Anti-TNF (Adalimumabe- ADA, Certolizumabe- CERT, Etanercepte- ETN,
Golimumabe- GOL, Infliximabe- IFX)
|
As infecções, bacterianas ou virais, são o mais frequente e
importante dentre os eventos adversos decorrentes do uso de anti-TNF,
afetando principalmente trato respiratório, pele, partes moles e trato
urinário.2727 Curtis JR, Patkar N, Xie A, Martin C, Allisson JJ, Saag M. Risk of
serious bacterial infections among rheumatoid arthritis patients exposed to tumor
necrosis factor alpha antagonists. Arthritis Rheum. 2007;56:1125–33. O risco de
hospitalização por infecção bacteriana é duas vezes maior no paciente
em uso de anti-TNF do que nos pacientes em uso de MTX isolado; este
risco aumenta quatro vezes quando se considera o primeiro semestre de
tratamento.2828 Galloway JB, Hyrich KL, Mercer KL, Dixon WG, Fu B, Ustianovski AP, et
al. Anti-TNF therapy is associated with anincreased risk of serious infections in
patients with rheumatoid arthritis especially in the first 6 months of treatment:
updated results from the British Society for Rheumatology Biologics Register with
special emphasis on risks in the elderly. Rheumatology (Oxford).
2011;50:124–33. Como o TNF tem
papel central na formação e na manutenção do granuloma, a tuberculose
é um evento adverso que potencialmente deveria ser muito frequente,
não fosse sua prevenção sistemática, que nunca deve ser
negligenciada.3434 Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D,
Pascual-Gómez E, Mola EM, et al. Effectiveness of recommendations to prevent
reactivation of latent tuberculosis infection in patients treated with tumornecrosis
factor antagonists. Arthritis Rheum. 2005;52:1766–72.
35 Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A.
Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with
anti-TNF therapy: results from the British Society of Rheumatology Biologic Register
(BSRBR). Ann Rheum Dis. 2010;69:522–8.-3636 Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L,
Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and
Cochrane overview. Cochrane Database Syst Rev. 2011;16:CD008794. Na
presença de infecção pelos vírus da hepatite B e C, o uso de anti-TNF
deve ser evitado. Em casos excepcionais de infecção pelo vírus C da
hepatite, drogas anti-TNF podem ser utilizadas com o tratamento
antiviral associado.3737 da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo
MB, et al. Brazilian Society of Rheumatology Consensus for the treatment of
rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):152–74.
|
A maioria das reações cutâneas relacionadas com a administração de
inibidores do TNF tem intensidade leve a moderada, não requerendo a
interrupção do medicamento.3939 Hernández MV, Sanmartí MMR. Lesiones cutáneas y terapia biológica con
antagonistas del factor de necrosis tumoral. Reumatol Clin.
2013;9:53–61.
As reações mais frequentes são: eritema, urticária, eczema ou
exantema, que podem, por sua vez, acompanhar-se de dor ou edema.3939 Hernández MV, Sanmartí MMR. Lesiones cutáneas y terapia biológica con
antagonistas del factor de necrosis tumoral. Reumatol Clin.
2013;9:53–61. Enquanto o aparecimento de
exantema foi descrito em cerca de 6,9% dos pacientes que receberam
IFX,4040 Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et
al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis
factor alpha monoclonal antibody combined with low-dose weekly methotrexate in
rheumatoid arthritis. Arthritis Rheum. 1998;41:1552–63. reações no local da
injeção foram relatadas em cerca de 40% dos casos com ETN4141 Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox
RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc
fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl
J Med. 1999;340:253–9. e 15% com ADA.4242 Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara
CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal
antibody, for the treatment of rheumatoid arthritis in patients taking concomitant
methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. Com os novos anti-TNF, a
incidência de reações no local da injeção parece ser menor, sendo de
2,3% com o CERT4343 Keystone E, Heijde D, Mason D Jr, Landewe R, Vollenhoven RV, Combe B, et
al. Certolizumab pegol plus methotrexate is significantly more effective than placebo
plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase
III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Arthritis Rheum. 2008;58:3319–29. e 2,4% com o
GOL.4444 Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, et
al. Golimumab, a human antibody to tumour necrosis factor alpha given by monthly
subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy:
the GO-FORWARD Study. Ann Rheum Dis. 2009;68:789–96.
|
O uso de agentes anti-TNF parece estar associado a baixo risco de
alterações hematológicas, sendo a plaquetopenia um evento raríssimo, e
a leucopenia por neutropenia a manifestação mais frequente.3737 da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo
MB, et al. Brazilian Society of Rheumatology Consensus for the treatment of
rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):152–74.,4545 Kiely PD, Deighton C, Dixey J, Ostör AJ, British Society for
Rheumatology Standards, Guidelines and Audit Working Group. Biologic agents for
rheumatoid arthritis–negotiating the NICE technology appraisals. Rheumatology
(Oxford). 2012;51:24–31.–4949 Wenham C, Gadsby K, Deighton C. Three significant cases of neutropenia
with etanercept. Rheumatology (Oxford). 2008;47:376–7. Como rotina, a avaliação de
hemograma poderia ser de utilidade imediatamente antes de dar inicio e
no seguimento desses pacientes utilizando imunobiológicos. |
Manifestações neurológicas foram descritas em pacientes em uso de
terapia anti-TNF, incluindo exacerbação ou aparecimento da esclerose
múltipla, Síndrome de Guillan-Barré, leucoencefalopatia multifocal
(LEM), neurite óptica e várias formas de neuropatia periférica
desmielinizante. A prevalência de doença desmielinizante induzida pelo
uso de anti-TNF é estimada entre 0,02%-0,20%. O uso de anti-TNF está
contraindicado em pacientes com doença desmielinizante, como neurite
óptica, neuropatia periférica desmielinizante ou esclerose múltipla.
Na suspeita de doença desmielinizante, suspender o anti-TNF
imediatamente, procurar estabelecer o nexo causal entre o uso e os
sintomas. Proceder a investigação e a documentação adequada dependendo
do tipo de manifestação neurológica. O tratamento deve ser
individualizado para cada paciente a depender da gravidade do
quadro.5050 Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D, Bertolaccini
L, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233
cases. Medicine (Baltimore). 2007;86:242–51.
51 Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ,
Khamashta MA, BIOGEAS Study Group. Autoimmune diseases induced by biological agents:
a double-edged sword? Autoimmun Rev. 2010;9:188–93.
52 Bosch X, Saiz A, Ramos-Casals M, BIOGEAS study group. Monoclonal
antibody therapy-associated neurological disorders. Nat Rev Neurol.
2011;7:165–72.
53 Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy
associated with immuno suppressive therapy in rheumatic diseases: evolving role of
biologic therapies. Arthritis Rheum. 2012;64:3043–51.
54 Lozeron P, Denier C, Lacroix C, Adams D. Long term course of
demyelinating neuropathies occurring during tumor necrosis factor alpha blocker
therapy. Arch Neurol. 2009;66:490–7.
55 The Lenercept Multiple Sclerosis Study group and the University of
British Columbia MS/MRI Analysis group. TNFneutralization in MS: results of
placebo-controlledmulticenter study. Neurology. 1999;53:457–65.
56 van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von
Blomberg BM, et al. Increased MRI activity andimmune activation in two multiple
sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody
cA2. Neurology. 1996;47:1531–4.
57 Fernández-Espartero CM, Pérez-Zafrilla B, Naranjo A, Esteban C, Ortiz
AM, Gomez-Reino JJ, BIOBADASER Study Group. Demyelinating Disease in Patients Treated
with TNF Antagonists in Rheumatology: Data from BIOBADASER, a Pharmacovigilance
Database, and a Systematic Review. Semin Arthritis Rheum.
