Abstract
The field of pediatric rheumatology has seen a decisive change in the way patients are being treated in last few decades. The diseases of this subspeciality be it JIA, SLE, vasculitis or JDM are chronic and require long term term treatment with drugs. The discovery of new drugs including BRMs and intelligent use of older drugs have made it possible to achieve remission in many of these conditions and provide patients with a better quality of life. This chapter highlights the pharmacology, intended uses and possible adverse side effects of many of these drugs. The information provided in this chapter should be a precursor for treating children with rheumatological illness
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References
Ilowite NT, Laxer RM. Pharmacology and drug therapy. In: Cassidy JT, Petty RE, editors. Text book of pediatric rheumatology. 6th ed. Philadelphia: WB Saunders Company; 2010.
Gilman AG, Brunton LL, Lazo JS, Parker KL. The pharmacologic basis of therapeutics. 11th ed. New York: Pergamon Press; 2005.
Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet. 1997;32:268–93.
Wells TG, Mortensen ME, Dietrich A, Walson PD, Blasier D, Kearns GL. Comparison of the pharmacokinetics of naproxen tablets and suspension in children. J Clin Pharmacol. 1994;34:30–3.
Sellers EM. Plasma protein displacement interactions are rarely of clinical significance. Pharmacology. 1979;18:225–7.
Burgos-Vargas R, Foeldvari I, Thon A, Linke R, Tuerck D. Pharmacokinetics of meloxicam in patients with juvenile rheumatoid arthritis. J Clin Pharmacol. 2004;44:866–72.
GarcÃa RodrÃguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:769–72. Erratum in: Lancet 1994; 23;343:1048.
Henry D, Lim LL, Rodriguez GLA, Gutthann PS, Carson JL, Griffin M. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996;312:1563–6.
Mulberg AE, Linz C, Bern E, Tucker L, Verhave M, Grand RJ. Identification of nonsteroidal anti-inflammatory drug-induced gastroduodenal injury in children with juvenile rheumatoid arthritis. J Pediatr. 1993;122:647–9.
Gazarian M, Berkovitch M, Koren G, Silverman ED, Laxer RM. Experience with misoprostol therapy for NSAID gastropathy in children. Ann Rheum Dis. 1995;54:277–80.
Hawkey CJ, Karrasch JA, Szczepañski L, Walker DG, Barkun A, Swannell AJ, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998;338:727–34.
Yeomans ND, Tulassay Z, Juhász L, Rácz I, Howard JM, van Rensburg CJ, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338:719–26.
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85:421–6.
Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. Retrospective study of 24 patients. Rheumatology (Oxford). 2001;40:1285–92.
Schäd SG, Kraus A, Haubitz I, Trcka J, Hamm H, Girschick HJ. Early onset pauciarticular arthritis is the major risk factor for naproxen-induced pseudoporphyria in juvenile idiopathic arthritis. Arthritis Res Ther. 2007;9:R10. PubMed.
Lindsley CB. Uses of nonsteroidal anti-inflammatory drugs in pediatrics. Am J Dis Child. 1993;147:229–36.
Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007;9:195–204.
Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum. 1998;41:761–7.
Fauci AS, Dale DC. The effect of hydrocortisone on the kinetics of normal human lymphocytes. Blood. 1975;46:235–43.
Priestley GC, Brown JC. Effects of corticosteroids on the proliferation of normal and abnormal human connective tissue cells. Br J Dermatol. 1980;102:35–41.
Pereira RM, Carvalho JF, Paula AP, Zerbini C, Domiciano DS, Gonçalves H et al.;Committee for Osteoporosis and Bone Metabolic Disorders of the Brazilian Society of Rheumatology; Brazilian Medical Association; Brazilian Association of Physical Medicine and Rehabilitation. Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Rev Bras Reumatol. 2012;52:580–93.
Kumar S, Rajam L. Posterior reversible encephalopathy syndrome (PRES/RPLS) during pulse steroid therapy in macrophage activation syndrome. Indian J Pediatr. 2011;78:1002–4.
Knox AJ, Mascie-Taylor BH, Muers MF. Acute hydrocortisone myopathy in acute severe asthma. Thorax. 1986;41:411–2.
Laaksonen AL, Sunell JE, Westerén H, Mulder J. Adrenocortical function in children with juvenile rheumatoid arthritis and other connective tissue disorders. Scand J Rheumatol. 1974;3:137–42.
Klein-Gitelman MS, Pachman LM. Intravenous corticosteroids: adverse reactions are more variable than expected in children. J Rheumatol. 1998;25:1995–2002.
Earley A, Cuttica RJ, McCullough C, Ansell BM. Triamcinolone into the knee joint in juvenile chronic arthritis. Clin Exp Rheumatol. 1988;6:153–5.
Ramanan AV, Whitworth P, Baildam EM. Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child. 2003;88:197–200.
Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS, Rabinovich CE, Turner D, Zulian F. Methotrexate: new uses for an old drug. J Pediatr. 2014;164:231–6.
Truckenbrodt H, Hafner R. Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum. 1986;29:801–7.
Wallace CA, Bleyer WA, Sherry DD, Salmonson KL, Wedgwood RJ. Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1989;32:677–81.
Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol. 1993;20:1845–9.
Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F et al.; Pediatric Rheumatology International Trials Organization. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004;50:2191–201.
Vilca I, Munitis PG, Pistorio A, Ravelli A, Buoncompagni A, Bica B, et al.;Pediatric Rheumatology International Trials Organisation (PRINTO). Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial. Ann Rheum Dis. 2010;69:1479–83.
Albarouni M, Becker I, Horneff G. Predictors of response to methotrexate in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2014;12:35.
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American college of rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762–84.
Foell D, Frosch M, Schulze zur Wiesch A, Vogl T, Sorg C, Roth J. Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop? Ann Rheum Dis. 2004;63:206–8.
Rouster-Stevens KA, Ardoin SP, Cooper AM, Becker ML, Dragone LL, Huttenlocher A, Jones KB, Kolba KS, Moorthy LN, Nigrovic PA, Stinson JN, Ferguson PJ, American College of Rheumatology Pediatric Rheumatology Core Membership Group. Choosing wisely: the American college of Rheumatology’s Top 5 for pediatric rheumatology. Arthritis Care Res (Hoboken). 2014;66:649–57.
Wallace CA, Smith AL, Sherry DD. Pilot investigation of naproxen/methotrexate interaction in patients with juvenile rheumatoid arthritis. J Rheumatol. 1993;20:1764–8.
Ravelli A, Caria MC, Buratti S, Malattia C, Temporini F, Martini A. Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2001;28:865–7.
Singsen BH, Goldbach-Mansky R. Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic disorders. Rheum Dis Clin North Am. 1997;23:811–40.
Salaffi F, Manganelli P, Carotti M, Subiaco S, Lamanna G, Cervini C. Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature. Clin Rheumatol. 1997;16:296–304.
Van der Meer A, Wulffraat NM, Prakken BJ, Gijsbers B, Rademaker CM, Sinnema G. Psychological side effects of MTX treatment in juvenile idiopathic arthritis: a pilot study. Clin Exp Rheumatol. 2007;25:480–5.
Mannion ML, Xie F, Curtis JR, Beukelman T. Recent trends in medication usage for the treatment of juvenile idiopathic arthritis and the influence of tumour necrosis factor inhibitors. J Rheumatol. 2014. pii: jrheum.140012. [Pub ahead of print] PubMed PMID: 25086081.
Fox R. Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol. 1998;25 Suppl 53:20–6.
Chickermane PR, Khubchandani RP. Evaluation of the benefits of sequential addition of leflunomide in patients with polyarticular course juvenile idiopathic arthritis failing standard dose methotrexate. Clin Exp Rheumatol. 2015;33:287–92. Epub 2015Feb 18.
Firestein GS, Kelley WN. Kelley’s textbook of rheumatology. Philadelphia: Elsevier/Saunders; 2013.
Behrens F, Finkenwirth C, Pavelka K, Štolfa J, Šipek-Dolnicar A, Thaçi D, Burkhardt H. Leflunomide in psoriatic arthritis: results from a large European prospective observational study. Arthritis Care Res (Hoboken). 2013;65:464–70.
Haibal H, Redwaleit M, Braun J, Sieper J. Six months open label trial of leflunomide in active ankylosing spondylitis. Ann Rheum Dis. 2005;64:124–6.
Metzler C, Fink C, Lamprecht P, et al. Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology. 2004;43:315–20.
Metzler C, Fink C, Lamprecht P, et al. Maintenance of remission in Wegener’s granulomatosis: unexpected high relapse rate under oral methotrexate. Ann Rheum Dis. 2005;64 Suppl 3:85.
Tam L, Li E, Wong C, et al. Double-blind, randomized, placebo- controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus. 2004;13:601–4.
Yamazaki T, Miyai E, Shibata H, et al. Pharmacological studies of salazosulfapyridine (SASP) evaluation of anti-rheumatic action. Pharmacometrics. 1991;41:563–74.
Clegg D, Reda D, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies. Arthritis Rheum. 1999;42:2325–9.
Chen J, Liu C. Is sulfasalazine effective in ankylosing spondylitis? A systematic review of randomized controlled trials. J Rheumatol. 2006;33:722–31.
Brooks C. Sulfasalazine for the management of juvenile rheumatoid arthritis. J Rheumatol. 2001;28:845–53.
Soriano E, McHugh N. Therapies for peripheral joint disease in psoriatic arthritis: a systematic review. J Rheumatol. 2006;33:1422–30.
Clegg D, Reda D, Weisman M, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). Arthritis Rheum. 1996;39:2021–7.
Canadian Hydroxychloroquine Study Group. A randomized study of the effects of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 1991;324:150–4.
Toubi E, Rosner I, Rosenbaum M, et al. The benefit of combining hydroxychloroquine with quinacrine in the treatment of SLE patients. Lupus. 2000;9:92–5.
Erkan D, Yazici Y, Peterson M, et al. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology. 2002;41:924–9.
Espinola R, Pierangeli S, Harris E. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost. 2002;87:518–22.
