Anti-TNF (adalimumab – ADA, certolizumab – CERT, etanercept – ETN,
golimumab – GOL, infliximab – IFX)
|
Infections, bacterial or viral, are the most frequent and
important adverse events arising from the use of anti-TNF, mainly
affecting the respiratory tract, skin, soft tissues and urinary
tract.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. The risk of
hospitalization caused by bacterial infection is two times higher
in the patient using anti-TNF than in patients on MTX alone; this
risk increases four times when considering the first six months of
treatment.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. Since TNF
plays a central role in the formation and maintenance of the
granuloma, tuberculosis is an adverse event that potentially should
be very frequent, if it had not been for its systematic prevention,
which should never be neglected.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.
In the presence of infection by hepatitis B and C viruses, the use
of anti-TNF should be avoided. In exceptional cases of infection by
hepatitis C virus, anti-TNF drugs can be used with the associated
antiviral treatment.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.
|
Most skin reactions related to the administration of TNF
inhibitors have mild to moderate intensity, and do not require
discontinuation of the drug.3939 Hernández MV, Sanmartí MMR. Lesiones cutáneas y terapia biológica con
antagonistas del factor de necrosis tumoral. Reumatol Clin.
2013;9:53–61. The most common reactions are: erythema, urticaria
and eczema or rash, which may, in turn, be accompanied by pain or
edema.3939 Hernández MV, Sanmartí MMR. Lesiones cutáneas y terapia biológica con
antagonistas del factor de necrosis tumoral. Reumatol Clin.
2013;9:53–61. While the
appearance of rash has been described in approximately 6.9% of the
patients receiving 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.
injection site reactions were reported in 40% of the cases with
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. and 15% with
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. With the new
anti-TNF antibodies, the incidence of injection site reactions
appears to be smaller: 2.3% with 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. and 2.4% with 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.
|
The use of anti-TNF agents seems to be associated with low risk of
hematological changes, thrombocytopenia being a very rare event,
and leucopenia caused by a severe neutropenia being the most
frequent manifestation.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.
46 Bessissow T, Renard M, Hoffman I, Vermeire S, Rutgeerts P, Van Assche G.
Non-malignant haematological complications of anti-tumour necrosis factor alpha
therapy. Aliment Pharmacol Ther. 2012;36:312–23.
47 Hyrich KL, Silman AJ, Watson KD, Symmons DP. Anti-tumor necrosis factor
alpha terapy in rheumatoid arthritis: an update on safety. Ann Rheum Dis.
2004;63:1538–43.
48 Vidal F, Fontova R, Richart C. Severe neutropenia and thrombocytopenia
associated with infliximab. Ann Intern Med. 2003;139. W-W63.-4949 Wenham C, Gadsby K, Deighton C. Three significant cases of neutropenia
with etanercept. Rheumatology (Oxford). 2008;47:376–7.
As a routine, the cell blood count could be useful immediately
before start of immunobiological agents and through the follow-up
of these patients. |
Neurological manifestations have been described in patients using
anti-TNF therapy, including with exacerbation or onset of multiple
sclerosis, Guillain–Barré syndrome, multifocal leukoencephalopathy
(MLE), optic neuritis and various forms of demyelinating peripheral
neuropathy. The prevalence of demyelinating disease induced by the
use of anti-TNF is estimated between 0.02% and 0.20%. The use of
anti-TNF therapy is contraindicated in patients with a
demyelinating disease such as optic neuritis, peripheral
demyelinating neuropathy and multiple sclerosis. On suspicion of a
demyelinating disease, discontinue anti-TNF immediately and seek to
establish the causal link between the use and the symptoms.
Undertake a research and proper documentation, depending on the
type of neurological manifestation. Treatment should be
individualized for each patient, depending on the severity of the
clinical picture.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.
|
Gastrointestinal and hepatic manifestations associated with the
use of anti-TNF are unusual. |
The use of anti-TNF in RA appears to be associated with lower
cardiovascular morbidity when the manifestations are jointly
evaluated; however, the individual assessment of the risk of
stroke, myocardial infarction (MI) and congestive heart failure
(CHF) still has no definitive conclusions. CHF class II or IV (New
York Heart Association – NYHA) is a contraindication for
prescribing anti-TNF drugs.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.
|
While no increased risk for neoplasia was observed (except for
non-melanoma skin cancer) in patients using anti-TNF agents,
surveillance for the occurrence of malignancies (including
recurrence of solid tumors) in patients treated with TNF inhibitors
remains appropriate.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.
|
Compared with the general population, patients treated with TNF
inhibitors have an increased risk of lymphoma. However, when
compared with patients with RA treated with conventional drugs, no
increased risk for lymphoma and other hematologic malignancies was
observed.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.