2011;40:330–7.-5858 Bernatsky S, Renoux C, Suissa S. Demyelinating events in rheumatoid
arthritis after drug exposures. Ann Rheum Dis .2010;69:1691–3.
|
Manifestações gastrointestinais e hepáticas associadas ao uso de
anti-TNF são incomuns. |
O uso de agentes anti-TNF em AR parece estar associado a menor
morbidade cardiovascular quando as manifestações são avaliadas em
conjunto, entretanto a avaliação individual do risco de acidente
vascular encefálico (AVE), infarto do miocárdio (IM) e insuficiência
cardíaca congestiva (ICC) ainda não apresenta conclusões definitivas.
ICC classe II ou IV (New York Heart Association –
NYHA) é contraindicação para a prescrição de drogas anti-TNF.5959 Nicola PJ, Crowson CS, Maradit-Kremers H, Ballman KV, Roger VL, Jacobsen
SJ, Gabriel SE. Contribution of Congestive Heart Failure and Ischemic Heart Disease
to Excess Mortality in Rheumatoid Arthritis. Arthritis Rheum.
2006;54:60–7.
60 Heeneman S, Daemen JAP. Cardiovascular Risks in Spondyloarthritides.
Curr Opin Rheumatol. 2007;19:358–62.
61 Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, Garcia-Porrua
C, Llorca J, Martin J. Cardiovascular disease in Rheumatoid Arthritis. Biomed
Pharmacother. 2006;60:673–7.
62 Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating
levels of tumor necrosis factor in severe chronic heart failure. N Eng J Med.
1990;323:236–41.
63 Mann DL, McMurray JJV, Packer M, Swedberg K, Borer JS, Colucci WS, et
al. Targeted anticytokine therapy in patients with chronic heart failure. Results of
the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation.
2004;109:1594–602.
64 Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized,
Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal
Antibody to Tumor Necrosis Factor-alpha, in Patients with Moderate-to-Severe Heart
Failure. Results of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH)
Trial. Circulation. 2003;107:3133–40.
65 Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart
failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med.
2003;138:807–11.
66 Mann DL. Inflammatory mediators and the failing heart: past, present,
and the foreseeable future. Circ Res. 2002;91:988–98.
67 Weisman MH, Paulus HE, Burch FX, Kivitz AJ, Fierer J, DunnM, et al. A
placebo-controlled, randomized, double-blinded study evaluating the safety of
etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases.
Rheumatology (Oxford). 2007;46:1122–5.
68 Jacobsson LT, Turesson C, Gülfe A, Kapetanovic MC, Petersson IF, Saxne
T, et al. Treatment with tumor necrosis factor blockers is associated with a lower
incidence of first cardiovascular events in patients with rheumatoid arthritis. J
Rheumatol. 2005;32:1213–8.
69 Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo
T, et al. All-cause and cause-specific mortality in rheumatoid arthritis are not
greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum
Dis. 2007;66:880–5.
70 Kremer JM. Analysis of risk factors and effect of treatment on the
development of cardiovascular disease in patients with rheumatoid arthritis. Ann
Rheum Dis. 2006;65 Suppl.II:307.
71 Hochberg MC, Johnston SS, John AK. The incidence and prevalence of
extra-articular and systemic manifestations in a cohort of newly-diagnosed patients
with rheumatoid arthritis between 1999 and 2006. Curr Med Res Opin.
2008;24:469–80.
72 Solomon DH, Avorn J, Katz JN, Weinblatt ME, Setoguchi S, Levin R, et al.
Immuno suppressive medications and hospitalization for cardiovascular events in
patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:3790–8.
73 Naranjo A, Sokka T, Descalzo MA, Calvo-Alén J, Hørslev-Petersen
K, Luukkainen RK, et al. Cardiovascular disease in patients with rheumatoid
arthritis: results from the QUEST-RA study. Arthritis Res Ther.
2008;10:R30.
74 Dixon WG, Watson KD, Lunt M, Hyrich KL, Silman AJ, Symmons DP. Reduction
in the incidence of myocardial infarction in patients with rheumatoid arthritis who
respond to anti-tumor necrosis factor alpha therapy: results from the British Society
for Rheumatology Biologics Register. Arthritis Rheum.
2007;56:2905–12.
75 Suissa S, Bernatsky S, Hudson M. Antirheumatic drug useand the risk of
acute myocardial infarction. Arthritis Rheum. 2006;55:531–6.
76 Radovits BJ, Popa-Diaconu DA, Popa C, Eijsbouts A, Laan RF, van Riel PL,
et al. Disease activity as a risk factor for myocardial infarction in rheumatoid
arthritis. Ann Rheum Dis. 2009;68:1271–6.
77 Singh G. Combination TNF-inhibitor-methotrexate therapyis superior to
methotrexate monotherapy in reducing the risk of acute myocardial infarction in
patients with rheumatoid arthritis. Arthritis Rheum. 2007;56
Suppl:S535.
78 Wolfe F, Michaud K. The risk of myocardial infarction and pharmacologic
and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: a
cohort and nested case-control analysis. Arthritis
Rheum.2008;58:2612–21.
79 Dixon WG, Watson KD, Lunt M, Hyrich KL, BSRBR Control Centre Consortium,
Silman AJ, and Symmons DPM, on be half of the BSR Biologics Register. Rates of
myocardial infarction (MI) and cerebrovascular accident (CVA) in patients with
rheumatoid arthritis (RA) treated with anti-TNF therapy: results from the British
Society of Rheumatology Biologics Register (BSRBR). Arthritis Rheum. 2006;54
Suppl:S311.
80 Listing J, Strangfeld A, Kekow J, Schneider M, Kapelle A, Wassenberg S,
et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure
in patients with rheumatoid arthritis? Arthritis Rheum.
2008;58:667–77.
81 Curtis JR, Kramer JM, Martin C, Saag KG, Patkar N, Shatin D, et al.
Heart failure among younger rheumatoid arthritis and Crohn’s patients exposed to
TNF-alpha antagonists. Rheumatology (Oxford). 2007;46:1688–93.
82 Cole J, Busti A, Kazi S. The incidence of new onset congestive heart
failure and heart failure exacerbation in Veteran’s Affairs patients receiving tumor
necrosis factor alpha antagonists. Rheumatol Int. 2007;27:369–73.
83 Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates,
predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med.
2004;116:305–11.
84 Setoguchi S, Schneeweiss S, Avorn J, Katz JN, Weinblatt ME, Levin R, et
al. Tumor necrosis factor-alpha antagonist useand heart failure in elderly patients
with rheumatoid arthritis. Am Heart J. 2008;156:336–41.-8585 Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug useand risk of
hospitalization for congestive heart failurein rheumatoid arthritis. Rheumatology.
2005;44:677–80.
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Embora não tenha sido observado risco aumentado para neoplasias, com
exceção da neoplasia de pele não melanoma, nos pacientes em uso de
agentes anti-TNF, continua sendo apropriado fazer vigilância para a
ocorrência de doenças malignas (incluindo recorrência de tumores
sólidos) em pacientes tratados com inibidores do TNF.8686 Cush JJ, Dao KH. Malignancy risks with biologic therapies. Rheum Dis
Clin N Am. 2012;38:761–70.
87 Solomon DH, Mercer E, Kavanaugh A. Observational studies on the risk of
cancer associated with tumor factor inhibitors in rheumatoid arthritis: a review of
their methodologies and results (review). Arthritis Rheum.
2012;64:21–32.
88 Wolfe F, Michaud K. Biologic treatment of rheumatic arthritis and the
risk of malignancy: analyses from a large US observational study. Arthritis Rheum.
2007;56:2886–95.
89 Mariette X, Matucci-Cerinic M, Pavelka K, Taylor P, Van Vollenhoven R,
Heatley R, et al. Malignancies associated with tumour necrosis factor inhibitors in
registries and prospective observational studies: a systematic review and
meta-analysis. Ann Rheum Dis. 2011;70:1895–904.
