References 1. Holmes B, Sorkin EM. Indoramin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and related vascular, cardiovascular and airway diseases. Drugs 1986;31(6):67–99. Erratum in: Drugs 1986;32(4):preceding 291. 2. Marshall AJ, Kettle MA, Barritt DW. Evaluation of indoramin added to oxprenolol and bendrofluazide as a third agent in severe hypertension. Br J Clin Pharmacol 1980;10(3):217–21. 3. Abrams SM, Pierce DM, Johnston A, Hedges A, Franklin RA, Turner P. Pharmacokinetic interaction between indoramin and ethanol. Hum Toxicol 1989;8(3):237–41.
Death due to worsening of cardiac insufficiency in patients with congestive heart failure has been reported (SEDA-26, 401). Respiratory Allergic granulomatosis of the lung has been described after a second infusion of infliximab in one of 35 patients with active ankylosing spondylitis (8). The clinical and radiological symptoms resolved 8 weeks after withdrawal, but no other details were given.
A 32-year-old man with Crohn’s disease developed an eosinophilic pleural effusion soon after a second infusion of infliximab (9). He recovered within 8 weeks, but the effusion recurred after infliximab re-treatment 1 year later.
See also Monoclonal antibodies
Features of aseptic meningitis have been reported after multiple infliximab injections (10).
General Information Infliximab, a monoclonal chimeric human/murine antibody directed against tumor necrosis alfa, has been used in the treatment of severe active Crohn’s disease (1,2), rheumatoid arthritis (3), and ankylosing spondylitis (4). From the available data submitted for Crohn’s disease to the US and European regulatory agencies, the most significant acute adverse reactions were infusion reactions, defined as symptoms within 2 hours after intravenous infusion. The symptoms consisted of fever, chills, urticaria, dyspnea, chest pain, or hypotension, and occurred in 16% of infliximab-treated patients versus 6–7% of placebo-treated patients. Several adverse effects, such as upper respiratory tract infections, headaches, rash, or cough, were more common than with placebo, but severe adverse effects were only slightly more frequent (3.6 versus 2.6%). Clinical trials also showed an increase in the prevalence of antinuclear antibodies or the development of double-stranded DNA antibodies (9% of patients). Although there were clinical features suggestive of the lupus-like syndrome in only very few patients, this issue needs to be further investigated. Also of great concern is the report in several patients of lymphoma (5) or severe opportunistic infections (6). Patients taking concomitant immunosuppressive drugs should be carefully observed for such complications.
Organs and Systems Cardiovascular The preliminary results of a phase II trial in patients with moderate to severe congestive heart failure showed a higher incidence of worsening congestive heart failure and death in patients treated with infliximab compared with placebo (7). This led to warnings from regulatory agencies and to the limited use of infliximab in patients with congestive heart failure. ª 2006 Elsevier B.V. All rights reserved.
A 53-year-old man with severe rheumatoid arthritis and mixed type III cryoglobulinemia received his first four injections of infliximab uneventfully, but 4 hours after the fifth injection had severe muscle pain in the lower limbs, which required morphine and abated within 3 days. Similar symptoms were observed after the sixth injection. There were no signs of meningitis, the cerebrospinal fluid contained lymphocytes and increased concentrations of protein and IgG. Cultures were negative and MRI scans of the brain and the spine were normal. The CSF was normal 1 month later.
The authors speculated that the most likely explanation for these observations was linked to the lack of transfer of high-molecular weight soluble receptors and IgG across the blood–brain barrier, implying that control of brain tumor necrosis factor alfa cannot be obtained with monoclonal antibodies. They thought that neurological complications in diseases other than multiple sclerosis might be related to control of tumor necrosis factor alfa in the periphery, resulting in an enhanced contribution of brain-derived tumor necrosis factor alfa or other cytokines, such as interleukin-1. Neurological events suggestive of demyelinating disorders in patients treated with tumor necrosis factor alfa antagonists and reported to the FDA’s Adverse Events Reporting System have been reviewed (11). These included 17 cases temporarily associated with etanercept and two with infliximab, but complete information was lacking in a number of cases. The various hypothetical mechanisms by which tumor necrosis factor alfa antagonists might produce demyelinating events have been discussed (12). Briefly, they cause an increase in peripheral T cell autoreactivity, and their inability to cross the blood–brain barrier may account for exacerbation of central demyelinating disorders. Sensory systems Optic neuropathy has been described in patients with rheumatoid arthritis taking infliximab. In three patients aged 54–62 years, blurred vision or visual field loss in one or both eyes occurred after the third dose (13).