|
HACA (human anti-chimeric antibodies) and HAHA (human anti-human
antibodies) can occur with all drugs of this class, but their
effect on the effectiveness of therapy is unclear. The induction of
production of antibodies against anti-TNFα agents depends
mainly on its structure. Chimeric drugs have a greater capacity to
induce immunogenicity compared to fully human drugs.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. The immunological
tolerance to ADA and IFX may be increased with concomitant use of
immunomodulators, such as methotrexate and azathioprine. There is
no evidence in the literature that HACA and HAHA cross-react with
the different anti-TNF agents.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.
|
Dermatological manifestations described in users of anti-TNF
inhibitors include skin reactions related to its administration,
skin infections, skin cancer and immune-mediated diseases, such as
psoriasis9797 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. cutaneous lupus,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 areata,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. cutaneous vasculitis,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. relapsing polychondritis,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. polymyositis/dermatomyositis,142142 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. localized scleroderma
(morphea),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 annulare135135 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. lichen or lichenoid reaction120120 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. and pemphigus.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.
|
The response to influenza vaccine does not appear to be impaired
in patients using anti-TNF agents, even when combined with
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. A study conducted in
Brazil and that evaluated the vaccine against H1N1 influenza,
found, besides a good safety profile, reduced serum protection in
patients with RA independently of disease activity. MTX was the
only DMD associated with reduced response to the vaccine.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. As for the pneumococcal
vaccine, the use of MTX in isolation or combined with some
anti-TNFs (ADA, ETN and IFX), may decrease the effectiveness of the
vaccine, while the isolated use of these biologicals does not
influence the vaccine response.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. Additionally, the use of anti-TNF can significantly
reduces the vaccine response against hepatitis 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. Vaccines with live
attenuated components should preferably be given three to four
weeks before initiation of immunosuppressive therapy, to ensure
that viral replication has finished before the change of the
patient's immune competence (in terms of drug use). Otherwise,
under treatment, the vaccination should be delayed for at least the
equivalent time of four half-lives of each anti-TNF drug.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.
|
Abatacept (ABAT) |
ABAT is contraindicated in patients with active infections,
including skin ulcers, with infected prostheses, or in those using
a catheter. Risk of serious infection is reported in 3% with ABAT
versus 1.9% with 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. The use of ABAT do not increase
Mycobacterium tuberculosis infection.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. As for patients who
initiate other biological agents, screening tests for hepatitis B
and C must be made before the use of 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.
|
The infusion reactions with ABAT are infrequent. The most common
symptoms are dizziness, nausea, headache, systemic hypertension,
hypotension and dyspnea. Severe hypersensitivity reactions are rare
(0.4% versus 0.2% with 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.
|
Hematologic manifestations related to the use of ABAT are
rare. |
To date, there are no reports of peripheral neuropathy or central
nervous system disease associated with the use of ABAT. |
Liver enzyme abnormalities are mild, occurring only rarely with
ABAT (0.1–1% of patients), and thus of little clinical value. The
combination with MTX, NSAIDs, corticosteroids, sulfasalazine and
leflunomide does not increase hepatotoxicity.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.
|
Regarding the increased cardiovascular risk of RA patients,
studies show that the use of ABAT does not determine higher risk.
Cardiovascular disease does not contraindicate the use of ABAT, and
this drug does not interact with cardiovascular drugs or with oral
anticoagulation.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.
|
The risk of other malignancies, e.g. non-melanoma skin cancer,
lung cancer, colorectal cancer and breast cancer, with ABAT is
comparable with RA patients using synthetic DMD.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.
|
Regarding the risk of lymphoma and other blood diseases,
double-blind and open studies with 4149 patients treated with ABAT
(11,658 patient-years) showed hematologic malignancy in only
0.13/100 patient-years (similar to RA), but as with the use of
anti-TNF biological agents, the use of ABAT should be avoided in
patients with lymphoma over the past five years.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.
|
Different from that observed with the use of anti-TNF biological
DMDs, the antinuclear factor (ANA) and anti-DNA did not show
positivity over time in patients treated with 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. Apparently, no formation
of HACA and HAHA occurred with the use of abatecept. |
The use of ABAT is contraindicated in patients with a diagnosis of
chronic obstructive pulmonary disease (COPD) due to exacerbation of
dyspnea and increased occurrence of infections.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. There are reports of
occurrence of psoriasiform rash169169 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. and lupus-like syndrome and Sjögren syndrome,170170 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. possibly in combination
with the use ABAT. The risk of development of autoimmune events
with the use of ABAT, based on the accumulated data of 4149
patients and 12,132 patient-years, has resulted in rare cases of
cutaneous psoriasis (OR = 0.60), Sjögren's syndrome (OR = 0, 26)
and vasculitis (OR = 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.