90 Amari W, Zeringue AL, McDonald JR, Caplan L, Eisen SA, Ranganathan P.
Risk of non-melanoma skin cancer in anational cohort of veterans with rheumatoid
arthritis. Rheumatology (Oxford). 2011;50:1431.
91 Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer
risk with tumor necrosis factor alpha(TNF) inhibitors: meta-analysis of randomized
controlled trials of adalimumab, etanercept, and infliximab using patient level data.
Pharmacoepidemiol Drug Saf. 2011;20:119.
92 Carmona L, Abasolo L, Descalzo MA, Perez-Zafrilla B, Sellas A, De Abajo
F, et al. Cancer in patients with rheumatic diseases exposed to TNF antagonists.
Semin Arthritis Rheum. 2011;41:71–80.
93 Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis,
and tumor necrosis factor inhibitors. J Rheumatol. 2005;32:2130–5.
94 Katoulis AC, Kanelleas A, Zambacos G, Panayiotides I, Stavrianeas NG.
Development of two primary malignantmelanomas after treatment with adalimumab: a case
reportand review of the possible link between biological therapy with TNF-alpha
antagonists and melanocytic proliferation. Dermatology.
2010;221:9–12.
95 Kowalzick L, Eickenscheidt L, Komar M, Schaarschmidt E. Long term
treatment of psoriasis with TNF-alpha antagonists Occurrence of malignant melanoma.
Hautarzt. 2009;60:655–7.
96 Khan I, Rahman L, McKenna DB. Primary cutaneousmelanoma: a complication
of infliximab treatment. Clin Exp Dermatol. 2009;34:524–6.
97 Basavaraj KH, Ashok NM, Rashmi R, Praveen TK. The role of drugs in the
induction and/or exacerbation of psoriasis. Int J Dermatol.
2010;49:1351–61.
98 Scheinberg M, Gonçalves DP, Laurindo IM. Anti-TNF agents inducing
psoriasis: a recognized adverse effect. J Clin Rheumatol.
2008;14:130.
99 Lee HH, Song IH, Friedrich M, Gauliard A, Detert J, Rowert J, et al.
Cutaneous side-effects in patients with rheumatic diseases during application of
tumour necrosis factor-alpha antagonists. Br J Dermatol.
2007;156:486–91.
100 Harrison MJ, Dixon WG, Watson KD, King Y, Groves R, Hyrich KL, et al.
Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving
anti-tumour necrosis factor alpha therapy: results from the British Society for
Rheumatology Biologics Register. Ann Rheum Dis. 2009;68:209–15.
101 Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation of
psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog
Treat. 2009;20:100–8.
102 De Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S, et al.
Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients
with rheumatologic conditions. Arch Dermatol. 2007;143:223–31.
103 Michaelsson G, Kajermo U, Michaelsson A, Hagforsen E. Infliximab can
precipitate as well as worsen palmo plantar pustulosis: possible linkage to the
expression of tumour necrosis factor-alpha in the normal palmar eccrine sweat duct.
Br J Dermatol. 2005;153:1243–4.-104104 Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor
necrosis factor antagonist therapy: clinical features and possible
immunopathogenesis. Semin Arthritis Rheum. 2010;40:233–40.
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Em comparação com a população geral, os pacientes tratados com
inibidores do TNF têm um risco aumentado de linfoma. Quando comparados
com pacientes de AR tratados com medicamentos clássicos, entretanto,
não foi observado um risco aumentado para linfoma ou outras neoplasias
hematológicas.105105 Isomaki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas,
leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis.
1978;31:691–6.
106 Hellgren K, Smedby KE, Feltelius N, Baecklund E, Askling J.Do rheumatoid
arthritis and lymphoma share risk factors?. A comparison of lymphoma and cancer risks
before and after diagnosis of rheumatoid arthritis. Arthritis Rheum.
2010;62:1252–8.
107 Mercer LK, Davies R, Galloway JB, Low A, Lunt M, Dixon WG, et al. Risk
of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid
arthritis compared with the UK general population. Rheumatology (Oxford).
2013;52:91–8.
108 Baecklund E, Ekbom A, Sparén P, Feltelius N, Klareskog L. Disease
activity and risk of lymphoma in patients with rheumatoid arthritis: nested
case-control study. BMJ. 1998;18(317):180–1.
109 Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al.
Association of chronic inflammation, not its treatment, with increased lymphoma risk
in rheumatoid arthritis. Arthritis Rheum. 2006;54:692–701.
110 Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP,
Gonzales-Crespo MR, et al. Risk of malignancies in patients with rheumatoid arthritis
treated with biologic therapy: a meta-analysis. JAMA.
2012;308:898–908.
111 Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis
factor antagonist therapy and lymphoma development: twenty-six cases reported to the
Food and Drug Administration. Arthritis Rheum. 2002;46:3151-8.
112 Askling J, van Vollenhoven RF, Granath F, Raaschou P,Fored CM, Baecklund
E, et al. Cancer risk in patients with rheumatoid arthritis treated with anti-tumor
necrosis factor alpha therapies: does the risk change with the time since start of
treatment? Arthritis Rheum. 2009;60:3180-9.
113 Pallavicini FB, Caporali R, Sarzi-Puttini PAtzeni FBazzani C, Gorla R,
et al. Tumour necrosis factor antagonist therapy and cancer development: analysis of
the LORHEN registry. Autoimmun Rev. 2010;9:175-80.
114 Mariette X, Tubach F Bagheri H, Bardet M, Berthelot JM, Gaudin P, et al.
Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French
RATIO registry. Ann Rheum Dis. 2010;69:400-8.
115 Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of
methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis
Rheum. 2004;50:1740-51.
116 Greenberg J, Strand V,Keystone E, Curtis J, Maury E, Reed G, et al. TNF
inhibitors (TNF-I) and risk of malignancy in 8,072 RA patients followed over 15,495
patient years (Abstract 282). American College of Rheumatology Annual Meeting;
2007.-117117 Askling J, Baecklund E, Granath F Geborek PFored M, Backlin C, et al.
Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant
lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann
Rheum Dis. 2009;68:648-53.
|
Anticorpos anti-quiméricos humanos (HACA, do inglês human
anti-chimeric antibody ) e -HAHA (do inglês human
anti-human antibody ) podem ocorrer com todas as drogas da
classe, mas seu efeito sobre a eficácia da terapia é incerto. A
indução da produção de anticorpos contra os agentes anti-TNF-α
depende principalmente de sua estrutura. Drogas quiméricas tem uma
maior capacidade de induzir imunogenicidade em comparação a
medicamentos completamente humanos.118118 Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ,
et al., Pediatric Rheumatology Collaborative Study Group. Etanercept in children with
polyarticular juvenile rheumatoid arthritis. N Engl J Med.
2000;342:763-9.,119119 Aikawa NE, de Carvalho JF, Silva CAA, Bonfa E. Immunogenicity of
Anti-TNF-alpha agents in autoimmune diseases. Clin Rev Allergy Immunol.
2010;38:82-9.
A tolerância imunológica ao ADA e IFX pode ser aumentada com o uso
concomitante de imunomoduladores, tais como o MTX e azatioprina. Não
existe evidencia na literatura que a reatividade dos HACA e HAHA seja
cruzada para os diferentes agentes anti-TNF.125125 Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using
infliximab: new insights into the role of tumor necrosis factor on human hair
follicles. Arch Dermatol. 2004;140:1012.
|
As manifestações dermatológicas descritas nos usuários de inibidores
de anti-TNF incluem reações cutâneas relacionadas com a sua
administração, infecções cutâneas, neoplasias cutâneas e enfermidades
imunomediadas, como psoríase,9797 Basavaraj KH, Ashok NM, Rashmi R, Praveen TK. The role of drugs in the
induction and/or exacerbation of psoriasis. Int J Dermatol.
2010;49:1351–61.
98 Scheinberg M, Gonçalves DP, Laurindo IM. Anti-TNF agents inducing
psoriasis: a recognized adverse effect. J Clin Rheumatol.