1748 Infliximab Ophthalmic examination showed anterior optic neuropathy in all three patients and MRI scanning ruled out demyelinating optic neuritis. In one patient an additional infusion of infliximab produced similar symptoms in the previously unaffected eye; vision failed to improve despite infliximab withdrawal and steroid treatment.
Retrobulbar optic neuritis was diagnosed after the ninth dose of infliximab in a 55-year-old woman (14). MRI scanning showed demyelination of the left optic nerve and the visual field defect improved after treatment with prednisone.
antibodies were positive, as were antinuclear antibodies, and he completely recovered after treatment with prednisone. In three patients with severe Crohn’s disease who required digestive surgery, infliximab before or immediately after surgery was discussed as an additional possible cause of postoperative poor wound healing with serious complications (19). Patients with congestive heart failure has been reported (SEDA-26, 401). Immunologic
Hematologic The possible role of infliximab in the development of hypercoagulability disorders has been discussed in the context of a case of arterial thrombosis (15).
A 72-year-old woman with refractory sarcoidosis developed venous thrombosis at a catheter site and extensive multiple thromboses in small arteries in her legs after receiving a third dose of infliximab for severe enteropathy. Anticardiolipin antibodies were detected, but antinuclear and anti-double-stranded DNA antibodies were negative.
Although infliximab has been associated with autoantibody production, it is not known whether it contributed to hypercoagulability in this patient. Liver Acute hepatitis with infliximab has been described (16).
A 44-year-old woman, who had used oral contraceptives for many years and had taken mesalazine, mercaptopurine, and prednisone for Crohn’s disease for 7 years, developed clinical and biological signs of acute mixed hepatitis 19 days after a single dose of infliximab 5 mg/kg. There were no symptoms suggestive of hypersensitivity and liver histology showed cholestasis without inflammation or eosinophilia. Other causes, such as a recent viral infection (hepatitis A, B, C, cytomegalovirus, Herpes simplex) or gallstones, were ruled out. Among various autoantibodies, only antinuclear antibody titers were slightly raised. Complete normalization was observed 2 months later.
Although the patient took other potentially hepatotoxic drugs, the time-course suggested that infliximab was the cause. Skin Skin reactions, including erythema multiforme in three patients and a lichenoid eruption in one, were attributed to infliximab (17). One patient had similar lesions after etanercept. Patch tests with infliximab in three patients were negative, but produced a flare-up of lesions in one patient and recurrence of malaise and nausea in another patient, suggesting that infliximab is well absorbed percutaneously.
A 72-year-old man developed bullous skin lesions the day after receiving his fourth dose of infliximab for rheumatoid arthritis (18). Human antichimeric
ª 2006 Elsevier B.V. All rights reserved.