|
Regarding vaccination in patients with RA in use of ABAT, a
sub-analysis of a study evaluated the efficacy and safety of
influenza vaccination in 20 patients.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. A total of 55%, 50% and 35% of the
patients developed vaccine response to H1N1, H3N2 and influenza B
virus strains, respectively. A study in Brazil investigated the
humoral response to vaccination against H1N1 virus in 11 patients
with RA treated with MTX in combination with ABAT.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. Only 9% of the patients
treated with a combination of MTX and ABAT achieved seroprotection,
compared with 58% of the patients with MTX alone and 70% of healthy
individuals. The analysis of the response to pneumococcal vaccine
in 21 RA patients treated with ABAT showed that 81% achieved an
immune response to at least one serotype.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.
|
Rituximab (RTX) |
With regard to infections, a meta-analysis that included 745
patients treated with RTX in three randomized clinical trials found
that there was no increased risk of serious infections compared
with 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. The
subgroup of patients with low IgG levels showed a higher risk of
serious infections compared to patients who never presented this
finding, but the risk of infection was already increased in these
patients even before developing decreased levels of IgG. IgG levels
must be measured prior to treatment with RTX and monitored over
time.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. With regard to
TB, most patients using RTX have been pre-selected for latent
tuberculosis in clinical trials and in daily practice. Having
emphasized these points, reactivation of tuberculosis was not
observed, although the package leaflet for this drug recommend
searching for latent tuberculosis infection prior to
medication.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. Regarding hepatitis B and hepatitis C, experts
recommend that serology for hepatitis B should be performed before
starting treatment with 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. In both negative and positive patients, reactivation
was documented for the surface antigen of hepatitis 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.
|
The most frequent adverse events are infusion reactions, which
occur in 30–40% of patients in the first infusion and in about 10%
in the second infusion.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.
In most cases, the reactions are mild to moderate. Severe cases
that require drug discontinuation occur in less than 1% of the
treated patients.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. Each
infusion of RTX should be preceded by the prior use (60 min) of
methylprednisolone 100 mg IV, 1 g of paracetamol and an
antihistamine to decrease the severity and frequency of infusion
reactions.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.
|
The effect of B lymphocytes with its depletion is expected and is
part of the mechanism of action of this drug. However, a
significant reduction in total lymphocyte count is not expected.
Patient safety, in the face of B lymphocyte depletion after
multiple infusions of RTX (especially related to the cumulative
risk of serious infections and malignancies), is not fully
established in patients with rheumatoid arthritis.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. Hematologic adverse events
have not been shown relevant in long-term studies.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.
|
To date, six cases of MLE have been reported in patients with RA
treated with 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. Most cases had long-term RA and use of multiple
immunosuppressive agents. The number of reported cases of MLE in
patients with a diagnosis of RA being treated with RTX confers a
risk of 0.4/100,000 patient-years, slightly increased versus
general population (0.2/100,000) and lower than that observed in
patients with systemic lupus erythematosus (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. Thus, although its
occurrence is considered rare (1:20,000) due to the high morbidity
and mortality of the condition, clinical surveillance for diagnosis
is recommended in this patient population. To date, no reports of
peripheral neuropathy associated with the use of RTX were
published. |
An increase in gastrointestinal adverse events after exposure to
RTX has not been observed.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.,192192 Dass S, Vital EM, Emery P. Development of psoriasis after B cell
depletion with rituximab. Arthritis Rheum. 2007;56:2715–8.
|
An increased risk of acute myocardial infarction over time in
patients treated with RTX has not been observed.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.
|
An increased risk of solid tumors over time in patients treated
with RTX has not been observed.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.
|
An increased risk of hematological neoplasia over time in patients
treated with RTX has not been observed.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. RTX is even used in the treatment of
certain types of lymphoma. |
Safety data from long-term randomized clinical trials in RA
indicate that 11% (273/2578) of the patients exposed to RTX develop
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. HACA-positive
patients did not show a higher number of infusion reactions during
the second course of RTX in relation to HACA-negative
patients. |
Few cases of psoriasiform condition were reported after infusion
of RTX for the treatment of rheumatic diseases, or for other
indications.192192 Dass S, Vital EM, Emery P. Development of psoriasis after B cell
depletion with rituximab. Arthritis Rheum. 2007;56:2715–8.
Interstitial lung disease appears to be a rare occurrence with the
use of RTX, but with potential for morbidity and mortality.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. There are case reports of
serum sickness, with the appearance of mild to moderate
manifestations after infusion of RTX.195195 Todd DJ, Helfgott SM. Serum sickness following treatment with rituximab.
