Resumen
Introducción: un diagnóstico rápido del compromiso neurológico en las enfermedades reumáticas es esencial para iniciar un tratamiento oportuno y prevenir la progresión de la enfermedad.
Objetivo: describir las características principales de los inmunosupresores utilizados en las patologías reumáticas con afectación del sistema nervioso.
Materiales y métodos: se realizó una revisión panorámica mediante una búsqueda ampliada de la literatura en bases de datos como Pubmed, Cochrane y BVS, así como en literatura gris.
Resultados: se identificaron los inmunosupresores más usados en patologías reumáticas con afectación neurológica. La ciclofosfamida, azatioprina, micofenolato y rituximab tienen indicaciones específicas. Es crucial monitorear su toxicidad, priorizando la función renal en inmunoglobulina y la hematológica en otros fármacos.
Discusión: la ciclofosfamida es un agente alquilante indicado en afecciones neurológicas causadas por patologías como lupus eritematoso sistémico (LES), síndrome de Sjögren, sarcoidosis, enfermedad de Behçet, entre otras, y forma parte de esquemas como el NIH y el CYCLOPS. La azatioprina, un análogo de las purinas, se utiliza en enfermedades como lupus neuropsiquiátrico y neuro-Behçet, entre otras, compartiendo indicaciones similares al micofenolato. El rituximab actúa contra el antígeno CD20 de las células B y se usa en diferentes dosis para múltiples compromisos neurorreumatológicos. Es fundamental realizar un monitoreo de estos medicamentos, especialmente de su toxicidad hematológica, con excepción de la inmunoglobulina, en cuyo caso se debe vigilar la función renal y el riesgo de episodios trombóticos.
Conclusiones: el conocimiento de las terapias utilizadas en las complicaciones neurológicas de patologías reumáticas, así como la monitorización y prevención de eventos adversos, es fundamental para optimizar el manejo del paciente.
Citas
Ahn GY, Kim D, Won S, Song ST, Jeong HJ, Sohn IW, et al. Prevalence, risk factors, and impact on mortality of neuropsychiatric lupus: a prospective, single-center study. Lupus. 2018;27(8):1338-47. https://doi.org/10.1177/0961203318772021
Sloan M, Bourgeois JA, Leschziner G, Pollak TA, Pitkanen M, Harwood R, et al. Neuropsychiatric prodromes and symptom timings in relation to disease onset and/or flares in SLE: results from the mixed methods international INSPIRE study. EClinicalMedicine. 2024;73:102634. https://doi.org/10.1016/j.eclinm.2024.102634
Legge AC, Hanly JG. Recent advances in the diagnosis and management of neuropsychiatric lupus. Nat Rev Rheumatol. 2024;20(11):712-28. https://doi.org/10.1038/s41584-024-01163-z
Rice-Canetto TE, Joshi SJ, Kyan KA, Siddiqi J. Neuropsychiatric systemic lupus erythematosus: a systematic review. Cureus. 2024;16(6):e61678. https://doi.org/10.7759/cureus.61678
Serdaro?lu P. Behçet’s disease and the nervous system. J Neurol. 1998;245(4):197-205. https://doi.org/10.1007/s004150050205
Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations. Arch Neurol. 1985;42(9):909-17. https://doi.org/10.1001/archneur.1985.04060080095022
Smiyan S, Komorovsky R, Koshak B, Duve K, Shkrobot S. Central nervous system manifestations in rheumatic diseases. Rheumatol Int. 2024;44(10):1803-12. https://doi.org/10.1007/s00296-024-05679-1
Jazayeri SB, Rahimian A, Ahadi MS, Tavakolpour S, Alesaeidi S. Neurologic involvement in granulomatosis with polyangiitis: a comparative study. Biol Life Sci Forum. 2022;19(1):19. http://dx.doi.org/10.3390/IECBS2022-13963
DeQuattro K, Imboden JB. Neurologic manifestations of rheumatoid arthritis. Rheum Dis Clin North Am. 2017;43(4):561-71. https://doi.org/10.1016/j.rdc.2017.06.005
Galiano A. CICLOFOSFAMIDA. Vademecum. 2009. p. 1-6. https://iqb.es/cbasicas/farma/farma04/c049.htm
De Cos MA, Merino J. Farmacología de la respuesta inmunitaria. En: Farmacología humana. Madrid: Elsevier; 2014. p. 305-89.