Ruiz-Irastorza G, Crowther M, Branch W, et al. Antiphospholipid syndrome. Lancet. 2010;376:1498–509.
Fox R, Dixon R, Guarrasi V, Kruble S. Treatment of primary Sjogren’s syndrome with hydroxychloroquine: a retrospective open-label study. Lupus. 1996;5 Suppl 1:S31.
Dawson L, Caulfield V, Stanbury J, et al. Hydroxychloroquine therapy in patients with primary Sjogren’s syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase. Rheumatology. 2005;44:449–55.
Olson N, Lindsley C. Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol. 1989;16:12.
Marmor M, Carr R, Easterbrook M, et al. Information statement: recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2002;109:1377–82.
Browning D. Hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity. Am J Ophthalmol. 2002;133:649–56.
Marmor MF, Kellner U, Lai TY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;11:415–22.
Haubitz M, Bohnenstengel F, Brunkhorst R, et al. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int. 2002;61:1495–501.
Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response in Wegener’s granulomatosis. N Engl J Med. 1971;285:1493–6.
Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 2001;135:248–57.
Houssiau FA, Vasconcelos C, D’Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010;69:61–4.
Trevisani VF, Castro AA, NevesNeto JF, et al. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus, Cochrane Database Syst Rev. 2006;:CD002265.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354:2655–66.
Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54:3962–70.
Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum. 1997;40:2187–98.
Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum. 1998;41:1835–44.
De Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670–80.
Virdi RP, Bashir A, Shahzad G, Iqbal J, Mejia JO. Diffuse alveolar hemorrhage: a rare life-threatening condition in systemic lupus erythematosus. Case Rep Pulmonol. 2012;2012:836017. doi:10.1155/2012/836017. Epub 2012 May 27. PubMed PMID: 22934226; PubMed Central PMCID: PMC3420594.
Petri M, Brodsky RA, Jones RJ, et al. High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomised trial. Arthritis Rheum. 2010;62:1487–93.
Suthanthiran M, Strom TB. Immunoregulatory drugs: mechanistic basis for use in organ transplantation. Pediatr Nephrol. 1997;11:651–7.
Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis Hong Kong- Guangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156–62.
Derk CT, Grace E, Shenin M, et al. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology. 2009;48:1595–9.
Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum. 2004;51:278–83.
Majithia V, Harisdangkul V. Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune inflammatory myopathy. Rheumatology (Oxford). 2005;44:386–9.
Morganroth PA, Kreider ME, Werth VP. Mycophenolate mofetil for interstitial lung disease in dermatomyositis. Arthritis Care Res. 2010;62:1496–501.
Riskalla MM, Somers EC, Fatica RA, et al. Tolerability of mycophenolate mofetil in patients with systemic lupus erythematosus. J Rheumatol. 2003;30:1508–12.
Grootscholten C, Ligtenberg G, Hagen EC, et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis: a randomized controlled trial. Kidney Int. 2006;70:732–42.
Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350:971–80.
Rahman P, Humphrey-Murto S, Gladman DD, et al. Cytotoxic therapy in systemic lupus erythematosus: experience from a single center. Medicine. 1997;76:432–7.
Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behçet’s syndrome: effects on long-term prognosis. Arthritis Rheum. 1997;40:769–74.
Jones G, Crotty M, Brooks P. Psoriatic arthritis: a quantitative overview of therapeutic options. The Psoriatic Arthritis Meta-Analysis Study Group. Br J Rheumatol. 1997;36:95–9.
Benenson E, Fries JW, Heilig B, et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin Rheumatol. 2005;24:251–7.
Bérezné A, Ranque B, Valeyre D, et al. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J Rheumatol. 2008;35:1064–72.
Szumlanski CL, Honchel R, Scott MC, et al. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver- erythrocyte correlation and presence of isozymes. Pharmacogenetics. 1992;2:148–59.
Mouy R, Stephan JL, Pillet P, et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996;129:750–4.
Caccavo D, Lagana B, Mitterhofer AP, et al. Long-term treatment of systemic lupus erythematosus with cyclosporin A. Arthritis Rheum. 1997;40:27–35.
Griffiths B, Emery P, Ryan V, et al. The BILAG multi-centre open randomized controlled trial comparing cyclosporine vs azathioprine in patients with severe SLE. Rheumatology. 2010;49:723–32.
Robert N, Wong GW, Wright JM. Effect of cyclosporine on blood pressure. Cochrane Database Syst Rev. 2010;:CD007893.
Lee T, Oh KH, Joo KW, et al. Tacrolimus as an alternative therapeutic option for the treatment of refractory lupus nephritis. Lupus. 2010;19:974–80.
D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082–5.
Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991;173:699–703.
Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr. 2002;140:125–7.
Sathe K, Khubchandani RP. Thalidomide for systemic onset juvenile idiopathic arthritis. Indian Pediatr. 2013;50:237–9.
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Rao, A.P., Kamath, N. (2017). Nonbiologic Drugs in Pediatric Rheumatology. In: Sawhney, S., Aggarwal, A. (eds) Pediatric Rheumatology. Springer, Singapore. https://doi.org/10.1007/978-981-10-1750-6_7
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