2008;14:130.-9999 Lee HH, Song IH, Friedrich M, Gauliard A, Detert J, Rowert J, et al.
Cutaneous side-effects in patients with rheumatic diseases during application of
tumour necrosis factor-alpha antagonists. Br J Dermatol.
2007;156:486–91.,101101 Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation of
psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog
Treat. 2009;20:100–8.
102 De Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S, et al.
Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients
with rheumatologic conditions. Arch Dermatol. 2007;143:223–31.
103 Michaelsson G, Kajermo U, Michaelsson A, Hagforsen E. Infliximab can
precipitate as well as worsen palmo plantar pustulosis: possible linkage to the
expression of tumour necrosis factor-alpha in the normal palmar eccrine sweat duct.
Br J Dermatol. 2005;153:1243–4.-104104 Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor
necrosis factor antagonist therapy: clinical features and possible
immunopathogenesis. Semin Arthritis Rheum. 2010;40:233–40.
lúpus cutâneo,121121 Wetter DA, Davis MD. Lupus-like syndrome attributable to anti-tumor
necrosis factor alpha therapy in 14 patients during an 8-year period at Mayo Clinic.
Mayo Clin Proc. 2009;84:979-84.
122 Stratigos AJ, Antoniou C, Stamathioudaki S, Avgerinou G, Tsega A,
Katsambas AD. Discoid lupus erythematosus-like eruption induced by infliximab. Clin
Exp Dermatol. 2004;29:150-3.
123 Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor
necrosis factor alpha agents. Semin Arthritis Rheum. 2008;37:381-7.-124124 Vezzoli P, Violetti SA, Serini SM, Muratori S, Berti E, Crosti C.
Cutaneous lupus erythematosus induced by adalimumab. J Dermatol.
2011;38:283-4.
alopecia aerata,9999 Lee HH, Song IH, Friedrich M, Gauliard A, Detert J, Rowert J, et al.
Cutaneous side-effects in patients with rheumatic diseases during application of
tumour necrosis factor-alpha antagonists. Br J Dermatol.
2007;156:486–91.,125125 Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using
infliximab: new insights into the role of tumor necrosis factor on human hair
follicles. Arch Dermatol. 2004;140:1012.
126 Posten W, Swan J. Recurrence of alopecia areata in a patient receiving
etanercept injections. Arch Dermatol. 2005;141:759-60.
127 Garcia Bartels N, Lee HH, Worm M, Burmester GR, Sterry W, Blume-Peytavi
U. Development of alopecia areata universalis in a patient receiving adalimumab. Arch
Dermatol. 2006;142:1654-5.
128 Hernandez MV, Nogues S, Ruiz-Esquide V,Alsina M, Canete JD, Sanmarti R.
Development of alopecia areata after biological therapy with TNF-alpha Blockers:
description of a case and review of the literature. Clin Exp Rheumatol.
2009;27:892-3.
129 Pelivani N, Hassan AS, Braathen LR, Hunger RE, Yawalkar N. Alopecia
areata universalis elicited during treatment with adalimumab. Dermatology.
2008;216:320-3.
130 Chaves Y, Duarte G, Ben-Said B, Tebib J, Berard F, Nicolas JF. Alopecia
areata universalis during treatment of rheumatoid arthritis with anti-TNF-alpha anti-
body (adalimumab). Dermatology. 2008;217:380.
131 Fabre C, Dereure O. Worsening alopecia areata and de novo occurrence of
multiple halo nevi in a patient receiving infliximab. Dermatology.
2008;216:185-6.
132 Ferran M, Calvet J, Almirall M, Pujol RM, Maymo J. Alopecia areata as
another immune-mediated disease developed in patients treated with tumour necrosis
factor-alpha blocker agents: Report of five cases and review of the literature. J Eur
Acad Dermatol Venereol. 2011;25:479-84.-133133 Tosti A, Pazzaglia M, Starace M, Bellavista S, Vincenzi C, Tonelli G.
Alopeci areata during treatment with biologic agents. Arch Dermatol.
2006;142:1653-4.
vasculite cutânea,134134 Ramos-Casals M, Brito-Zeron P, Munoz S, Soria N, Galiana D, Bertolaccini
L, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of233
cases. Medicine (Baltimore). 2007;86:242-51.
135 Exarchou SA, Voulgari PV, Markatseli TE, Zioga A, Drosos AA.
Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor
alpha inhibi- tors. Scand J Rheumatol. 2009;38:328-31.
136 Pontikaki I, Shahi E, Frasin LA, Gianotti R, Gelmetti C, Gerloni V, et
al. Skin Manifestations Induced by TNF-Alpha Inhibitors in Juvenile Idiopathic
Arthritis. Clin Rev Allergy Immunol. 2012;42:131-4.
137 Mohan N, Edwards ET, Cupps TR, Slifman N, Lee JH, Siegel JN, et al.
Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking
agents. J Rheumatol. 2004;31:1955-8.-138138 Fujikawa K, Kawakami A, Hayashi T, Iwamoto N, Kawashiri SY, Aramaki T,
et al. Cutaneous vasculitis induced by TNF inhibitors: a report of three cases. Mod
Rheumatol. 2010;20:86-9.
vitiligo,135135 Exarchou SA, Voulgari PV, Markatseli TE, Zioga A, Drosos AA.
Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor
alpha inhibi- tors. Scand J Rheumatol. 2009;38:328-31.,139139 Ramirez-Hernandez M, Marras C, Martinez-Escribano JA. Infliximab-induced
vitiligo. Dermatology. 2005;210:79-80.,140140 Lahita RG, Vernace MA. Vasculitis, vitiligo, thyroiditis, and altered
hormone levels after anti-tumor necrosis factor therapy. J Rheumatol.
2011;38:579-80.
policondrite recidivante,141141 Hernandez MV, Ruiz-Esquide V, Gomez-Caballero ME, Gomez-Puerta JA,
Canete JD, Sanmarti R. Relapsing polychondritis: a new adverse event secondary to the
use of tumour necrosis factor antagonists. Rheumatology (Oxford).
2011;50:1523-5.
polimiosite/dermatomiosite142142 Hall HA, Zimmermann B. Evolution of dermatomyositis during therapy with
a tumor necrosis factor alpha inhibitor. Arthritis Rheum.
2006;55:982-4.,143143 Ishikawa Y, Yukawa N, Ohmura K, Hosono Y, Imura Y, Kawabata D, et al.
Etanercept-induced anti-Jo-1-antibody-positive polymyositis in a patient with
rheumatoid arthritis: a case report and review of the literature. Clin Rheumatol.
2010;29:563-6.,
esclerodermia localizada (morfea),144144 Ramirez J, Hernandez MV, Galve J, Canete JD, Sanmarti R. Morphea
associated with the use of adalimumab: a case report and review of the literature.
Mod Rheumatol. 2011 [Epub ahead of print].
145 Ranganathan P. Infliximab-induced scleredema in a patient with
rheumatoid arthritis. J Clin Rheumatol. 2005;11:319-22.-146146 Mattozzi C, Richetta AG, Cantisani C, Giancristoforo S, D'Epiro S,
Gonzalez Serva A, et al. Morphea, an unusual side effect of anti-TNF-alpha treatment.
Eur J Dermatol. 2010;20:400-1.
granuloma anular135135 Exarchou SA, Voulgari PV, Markatseli TE, Zioga A, Drosos AA.
Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor
alpha inhibi- tors. Scand J Rheumatol. 2009;38:328-31.,147147 Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. Granuloma
annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis.
2008;67:567-70.
líquen ou reação liquenoide120120 Flendrie M, Vissers WH, Creemers MC, De Jong EM, Van de Kerkhof PC, Van
Riel PL. Dermatological conditions during TNF-alpha-blocking therapy in patients with
rheumatoid arthritis: a prospective study. Arthritis Res Ther.