Iglesias-Gamarra A, Peñaranda-Parada E, Cajas-Santana LJ, Quintana-López G, Restrepo-Suárez JF, Arbeláez-Cortés Á, et al. Historia del tratamiento de las vasculitis primarias. Rev Colomb Reumatol. 2012;19(3):131-57. https://doi.org/10.1016/S0121-8123(12)70022-1
Bagley CM, Bostick FW, DeVita VT. Clinical pharmacology of cyclophosphamide. Cancer Res. 1973;33(2):226-33.
Wiernik P, Duncan JH. Cyclophosphamide in human milk. Lancet. 1971;1(7705):912. https://doi.org/10.1016/s0140-6736(71)92474-3
Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int. 2002;61(4):1495-501. https://doi.org/10.1046/j.1523-1755.2002.00279.x
Cohen JL, Jao JY. Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. J Pharmacol Exp Ther. 1970;174(2):206-10.
Struck RF, Alberts DS, Horne K, Phillips JG, Peng YM, Roe DJ. Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res. 1987;47(10):2723-6.
Regan MJ, Hellmann DB, Stone JH. Treatement of Wegener’s granulomatosis. Rheum Dis Clin North Am. 2001;27(4):863-86. https://doi.org/10.1016/s0889-857x(05)70240-4
Colvin M, Brundrett RB, Kan MN, Jardine I, Fenselau C. Alkylating properties of phosphoramide mustard. Cancer Res. 1976;36(3):1121-6.
Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992;6(3):163-73. https://doi.org/10.1016/0268-960x(92)90028-o
Winkelstein A. Mechanisms of immunosuppression: effects of cyclophosphamide on cellular immunity. Blood. 1973;41(2):273-84.
Brode S, Raine T, Zaccone P, Cooke A. Cyclophosphamide-induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+ Regulatory T Cells. J Immunol. 2006;177(10):6603-12. https://doi.org/10.4049/jimmunol.177.10.6603
Gourley MF, Austin HA, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. Ann Intern Med. 1996;125(7):549-57. https://doi.org/10.7326/0003-4819-125-7-199610010-00003
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido ER, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: The Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31. https://doi.org/10.1002/art.10461
Papp KA, Haraoui B, Kumar D, Marshall JK, Bissonnette R, Bitton A, et al. Vaccination guidelines for patients with immune-mediated disorders on immunosuppressive therapies. J Cutan Med Surg. 2019;23(1):50-74. https://doi.org/10.1177/1203475418811335
Donelli MG, Bartosek I, Guaitani A, Martini A, Colombo T, Pacciarini MA, et al. Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect. Cancer Treat Rep. 1976;60(4):395-401.
Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer. 1977;39(4):1403-9. https://doi.org/10.1002/1097-0142(197704)39:4%3C1403::aid-cncr2820390408%3E3.0.co;2-8
Stahl PJ, Stember DS, Hsiao W, Schlegel PN. Indications and strategies for fertility preservation in men. Clin Obstet Gynecol. 2010;53(4):815-27. https://doi.org/10.1097/grf.0b013e3181f980b3
Zard E, Arnaud L, Mathian A, Chakhtoura Z, Hie M, Touraine P, et al. Increased risk of high grade cervical squamous intraepithelial lesions in systemic lupus erythematosus: a meta-analysis of the literature. Autoimmun Rev. 2014;13(7):730-5. https://doi.org/10.1016/j.autrev.2014.03.001
Yilmaz ER, Kertmen H, Gürer B, Kanat MA, Arikok AT, Ergüder BI, et al. The protective effect of 2-mercaptoethane sulfonate (MESNA) against traumatic brain injury in rats. Acta Neurochir. 2013;155(1):141-9. https://doi.org/10.1007/s00701-012-1501-3
McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med. 1988;318(22):1423-31. https://doi.org/10.1056/nejm198806023182203
Galindo-Rodr??guez G, Aviña-Zubieta JA, Pizarro S, D??az de León V, Saucedo N, Fuentes M, et al. Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial. Am J Med. 1999;106(1):65-9. https://doi.org/10.1016/s0002-9343(98)00372-6
Martinez-Taboada V, Blanco Alonso R, Armona J, Femandez-Sueiro J, Gonzalez Vela C, Rodriguez-Valverde V. Mononeuritis multiplex in systemic lupus erythematosus: response to pulse intravenous cyclophosphamide. Lupus. 1996;5(1):74-6. https://doi.org/10.1177/096120339600500114
Bertsias GK, Ioannidis JPA, Aringer M, Bollen E, Bombardieri S, Bruce IN, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010;69(12):2074-82. https://doi.org/10.1136/ard.2010.130476
Carsons SE, Vivino FB, Parke A, Carteron N, Sankar V, Brasington R, et al. Treatment guidelines for rheumatologic manifestations of Sjögren’s syndrome: use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res. 2017;69(4):517-27. https://doi.org/10.1002/acr.22968
Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med. 2003;42(4):313-7. https://doi.org/10.2169/internalmedicine.42.313
Gayraud M, Guillevin L, Cohen P, Lhote F, Cacoub P, Deblois P, et al. Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol. 1997;36(12):1290-7. https://doi.org/10.1093/rheumatology/36.12.1290
Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med. 1984;76(3):377-84. https://doi.org/10.1016/0002-9343(84)90654-5
Daniel LL, Dickson AL, Chung CP. Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine. Clin Rheumatol. 2021;40(1):65-73. https://doi.org/10.1007/s10067-020-05258-2
Broen JCA, van Laar JM. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020;16(3):167-78. https://doi.org/10.1038/s41584-020-0374-8
Mohammadi O, Kassim TA. Azathioprine [internet]. En: StatPearls. Florida: StatPearls; 2023.
Misdaq M, Ziegler S, von Ahsen N, Oellerich M, Asif AR. Thiopurines induce oxidative stress in T-lymphocytes: a proteomic approach. Mediators Inflamm. 2015:434825. https://doi.org/10.1155/2015/434825
Coulthard S, Hogarth L. The thiopurines: an update. Invest New Drugs. 2005;23(6):523-32. https://doi.org/10.1007/s10637-005-4020-8
Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64(8):753-67. https://doi.org/10.1007/s00228-008-0478-6
de Boer NKH, van Bodegraven AA, Jharap B, de Graaf P, Mulder CJJ. Drug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol. 2007;4(12):686-94. https://doi.org/10.1038/ncpgasthep1000
Moon W, Loftus EV. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016;43(8):863-83. https://doi.org/10.1111/apt.13559
Roblin X, Williet N, Peyrin-Biroulet L. Thiopurine metabolism in the era of combotherapy. Inflamm Bowel Dis. 2016;22(6):1496-501. https://doi.org/10.1097/mib.0000000000000737
Katara P, Kuntal H. TPMT polymorphism: when shield becomes weakness. Interdiscip Sci. 2016;8(2):150-5. https://doi.org/10.1007/s12539-015-0111-1
Espiritu AI, D Pasco PM. Efficacy and tolerability of azathioprine for neuromyelitis optica spectrum disorder: a systematic review and meta-analysis. Mult Scler Relat Disord. 2019;33:22-32. https://doi.org/10.1016/j.msard.2019.05.011
