable membrane. This allows for disease-promoting blood components to be removed while the remaining components are returned to the patient. Plasma proteins, including antibodies-promoting disease, can be removed from the patient's blood.	Related to IV access: pain, bleeding, infection, and, thrombosis. Risks of sedation. Risks of fluid shifts. Complications related to citrate anticoagulation/calcium chelating, and replaced with albumin. Risks of exposure to blood products. Syncope, pseudoseizures, and pain amplification have been reported immediately after TPE. TPE can cause hypogammaglobulinemia.	1.5 volume therapeutic exchanges for 3–5 days (3–4 runs) (Latimer et al. 2015). As soon as TPE is stopped, autoantibodies will continue to be produced (if autoimmune disease is present), thus adjunct therapy is recommended. In infection-triggered PANS, TPE alone can be effective if infectious driver is eliminated.
	Benefit: Rapidly removes antibodies from plasma and quickly eliminates autoreactive immune responses caused by antibodies.
Rituximab	FDA approved for use in microscopic polyangiitis, granulomatosis with polyangiitis (formerly Wegener's), and rheumatoid arthritis. It is frequently used in idiopathic thrombocytopenic purpura, lupus nephritis, and autoimmune encephalitis. A chimeric antibody directed against CD20, a surface protein found on B cells that leads to rapid B cell depletion. Benefit: B cell depletion frequently occurs within 24–48 hours after infusion and can be sustained for 3 months to >1 year. In chronic-static or refractory cases, benefits may not be seen for 6 months.	PANS patients can have escalation of psychiatric symptoms and pain symptoms after the first round (lasting 1–5 months), but the second round at 6 months is generally better tolerated. Infusion reactions are frequent, especially with the first dose, but can be mitigated by slowing the infusion rate and premedication with corticosteroids, acetaminophen, and diphenhydramine. Serious infections have been reported but are rare. Reported infections after rituximab include CMV-related retinitis/colitis, progressive myelitis leukoencephalipathy (JC virus), pneumonia, and empyema.	Most autoimmune diseases are treated with the protocol used in rheumatoid arthritis of 750 mg/m2 (maximum dose 1000 mg) × 2 doses separated by 2 weeks. Although the effect can last up to a year, many patients relapse at the 6-month mark so most protocols aimed to treat chronic autoimmune disease require redosing at 6-month intervals.
MMF	An inhibitor of inosine monophosphate dehydrogenase, a rate-limiting enzyme for de novo synthesis of guanosine nucleotides. Several potential immunomodulatory roles including inhibition of lymphocyte proliferation, suppression of glycosylation and expression of some adhesion molecules, and suppression of nitric oxide. Benefit: Decreased B and T lymphocyte proliferation. Decreased antibody response. Induction of apoptosis of activated T lymphocytes. Decreased lymphocyte and monocyte recruitment to sites of inflammation. Suppression of tissue damage.	Pans patients can have sensory disturbances after introduction, generally better tolerated when patient is remitting on induction corticosteroids. Common side effects include cytopenia, dizziness, nausea, diarrhea, and abdominal pain. Rare side effects include dermatologic reactions, hemolytic reactions, and abnormal renal or hepatic function tests. Increased risk of infections and sepsis. Reported infections following MMF include: CMV, herpes zoster, BK virus, hepatitis B, and hepatitis C. Malignant neoplasms have been reported but are rare.	MMF: 600 mg/m2/dose twice daily (max dose 1500 mg/dose) For patients who do not tolerate MMF, mycophenolic acid (MPA) can be used but has a different dosing regimen.

^a IVIG-related headaches generally respond well to steroids (1–2 mg/kg prednisone equivalent, maximum dose 60–120 mg/day) when given along with and/or 2–5 days after the infusions. For patients who do not tolerate corticosteroids, NSAIDs can be used (IV ketorolac or ibuprofen around the clock). Premedication with diphenhydramine (or other antihistamines) and acetaminophen can also improve tolerability. Nausea can be treated with ondansetron and it may be needed around the clock during and after the infusion. Some patients may need opiates to manage severe headaches.

CMV, cytomegalovirus; IgA, immunoglobulin A; IV, intravenous; IVIG, intravenous immunoglobulin; JC, John Cunningham; MMF, mycophenolate mofetil; OTC, over the counter; PANS, pediatric acute-onset neuropsychiatric syndrome; TPE, therapeutic plasma exchange.