2005;7:R666-76.,135135 Exarchou SA, Voulgari PV, Markatseli TE, Zioga A, Drosos AA.
Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor
alpha inhibi- tors. Scand J Rheumatol. 2009;38:328-31.,148148 Bonnet N, Guis S, Koeppel MC, Roudier J, Grimaud JC, Jean-Pastor MJ, et
al. Cutaneous events during anti-TNF alpha therapy: a prospective observational study
of 41 cases. Ann Dermatol Venereol. 2010;137:12-20.
e pênfigo.149149 Boussemart L, Jacobelli S, Batteux F, Goulvestre C, Grange P, Carlotti
A, et al. Autoimmune bullous skin diseases occurring under anti-tumor necrosis factor
therapy: two case reports. Dermatology. 2010;221:201-5.
|
A resposta à vacina contra influenza parece não estar comprometida em
pacientes em uso de agentes anti-TNF mesmo quando associados ao
MTX.152152 Fomin I, Caspi D, Levy V, Varsano N, Shalev Y, Paran D, et al.
Vaccination against influenza in rheumatoid arthritis: the effect of disease
modifying drugs, including TNF alpha blockers. Ann Rheum Dis.
2006;65:191-4.
153 Kaine JL, Kivitz AJ, Birbara C, Luo AY. Immune responses following
administration of influenza and pneumococcal vaccines to patients with rheumatoid
arthritis receiving adalimumab. J Rheumatol. 2007;34:272-9.-154154 Kubota T, Nii T, Nanki T, Kohsaka H, Harigai M, Komano Y, et al.
Anti-tumor necrosis factor therapy does not diminish the immune response to influenza
vaccine in Japanese patients with rheumatoid arthritis. Mod Rheumatol.
2007;17:531-3. Estudo realizado no Brasil
que avaliou a vacina contra influenza H1N1, constatou, além do bom
perfil de segurança, redução da soro proteção em pacientes com AR
independentemente da atividade de doença. O MTX foi a única DMCD
associada à redução de resposta à vacina.156156 Ribeiro AC, Guedes LK, Moraes JC, Saad CG, Aikawa NE, Calich AL, et al.
Reduced seroprotection after pandemic H1N1 influenza adjuvant-free vaccination in
patients with rheumatoid arthritis: implications for clinical practice. Ann Rheum
Dis. 2014;70:2144-7. Quanto à vacina anti-pneumocócica, o uso
isolado do MTX ou combinado a alguns anti-TNF (ADA, ETN e IFX), pode
diminuir a eficácia da vacina, enquanto o uso isolado destes
biológicos não influencia a reposta vacinal.153153 Kaine JL, Kivitz AJ, Birbara C, Luo AY. Immune responses following
administration of influenza and pneumococcal vaccines to patients with rheumatoid
arthritis receiving adalimumab. J Rheumatol. 2007;34:272-9.,155155 Kapetanovic MC, Saxne T, Nilsson JA, Geborek P.Influenza vaccination as
model for testing immune modulation induced by anti-TNF and methotrexate therapy in
rheumatoid arthritis patients. Rheumatology (Oxford).
2007;46:608-11. Adicionalmente, o uso de anti-TNF pode reduzir
significativamente a resposta vacinal à vacina contra hepatite B.157157 Garrido Lopez BC, Navarro Compain MV, Navarro Sarabia F. [Vaccines and
chemo-prophylaxis in rhemautoid arthritis: is a vaccine calendar necessary?].
Reumatol Clin. Nov;7:412-6. As vacinas com componentes
vivos atenuados devem, preferencialmente, ser indicadas três a quatro
semanas antes início da terapia imunossupressora, para garantir que a
replicação viral tenha terminado antes da alteração da competência
imune do paciente (em função do uso da droga). Caso contrário, em
vigência de tratamento, a vacinação deve ser adiada por pelo menos o
tempo correspondente a quatro meias-vidas de cada droga anti-TNF.158158 Brenol CV, da Mota LM, Cruz BA, Pileggi GS, Pereira IA, Rezende LS, et
al. 2012 Brazilian Society of Rheumatology Consensus on vaccination of patients with
rheumatoid arthritis. Rev Bras Reumatol. 2013;53:4-23.
|
Abatacepte – ABAT |
ABAT é contraindicado em pacientes com infecção ativa, incluindo
úlceras cutâneas, próteses infectadas e que sejam portadores de
cateter. Risco de infecção grave é relatado em 3% com ABAT
versus 1,9% com placebo.164164 Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety
of the selective costimulation modulator abatacept in rheumatoid arthritis patients
receiving background biologic and nonbiologic disease-modifying antirheumatic drugs:
A one-year randomized, placebo-controlled study. Arthritis Rheum.
2006;54:2807–16.,165165 von Kempis J, Dudler J, Hasler P, Kyburz D, Tyndall A, Zufferey P,
Villiger PM. Use of abatacept in rheumatoid arthritis. Swiss Med Wkly.
2012;142:w13581. ABAT não aumenta infecção por Mycobacterium
tuberculosis .162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97.,166166 Bigbee CL, Gonchoroff DG, Vratsanos G, Nadler SG, Haggerty HG, Flynn JL.
Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection
in mice. Arthritis Rheum. 2007;56:2557–65.
Assim como para pacientes que iniciam outros agentes biológicos,
testes de rastreamento para hepatite B e C devem ser feitos antes do
início do ABAT.161161 Pham T, Bachelez H, Berthelot JM, Blacher J, Claudepierre P, Constantin
A, et al. Abatacept therapy and safety management. Joint Bone Spine. 2012;79 Suppl
1:3–84.
|
As reações infusionais com ABAT são infrequentes. Os sintomas mais
relatados são tonturas, náuseas, cefaleia, hipertensão arterial
sistêmica, hipotensão arterial e dispneia. As reações de
hipersensibilidade grave são raras (0,4% vs 0,2% com
placebo).162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97.,167167 Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C,
Szechinski J, Li T, Ge Z, Becker JC, Westhovens R. Effects of abatacept in patients
with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann
Intern Med. 2006;144:865–76.
|
Manifestações hematológicas relacionadas ao uso de ABAT são
raras. |
Não há relatos de neuropatia periférica ou doenças do Sistema Nervoso
Central associadas ao uso do ABAT até o momento. |
Alterações de enzimas hepáticas são discretas e raras com ABAT
(0,1%-1% dos pacientes), e assim de pequeno valor clínico. A
combinação com MTX, AINE, corticoide, sulfasalazina e leflunomida não
aumenta hepatotoxicidade.161161 Pham T, Bachelez H, Berthelot JM, Blacher J, Claudepierre P, Constantin
A, et al. Abatacept therapy and safety management. Joint Bone Spine. 2012;79 Suppl
1:3–84.
|
Em relação ao risco cardiovascular aumentado dos pacientes com AR, os
estudos realizados mostram que o uso do ABAT não determina maior
risco. Doença cardiovascular não contraindica o uso de ABAT, e esta
droga não interage com drogas cardiovasculares ou com o uso de
anticoagulante oral.161161 Pham T, Bachelez H, Berthelot JM, Blacher J, Claudepierre P, Constantin
A, et al. Abatacept therapy and safety management. Joint Bone Spine. 2012;79 Suppl
1:3–84.,162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97.
|
O risco de outras neoplasias malignas como câncer de pele não
melanoma, câncer de pulmão, câncer coloretal e câncer de mama com ABAT
é comparável com os pacientes com AR em uso de DMCD sintético.162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97.,168168 Simon TA, Smitten AL, Franklin J, Askling J, Lacaille D, Wolfe F,
Hochberg MC, Qi K, Suissa S. Malignancies in the rheumatoid arthritis abatacept
clinical development programme: an epidemiological assessment. Ann Rheum Dis.