Wingerchuk DM, Lucchinetti CF. Neuromyelitis optica spectrum disorder. N Engl J Med. 2022;387(7):631-9. https://doi.org/10.1056/nejmra1904655
Carrión-Barberà I, Salman-Monte TC, Vílchez-Oya F, Monfort J. Neuropsychiatric involvement in systemic lupus erythematosus: a review. Autoimmun Rev. 2021;20(4):102780. https://doi.org/10.1016/j.autrev.2021.102780
McWilliam M, Khan U. Azathioprine and the neurologist. Pract Neurol. 2020;20(1):69-74. https://doi.org/10.1136/practneurol-2018-002161
Hatemi G, Christensen R, Bang D, Bodaghi B, Celik AF, Fortune F, et al. 2018 update of the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis. 2018;77(6):808-18. https://doi.org/10.1136/annrheumdis-2018-213225
Watelet B, Samson M, de Boysson H, Bienvenu B. Treatment of giant-cell arteritis, a literature review. Mod Rheumatol. 2017;27(5):747-54. https://doi.org/10.1080/14397595.2016.1266070
Pugh D, Karabayas M, Basu N, Cid MC, Goel R, Goodyear CS, et al. Large-vessel vasculitis. Nat Rev Dis Primers. 2022;7(1):93. https://doi.org/10.1038/s41572-021-00327-5
Sarwar S, Mohamed AS, Rogers S, Sarmast ST, Kataria S, Mohamed KH, et al. Neuropsychiatric systemic lupus erythematosus: a 2021 update on diagnosis, management, and current challenges. Cureus. 2021;13(9):e17969. https://doi.org/10.7759/cureus.17969
Caruso P, Moretti R. Focus on neuro-Behçet’s disease: a review. Neurol India. 2018;66(6):1619-28. https://doi.org/10.4103/0028-3886.246252
Bhat R, Tonutti A, Timilsina S, Selmi C, Gershwin ME. Perspectives on mycophenolate mofetil in the management of autoimmunity. Clin Rev Allergy Immunol. 2023;65(1):86-100. https://doi.org/10.1007/s12016-023-08963-3
van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int. 2015;28(5):508-15. https://doi.org/10.1111/tri.12554
Beuker C, Schmidt A, Strunk D, Sporns PB, Wiendl H, Meuth SG, et al. Primary angiitis of the central nervous system: diagnosis and treatment. Ther Adv Neurol Disord. 2018;11:1756286418785071. https://doi.org/10.1177/1756286418785071
Mandal J, Chung SA. Primary angiitis of the central nervous system. Rheum Dis Clin North Am. 2017;43(4):503-18. https://doi.org/10.1016/j.rdc.2017.06.001
Schneider-Gold C, Hartung HP, Gold R. Mycophenolate mofetil and tacrolimus: new therapeutic options in neuroimmunological diseases. Muscle Nerve. 2006;34(3):284-91. https://doi.org/10.1002/mus.20543
Schmidt J. Current classification and management of inflammatory myopathies. J Neuromuscul Dis. 2018;5(2):109-29. https://doi.org/10.3233/jnd-180308
Wang X, Zhang YY, Xu Y. Pregnancy-induced leukocytosis: a case report. World J Clin Cases. 2022;10(36):13349-55. https://doi.org/10.12998/wjcc.v10.i36.13349
Hauser RA, Malek AR, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil. Neurology. 1998;51(6):912-3. https://doi.org/10.1212/wnl.51.3.912-a
Omair MA, Alahmadi A, Johnson SR. Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. PLoS One. 2015;10(5): e0124205. https://doi.org/10.1371/journal.pone.0124205
Leandro M, Isenberg DA. Rituximab - The first twenty years. Lupus. 2021;30(3):371-7. https://doi.org/10.1177/0961203320982668
Maloney DG, Grillo-Lo?pez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-cd20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90(6):2188-95. https://doi.org/10.1182/blood.V90.6.2188
Drugbank. Rituximab. Canadá: Drugbank; 2011. https://go.drugbank.com/drugs/DB00073
Bohelay G, Caux F, Musette P. Clinical and biological activity of rituximab in the treatment of pemphigus. Immunotherapy. 2021;13(1):35-53. https://doi.org/10.2217/imt-2020-0189
Sood P, Hariharan S. Anti-CD20 blocker rituximab in kidney transplantation. Transplantation. 2018;102(1):44-58. https://doi.org/10.1097/tp.0000000000001849
Blosser N, Jupp J, Yau P, Stewart D. Clinical pharmacokinetic and pharmacodynamic considerations in treating non-Hodgkin lymphoma. Clin Pharmacokinet. 2020;59(1):7-23. https://doi.org/10.1007/s40262-019-00807-8
Grupo de Trabajo sobre Terapias Biológicas en EAS, Grupo de Estudio de Enfermedades Autoinmunes, Sociedad Española de Medicina Interna. Guías Práctica Clínica. Recomendaciones sobre el uso off-label de rituximab en enfermedades autoinmunes sistémicas. España; 2009.
Lünemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology-mode of action and clinical efficacy. Nat Rev Neurol. 2015;11(2):80-9. https://doi.org/10.1038/nrneurol.2014.253
Allen JA, Gelinas DF, Freimer M, Runken MC, Wolfe GI. Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG? J Neurol Sci. 2020;408:116497. https://doi.org/10.1016/j.jns.2019.116497
Prins C, Gelfand EW, French LE. Intravenous immunoglobulin: properties, mode of action and practical use in dermatology. Acta Derm Venereol. 2007;87(3):206-18. https://doi.org/10.2340/00015555-0249
Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. 2013;27(3):171-8. https://doi.org/10.1016/j.tmrv.2013.05.004
Vodopivec I, Miloslavsky EM, Kotton CN, Cho TA. A neurologist’s guide to safe use of immunomodulatory therapies. Semin Neurol. 2014;34(4):467-78. https://doi.org/10.1055/s-0034-1390395
Morales-Ruiz V, Juárez-Vaquera VH, Rosetti-Sciutto M, Sánchez-Muñoz F, Adalid-Peralta L. Efficacy of intravenous immunoglobulin in autoimmune neurological diseases. Literature systematic review and meta-analysis. Autoimmun Rev. 2022;21(3):103019. https://doi.org/10.1016/j.autrev.2021.103019
Yeh WZ, Dyck PJ, van den Berg LH, Kiernan MC, Taylor BV. Multifocal motor neuropathy: controversies and priorities. J Neurol Neurosurg Psychiatry. 2020;91:140-8. https://doi.org/10.1136/jnnp-2019-321532
Eftimov F, Lucke IM, Querol LA, Rajabally YA, Verhamme C. Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy. Brain. 2020;143(11):3214-24. https://doi.org/10.1093/brain/awaa265
Mulhearn B, Bruce IN. Indications for IVIG in rheumatic diseases. Rheumatology. 2015;54(3):383-91. https://doi.org/10.1093/rheumatology/keu429
Arumugham VB, Rayi A. Intravenous Immunoglobulin (IVIG) [internet]. En: StatPearls. Florida: StatPearls Publishing; 2023.
Brummaier T, Pohanka E, Studnicka-Benke A, Pieringer H. Using cyclophosphamide in inflammatory rheumatic diseases. Eur J Intern Med. 2013;24(7):590-6. https://doi.org/10.1016/j.ejim.2013.02.008
Hanif N, Anwer F. Rituximab [internet]. En: StatPearls. Florida: StatPearls Publishing; 2023.
Fragoulis GE, Nikiphorou E, Dey M, Zhao SS, Courvoisier DS, Arnaud L, et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2023;82(6):742-53. https://doi.org/10.1136/ard-2022-223335
Bass AR, Chakravarty E, Akl EA, Bingham CO, Calabrese L, Cappelli LC, et al. 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2023;75(3):333-48. https://doi.org/10.1002/art.42386
Ballow MC. Tratamiento con inmunoglobulinas: reposición e inmunomodulación. En: Inmunología clínica: principios y práctica. España: Elsevier; 2020. p. 1143-53.
Schutgens REG. First-line therapy for immune thrombocytopenia: time for change. Hemasphere. 2022;6(10):e783. https://doi.org/10.1097/hs9.0000000000000783
Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-SinDerivadas 4.0.