JRheumatol. 2007;34:430–3.
|
The use of RTX is related to a diminished response to vaccines,
either those T-cell independent and those T-cell dependent.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. There is evidence
suggesting a compromised response for anti-pneumococcal and
influenza vaccines, when administered to patients using 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. The response to
anti-influenza vaccine (including also influenza A and H1N1
vaccine) is also particularly compromised when the vaccine is
administered prematurely, four to eight weeks after administration
of RTX. Thus, influenza and anti-pneumococcal vaccines must be
applied before starting RTX, or six months after the first infusion
of this agent, and four weeks before the next 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. Patients with high risk of
contracting tetanus who were treated with RTX within last 24 weeks
must use passive immunization with tetanus immunoglobulin. Other
vaccine which should be administered before the use of RTX is that
against hepatitis 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.
|
Tocilizumab (TOCI) |
TOCI should not be used in patients with active infection by any
pathogen, including bacteria, viruses, fungi and parasites.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. The risk of infection is
1.2 times higher for patients treated with TOCI versus those using
synthetic DMD.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. The risk does not increase with exposure time, with
a rate for severe events ranging from 4 to 6/100,000
patient-years,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. even
if combined with other synthetic DMDs.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. Apparently, there is no increased risk of
reactivation of latent tuberculosis infection (LTBI).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. However, a LTBI screening
before and during the use of immunobiological agents, especially in
endemic areas is still recommended. Regarding viral hepatitis B and
C, data from studies are still preliminary. At the moment, TOCI
should not be used in this clinical setting.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.
|
Infusion reactions are rare events with TOCI and can be minimized
by slowing the speed of intravenous infusion and/or administration
of premedication with corticosteroids. Severe anaphylactic reaction
and a need for permanent discontinuation of TOCI are quite
rare. |
A mild and transient neutropenia may occur; this does not increase
the risk of infection per se. More severe or persistent cases
require dose reduction of the medication to 4 mg/kg/infusion, and
permanent discontinuation if this problem is not resolved.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.
|
There is a case report of peripheral neuropathy related to the use
of TOCI.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.
|
Elevations of hepatic enzymes may occur in 8–10% of the patients,
regardless of the synthetic DMD. In general, these elevations are
mild and transient, and do not increase the risk of irreversible
hepatocellular damage.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.
At the start of treatment, monitoring is recommended every four to
eight weeks, and then every three to six months. Persistent
elevations deserve wider investigation of other causes, as well as
a dose reduction and discontinuation of medication.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. Some cases of intestinal
perforation, especially in the colon, have been reported in
patients using TOCI. An anamnesis for personal history of colonic
diverticular disease and diverticulitis is recommended. This risk
increases with concomitant use of corticosteroids and NSAIDs.
Therefore, in this scenario these drugs should be used
sparingly.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.
|
No consistent clinical studies evaluating cardiovascular events as
primary outcomes using TOCI in patients with rheumatic diseases
were published. Apparently, the incidences of MI (0.25/100
patient-years) and stroke (0.19/100 patient-years) are low, without
increase with a longer exposure time to the drug.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.
|
Apparently, there is no higher risk than that observed in the
control group.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.
|
Apparently, there is no higher risk than that observed in the
control group.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 has antigenic potential, although few immunogenic reports
have been described. The ability of formation of neutralizing
antibodies HAHA, including intensity, isotype, specificity and
kinetics, has been studied, but the frequency is much lower than
that reported for TNF blockers.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.
|
There are some anecdotal cases or case reports of patients who
developed other unexpected adverse reactions after TCZ, including
skin (ulcers, necrotizing fasciitis)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. and mucosal (persistent aphthous
ulcerations in the oral mucosa) disorders,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. as well as eye (bilateral retinopathy with
hemorrhage and cotton-wool infiltrates)216216 Samimi M, Lauferon F, Hüttenberger B, Vaillant L, Goupille P, Machet L.
Ann Dermatol Venereol. 2013;140:120–4. and lung (organizing pneumonia and
exacerbation of interstitial picture)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. events. Just as observed with TNF
antagonists, some cases of psoriasis and uveitis onset ("de novo"
cases) were reported after IL-6 blockade, emphasizing paradoxical
events that can occur with the use also of this medication.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.
|
There are few studies on the vaccine response in patients exposed
to TOCI. Two studies demonstrated an adequate safety and efficacy
profile (seroprotection and seroconversion) for the vaccine against
influenza virus in patients with RA, regardless of MTX,222222 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. and systemic-onset
juvenile idiopathic arthritis.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. In addition, there was no exacerbation of the joint
status of these patients. Regarding other vaccines and
immunizations, at present there are no data on safety and efficacy
profiles. |