2009;68:1819–26.
|
Em relação ao risco de linfoma e outras doenças hematológicas, os
estudos duplo cego e aberto com 4.149 pacientes tratados com ABAT
(11.658 pacientes-ano) mostraram malignidade hematológica em apenas
0,13/100 pacientes-ano (similar a AR), mas da mesma forma que com o
uso dos agentes biológicos anti-TNF, o uso de ABAT deve ser evitado em
pacientes que tiveram linfoma nos últimos cinco anos.161161 Pham T, Bachelez H, Berthelot JM, Blacher J, Claudepierre P, Constantin
A, et al. Abatacept therapy and safety management. Joint Bone Spine. 2012;79 Suppl
1:3–84.
|
Diferente do observado com o uso de DMCD biológicos anti-TNF, o fator
antinuclear (FAN) e o anti-DNA não se positivaram ao longo do tempo em
pacientes em tratamento com ABAT.162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97. Não parece haver formação de HACA e HAHA com o uso de
abatacepte. |
O uso de ABAT é contraindicado em pacientes com quadro de doença
pulmonar obstrutiva crônica (DPOC), por exacerbação do quadro de
dispneia e maior ocorrência de infecções.3737 da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo
MB, et al. Brazilian Society of Rheumatology Consensus for the treatment of
rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):152–74. Há relatos de ocorrência de quadros de
rash psoriasiforme,169169 Sibilia T, Westhovens R. Safety of T-cell co-stimulation modulation with
abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007;25 Suppl
46:546–56. bem como síndrome lúpus like
e síndrome de Sjögren170170 Smitten AL, Qi K, Simon TA, Becken JC. Autoimmune adverse events in the
abatacept RA clinical development program: a safety analysis with > 10000 person –
years of exposure [abstract 1673]. Arthritis Rheum. 2008;58
Suppl:5786.
possivelmente associados ao uso de ABAT. O risco de desenvolvimento de
eventos autoimunes com ABAT baseado em dados acumulados de 4.149
pacientes e 12.132 pacientes-ano mostrou raros casos de psoríase
cutânea, com OR de 0,60, síndrome de Sjögren – OR de 0,26 e vasculite
– OR de 0,34.162162 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et
al. Safety of Abatacept Administered Intravenously in Treatment of Rheumatoid
Arthritis: Integrated Analyses of up to 8 Years of Treatment from the Abatacept
Clinical Trial Program. J Rheumatol. 2013;40:787–97.
|
Em relação à vacinação em pacientes com AR em uso de ABAT, uma
subanálise de um estudo avaliou a eficácia e a segurança da vacinação
contra influenza em 20 pacientes.177177 Lee YH, Bae SC, Song GG. The efficacy and safety of rituximab for the
treatment of active rheumatoid arthritis: a systematic review and meta-analysis of
randomized controlled trials. Rheumatol Int. 2011;31:1493–9. Um total de 55%, 50% e 35% dos pacientes desenvolveram
resposta vacinal ao H1N1, H3N2 e sorotipos de influenza B,
respectivamente. Um estudo no Brasil investigou a resposta humoral à
vacinação contra o vírus da gripe H1N1 em 11 pacientes com AR tratados
com ABAT combinado com MTX.172172 Ribeiro A, Guedes L, Moraes J, Saad C, Calich A, Aikawa N, et al.
Abatacept in association with traditional DMARDS severely impairs humoral response to
pandemic A H1N1 influenza vaccination in rheumatoid arthritis patients. AnnRheum Dis.
2011;70 Suppl 3:458. Abstract FRI0342.
Apenas 9% dos doentes tratados com a combinação ABAT e MTX obtiveram
soroproteção, comparado com 58% dos pacientes com MTX isolado e 70%
dos indivíduos saudáveis. A análise da resposta à vacina contra o
pneumococo em 21 pacientes com AR tratados com ABAT demonstrou que 81%
obtiveram resposta imunológica a pelo menos um sorotipo.173173 Schiff M, Kaell A, Tay L, Vratsanos G, Bahrt K. Response to pneumococcal
vaccine in rheumatoid arthritis patients with an inadequate response to anti-TNF
therapy treated with abatacept in the ARRIVE trial. Poster SAT0029, EULAR.
2007.
|
Rituximabe – RTX |
Com relação a infecções, metanálise que incluiu 745 pacientes
tratados com RTX em três ensaios clínicos randomizados observou que
não houve aumento de risco para infecções graves em comparação ao
grupo placebo.180180 Salliot C, Dougados M, Gossec L. Risk of serious infections during
rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses
of randomised placebo-controlled trials. Ann Rheum Dis.
2009;68:25–32. O subgrupo
de pacientes com baixos níveis de IgG apresentou maior risco de
infecções graves em comparação aos pacientes que nunca apresentaram
esse achado, mas o risco de infecção já era aumentado nesses pacientes
mesmo antes de desenvolver diminuição dos níveis de IgG. Os níveis de
IgG devem ser dosados antes do tratamento com RTX e monitorados ao
longo do tempo.179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20. Com relação
à tuberculose, a maioria dos pacientes, que utilizaram o RTX, foi
pré-selecionada para a tuberculose latente nos ensaios clínicos e na
prática diária. Tendo esses pontos enfatizados, a reativação de
tuberculose não foi observada, apesar de o bulário da medicação
recomendar a pesquisa de tuberculose latente antes do início da
medicação.3636 Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L,
Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and
Cochrane overview. Cochrane Database Syst Rev. 2011;16:CD008794.,181181 Ruderman EM. Overview of safety of non-biologic and biologic DMARDs.
Rheumatology (Oxford). 2012;51 Suppl 6:vi37–43.
Em relação à hepatite B e hepatite C, especialistas recomendam que a
sorologia para hepatite B deve ser realizada antes do início do
tratamento com RTX.179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20.
Reativação tem sido documentada tanto em pacientes negativos quanto
positivos para o antígeno de superfície do vírus da hepatite B.182182 Pei SN, Chen CH, Lee CM, Wang MC, Ma MC, Hu TH, et al. Reactivation of
hepatitis B virus following rituximab-based regimens: a serious complication in both
HBsAg-positive and HBsAg-negative patients. Ann Hematol.
2010;89:255–62.,183183 Koo YX, Tan DS, Tan BH, Quek R, Tao M, Lim ST. Risk of hepatitis B virus
reactivation in patients who are hepatitis B surface antigen negative/antibody to
hepatitis B core antigen positive and the role of routine antiviral prophylaxis. J
Clin Oncol. 2009;20(27):2570–1.
|
Os eventos adversos mais frequentes são as reações infusionais, que
ocorrem em 30%-40% dos pacientes na primeira infusão e cerca de 10% na
segunda infusão.190190 Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al.
efficacy and safety of different doses and retreatment of rituximab: a randomised,
placebo-controlled trial in patients who are biological naive with active rheumatoid
arthritis and an inadequate response to methotrexate (study evaluating rituximab's
efficacy in mtx inadequate responders (serene). Ann Rheum Dis.
2010;69:1629–35. Na maioria
das vezes, as reações são de intensidade leve à moderada. Casos graves
que requerem descontinuação da droga ocorrem em menos de 1% dos
pacientes tratados.179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20. Cada
infusão de RTX deve ser precedida da utilização de 100 mg de
metilprednisolona IV 60 minutos antes, 1 g de paracetamol e
anti-histamínico para diminuir a gravidade e a frequência das reações
infusionais.190190 Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al.
efficacy and safety of different doses and retreatment of rituximab: a randomised,
placebo-controlled trial in patients who are biological naive with active rheumatoid
arthritis and an inadequate response to methotrexate (study evaluating rituximab's
efficacy in mtx inadequate responders (serene). Ann Rheum Dis.
2010;69:1629–35.
|
O efeito sobre linfócitos B com a depleção dos mesmos é esperado e
faz parte do mecanismo de ação desta droga. Entretanto, não é esperada
redução significativa da contagem total de linfócitos. A segurança da
depleção de linfócitos B após múltiplas infusões de RTX, especialmente
relacionada ao risco cumulativo de infecções graves e neoplasias, não
está totalmente estabelecida em pacientes com artrite reumatoide.178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012. Os eventos adversos
hematológicos não têm se mostrado relevantes nos estudos de longo
prazo.178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012.,191191 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann R,
Furst DE, et al. Longterm safety of patients receiving rituximab in rheumatoid
arthritis clinical trials. J Rheumatol. 2010;37:558–67.
|
Até o momento, seis casos de LEM foram relatados em pacientes com AR
tratados com RTX.178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012.,179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20.
A maioria dos casos apresentava AR de longa duração e uso de múltiplos
imunossupressores. O número de casos de LEM relatado em pacientes com
diagnóstico de AR em uso de RTX confere um risco de 0,4/100.000
pacientes-ano, discretamente aumentado em relação à população geral
(0,2/100.000) e menor do que observado em pacientes com lúpus
eritematoso sistêmico (4/100.000).5353 Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy
associated with immuno suppressive therapy in rheumatic diseases: evolving role of
biologic therapies. Arthritis Rheum. 2012;64:3043–51. . Assim, embora a ocorrência seja considerada rara
(1:20.000), em função da grande morbimortalidade da condição,
recomenda-se vigilância clínica para este diagnóstico nesta população
de pacientes. Não há relatos de neuropatia periférica associada ao uso
do RTX até o momento. |
Não tem sido observado aumento de eventos adversos gastrointestinais
após a exposição ao RTX178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012.,192192 Dass S, Vital EM, Emery P. Development of psoriasis after B cell
depletion with rituximab. Arthritis Rheum. 2007;56:2715–8.
|
Não tem sido observado aumento do risco de infarto agudo do miocárdio
ao longo do tempo nos pacientes tratados com RTX178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012.
|
Não tem sido observado aumento do risco de neoplasias sólidas ao
longo do tempo nos pacientes tratados com RTX178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012.
|
Não tem sido observado aumento do risco de neoplasias hematológicas
ao longo do tempo nos pacientes tratados com RTX.178178 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann
RM, Furst DE, et al. long-term safety of rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme with a focus on adverse events of
interest in ra patients. Ann Rheum Dis. 2012. O RTX é inclusive utilizado no tratamento de
certos tipos de linfoma. |
Dados de segurança de longo prazo dos ensaios clínicos randomizados
em AR indicam que 11% (273/2578) dos pacientes expostos ao RTX
desenvolvem HACA.191191 van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann R,
Furst DE, et al. Longterm safety of patients receiving rituximab in rheumatoid
arthritis clinical trials. J Rheumatol. 2010;37:558–67. Pacientes
HACA-positivos não apresentaram maior número de reações infusionais
durante o segundo curso de RTX em relação aos pacientes
HACA-negativos. |
Foram relatados poucos casos de quadros psoriasiformes após infusão
do RTX para tratamento de doenças reumáticas ou outras
indicações.192192 Dass S, Vital EM, Emery P. Development of psoriasis after B cell
depletion with rituximab. Arthritis Rheum. 2007;56:2715–8. Doença
intersticial pulmonar parece ser uma ocorrência rara com o uso de RTX,
porém com potencial de morbidade e mortalidade.193193 Hadjinicolaou AV, Nisar MK, Parfrey H, Chilvers ER, Ostör AJ.
Non-infectious pulmonary toxicity of rituximab: asystematic review. Rheumatology
(Oxford). 2012;51:653–62. Há relatos de casos doença do soro, com o
aparecimento de quadros leves a moderados após infusão de RTX.195195 Todd DJ, Helfgott SM. Serum sickness following treatment with rituximab.
JRheumatol. 2007;34:430–3.
|
O uso de RTX está relacionado com a redução da resposta às vacinas
tanto de células T independentes quanto T dependentes.158158 Brenol CV, da Mota LM, Cruz BA, Pileggi GS, Pereira IA, Rezende LS, et
al. 2012 Brazilian Society of Rheumatology Consensus on vaccination of patients with
rheumatoid arthritis. Rev Bras Reumatol. 2013;53:4-23. Existem evidências que
sugerem uma resposta comprometida às vacinas anti-pneumocócica e
contra influenza quando administradas em pacientes em uso de RTX.179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20.,196196 van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M,
et al. Eular recommendations for vaccination in adult patients with autoimmune
inflammatory rheumatic diseases. Ann Rheum Dis Mar. 70:414-22.,197197 Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M,
Codding C, et al. Immunization responses in rheumatoid arthritis patients treated
with rituximab: results from a controlled clinical trial. Arthritis Rheum.
62;1:64-74. A reposta à vacina contra
influenza (incluindo também a vacina contra influenza A e H1N1) também
fica particularmente comprometida quando a vacina é administrada
precocemente, quatro a oito semanas após a administração do RTX.
Assim, as vacinas contra influenza e anti-pneumocócica devem ser
aplicadas antes de iniciar RTX ou seis meses após a primeira infusão e
quatro semanas antes da próxima dose.158158 Brenol CV, da Mota LM, Cruz BA, Pileggi GS, Pereira IA, Rezende LS, et
al. 2012 Brazilian Society of Rheumatology Consensus on vaccination of patients with
rheumatoid arthritis. Rev Bras Reumatol. 2013;53:4-23.,179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20.
Pacientes com grande risco de contrair tétano que receberam RTX dentro
das últimas 24 semanas devem utilizar imunização passiva com
imunoglobulina antitetânica. Outra vacina que deve ser administrada
antes do uso de RTX é contra a hepatite B.179179 Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T,
et al. updated consensus statement on the use of rituximab in patients with
rheumatoid arthritis. AnnRheum Dis. 2011;70:909–20.
|
Tocilizumabe- TOCI |
TOCI não deve ser usado em pacientes com infecção ativa por qualquer
patógeno, incluindo bactérias, vírus, fungos e parasitas.198198 Keyser FD. Choice of biological therapy for patients with rheumatoid
arthritis: The Infection Perspective. Curr Rheumatol Rev.
2011;7:77–87.,199199 Lang VR, Englbrecht M, Rech J, Nüsslein H, Manger K, Schuch F, et al.
Risk of infections in rheumatoid arthritis patientst reated with tocilizumab.
Rheumatology (Oxford).2012;51:852–7. O risco de infecção é 1,2
vezes maior para pacientes tratados com TOCI do que aqueles em uso de
DMCD sintéticas.3636 Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L,
Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and
Cochrane overview. Cochrane Database Syst Rev. 2011;16:CD008794.,200200 Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a
Cochrane systematic review. J Rheumatol. 2011;38:10–20. O
risco não aumenta com o tempo de exposição, com taxa para eventos
graves que varia de quatro a seis para cada 100.000
pacientes-ano,202202 Ogata A, Hirano T, Hishitani Y, Tanaka T. Safety and efficacy of
tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis
Musculoskelet Disord. 2012;5:27–42. mesmo se
combinado a outras DMCD sintéticas.203203 Schiff MH, van Vollenhoven RF, Jahreis A, Vernon E, Isaacs JD, van
Vollenhoven RF. Integrated safety in tocilizumab randomized clinical trials.
Arthritis Res Ther. 2011;13:R141. Parece não haver aumento o risco de reativação de
infecção tuberculosa latente (ITbL).204204 Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ. Risk of adverse
events including serious infections in rheumatoid arthritis patients treated with
tocilizumab: a systematic literature review and meta-analysis of randomized
controlled trials. Rheumatology (Oxford). 2011;50:552–62. No entanto, ainda é recomendado o rastreamento da ITbL
antes e durante o uso de agentes imunobiológicos, especialmente em
áreas endêmicas. Em relação às hepatites virais pelos vírus B e C, os
dados dos estudos ainda são preliminares. No momento, o TOCI não deve
ser usado nesse cenário clínico.204204 Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ. Risk of adverse
events including serious infections in rheumatoid arthritis patients treated with
tocilizumab: a systematic literature review and meta-analysis of randomized
controlled trials. Rheumatology (Oxford). 2011;50:552–62.,208208 Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, et al.
Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: ínterim
analysis of 3881 patients. Ann Rheum Dis. 2011;70:2148–51.
|
Reações infusionais são eventos raros com o TOCI e podem ser
minimizados com a lentificação da velocidade de infusão endovenosa
e/ou administração de pré-medicação com corticosteroides. Reação
anafilática grave e necessidade de descontinuação definitiva do TOCI
são bastante raras. |
Pode ocorrer neutropenia leve e transitória, que não aumenta o risco
de infecções per se . Casos mais graves ou
persistentes exigem redução da dose da medicação para 4 mg/kg/infusão
e descontinuação definitiva se não resolvida.210210 Nakamura I, Omata Y, Naito M, Ito K. Blockade of interleukin 6 signaling
induces marked neutropenia in patientswith rheumatoid arthritis. J Rheumatol.
2009;36:459–60.
|
Existe um relato de caso de neuropatia periférica relacionada ao uso
do TOCI210210 Nakamura I, Omata Y, Naito M, Ito K. Blockade of interleukin 6 signaling
induces marked neutropenia in patientswith rheumatoid arthritis. J Rheumatol.
2009;36:459–60.
|
Elevações das enzimas hepáticas podem ocorrer em 8%-10% dos
pacientes, independentemente das DMCD sintéticas. Em geral, são leves
e transitórias e não aumentam o risco de dano hepatocelular
irreversível.211211 Sugiura F, Kojima T, Oguchi T, Urata S, Yuzawa Y, Sakakibara A, Hayashi
H, Nishimoto N, Ishiguro N. A case of peripheral neuropathy and skin ulcer in a
patient with rheumatoid arthritis after a single infusion of tocilizumab Mod
Rheumatol. 2009;19:199–203.
Recomenda-se monitoração a cada quatro a oito semanas no início do
tratamento e, depois, a cada três a seis meses. Elevações persistentes
indicam investigação mais ampla de outras causas, assim como redução
da dose e descontinuação da medicação.203203 Schiff MH, van Vollenhoven RF, Jahreis A, Vernon E, Isaacs JD, van
Vollenhoven RF. Integrated safety in tocilizumab randomized clinical trials.
Arthritis Res Ther. 2011;13:R141. Alguns casos de perfuração intestinal, especialmente
colônica, têm sido descritos em pacientes usando TOCI. Recomenda-se
uma anamnese dirigida para antecedentes pessoais de doença
diverticular dos cólons e diverticulite. Esse risco aumenta com o uso
concomitante de corticosteroides e AINE que, portanto, devem ser
usados com parcimônia nesse cenário.203203 Schiff MH, van Vollenhoven RF, Jahreis A, Vernon E, Isaacs JD, van
Vollenhoven RF. Integrated safety in tocilizumab randomized clinical trials.
Arthritis Res Ther. 2011;13:R141.
|
Ainda não há estudos clínicos consistentes que avaliaram os eventos
cardiovasculares, como desfechos primários, com o uso de TOCI em
pacientes com doenças reumatológicas. Parece ser baixa a incidência de
IM (0,25/100 pacientes-ano) e AVE (0,19/100 pacientes-ano) e sem
aumento com o maior tempo de exposição à medicação.203203 Schiff MH, van Vollenhoven RF, Jahreis A, Vernon E, Isaacs JD, van
Vollenhoven RF. Integrated safety in tocilizumab randomized clinical trials.
Arthritis Res Ther. 2011;13:R141.
|
Parece não haver risco mais elevado do que o observado no grupo
controle.212212 Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al.
Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients
with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis.
2010;69:88–96.
|
Parece não haver risco mais elevado do que o observado no grupo
controle.212212 Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al.
Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients
with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis.
2010;69:88–96.
|
TOCI tem potencial antigênico, embora poucos relatos imunogênicos
tenham sido descritos. A capacidade de formação de anticorpos
neutralizantes HAHA, incluindo intensidade, isotipo, especificidade e
cinética, tem sido estudada, mas a frequência é bem inferior à
relatada para os bloqueadores do TNF.213213 Mariette X, Gottenberg JE, Ravaud P, Combe B. Registries inrheumatoid
arthritis and autoimune diseases: data from theFrench registries. Rheumatology
(Oxford). 2011;50:222–9.
|
Existem alguns casos anedóticos ou relatos de caso de pacientes que
desenvolveram outras reações adversas inesperadas após TCZ, incluindo
afecções da pele (ulcerações, fasciíte necrotizante)214214 Stubenrauch K, Wessels U, Vogel R, Schleypen J. Evaluation of a
biosensor immunoassay for simultaneous characterization of isotype and binding region
of humananti-tocilizumab antibodies with control by surrogate standards. Anal
Biochem. 2009;390:189–96. e mucosas (ulcerações
aftóides persistentes na mucosa oral),215215 van de Sande MG, van Slobbe-Bijlsma ER. Necrotizing fasciitis in a
rheumatoid arthritis patient treated with tocilizumab. Rheumatology (Oxford).
2012;51:577–8. bem como eventos oculares (retinopatia bilateral com
hemorragia e infiltrados algodonosos),216216 Samimi M, Lauferon F, Hüttenberger B, Vaillant L, Goupille P, Machet L.
Ann Dermatol Venereol. 2013;140:120–4. pulmonares (pneumonia em organização e exacerbação de
quadros intersticiais).217217 Tada A, Hashida N, Tanaka T, Nishida K. Anti-interleukin-6 receptor
antibody therapy-induced retinopathy in a patient with rheumatoid arthritis. Case Rep
Rheumatol. 2012;2012:270315.,218218 Ikegawa K, Hanaoka M, Ushiki A, Yamamoto H, Kubo K. A case of organizing
pneumonia induced by tocilizumab. Intern Med. 2011;50:2191–3.
Da mesma forma que o observado com os antagonistas do TNF, têm sido
relatados alguns casos de início da psoríase e uveíte ("de novo") após
o bloqueio da IL-6, enfatizando eventos paradoxais que podem ocorrer
com o uso também dessa medicação.219219 Kawashiri SY, Kawakami A, Sakamoto N, Ishimatsu Y, Eguchi K. A fatal
case of acute exacerbation of intersticial lung disease in a patient with rheumatoid
arthritis during treatment with tocilizumab. Rheumatol Int.
2012;32:4023–6.
220 Wendling D, Letho-Gyselinck H, Guillot X, Prati C. Psoriasis onset with
tocilizumab treatment for rheumatoid arthritis. J Rheumatol.
2012;39:657.-221221 Wendling D, Dernis E, Prati C, Frisch E, Delbosc B. Onset of
inflammatory eye disease under tocilizumab treatment for rheumatologic conditions: a
paradoxical effect? J Rheumatol. 2011;38:2284.
|
Há poucos estudos sobre a resposta vacinal em pacientes expostos ao
TOCI. Dois estudos demonstraram adequado perfil de segurança e
eficácia (soroproteção e soroconversão) da vacina contra o vírus da
influenza em pacientes com AR, independentemente do MTX222222 Laurent S, Le Parc JM, Clérici T, Bréban M, Mahé E. Onset of psoriasis
following treatment with tocilizumab. Br J Dermatol.
2010;163:1364–5. e artrite idiopática juvenil
de início sistêmico.223223 Mori S, Ueki Y, Hirakata N, Oribe M, Hidaka T, Oishi K. Impact of
tocilizumab therapy on antibody response to influenza vaccine in patients with
rheumatoid arthritis. Ann Rheum Dis. 2012;71:2006–10. Além
disso, não houve exacerbação do quadro articular desses pacientes. Com
relação às outras vacinas e imunizações, ainda não existem dados sobre
o perfil de segurança e eficácia. |