Antibodies to infliximab Treatment with infliximab can be associated with the formation of human antichimeric antibodies. Such antibodies were rarely detected in patients with rheumatoid arthritis who were also taking methotrexate, and low titers were detected in about 13% of patients with Crohn’s disease. Their clinical relevance is unclear, although their presence has sometimes been associated with an increased risk of infusion reactions, the occurrence of serum sickness-like reactions after delayed re-treatment, and a shorter duration of response. In a randomized, placebo-controlled trial in 573 patients with Crohn’s disease, who responded to an initial infusion of infliximab and were then given repeated infusions, antibodies to infliximab were found in 14%; there was a trend toward a lower incidence of antibodies in patients taking concurrent glucocorticoids and immunosuppressive drugs (20). The incidence of infusion reactions was also higher in patients positive for antibodies to infliximab compared with patients without antibodies (16 versus 8%) and lower in patients who were taking both glucocorticoids and immunosuppressants compared with patients who were receiving neither (8 versus 32%). The clinical significance of antibodies to infliximab has also been explored in 125 patients with Crohn’s disease who were given infliximab, of whom 61% had antibodies after the fifth infusion; however, there was no further increase in incidence after subsequent treatment (21). The presence of antibodies was associated with a 2.4fold increase in the risk of infusion reactions, lower serum infliximab concentrations, and a shorter duration of clinical response, compared with patients with no infliximab antibodies. Patients who received concomitant immunosuppressive therapy had a lower incidence of infliximab antibodies, higher infliximab serum concentrations, and a longer duration of clinical response. Pretreatment with glucocorticoids may reduce the risk of antibody formation, but it is not known whether a pretreatment test for human antichimeric antibodies has a predictive value for adverse reactions (22). However, there were technical issues relating to the antibody assay and definition of clinically relevant antibody titers in this study. Autoantibodies and autoimmunity Infliximab may increase the risk of autoimmunity, but the presence of antibodies did not predict the risk of lupuslike syndrome. In trials, the incidence of infliximabinduced anti-double-stranded DNA antibodies ranged from 5 to 34% of patients, depending on the assay method
Infliximab used and the duration of exposure (20–24). However, these abnormalities were rarely associated with clinical manifestations. In two large randomized trials in more than 900 infliximab-treated patients, only three developed a lupus-like syndrome, with no evidence of systemic organ involvement (20–24). However, since then, several reports have detailed infliximab-induced, lupus-like syndrome in patients with Crohn’s colitis or rheumatoid arthritis, with improvement on withdrawal of infliximab (25,26). Of 40 patients who had received multiple doses of an investigational liquid formulation of infliximab 2–4 years before, 10 had a severe delayed hypersensitivity reaction within 3–12 days after the first or the second re-infusion (27). This reaction mostly included myalgia, rash, fever, polyarthralgia, and pruritus. Although the six patients tested were negative for antibodies to infliximab before re-infusion, these antibodies were consistently raised after the reaction. Infliximab binds to tumor necrosis factor alfa on cell surfaces and produces apoptotic cell death, releasing the nucleosomal autoantigens that induce autoantibody formation (28).
A 69-year-old woman with a 5-year history of rheumatoid arthritis developed drug-induced lupus after receiving infliximab for 23 weeks. She had initially been given methotrexate and prednisone for 4 years. Then, because of lack of efficacy, infliximab was introduced. After three infusions of infliximab and only partial remission the dose was increased to 5 mg/kg, with success. However, before the sixth infusion she developed fever, polyarthralgia, myalgia, and general malaise. Serology excluded viral infection. Autoantibody assessment was positive, confirming the diagnosis of drug-induced lupus.
Hypersensitivity reactions Both acute and delayed hypersensitivity reactions to infliximab have been reported in clinical trials (SEDA24, 439). Immediate infusion reactions to infliximab are usually defined by any significant adverse effect that occurs during or within 1–2 hours after the infusion. The symptoms mostly consist of flushing, rash, shortness of breath, wheeze, hotness, chest pain, vomiting, and abdominal pain. Delayed reactions are defined by the occurrence of arthralgia and joint stiffness (that is a serum sicknesslike reaction) in the days after infliximab administration; they have mostly been observed in patients with Crohn’s disease who have received episodic treatment. In one patient the complication was associated with acute respiratory distress syndrome, which only became evident 10 days after re-treatment (22).
reactions from 1 to 14 days after treatment were noted in three instances only. Prophylaxis with diphenhydramine and paracetamol and the use of a test dose of infliximab allowed additional infusions without consequences in patients with mild or moderate previous acute infusion reactions. Three of the four patients who had acute severe reactions received the same prophylaxis plus corticosteroids before re-treatment: one had a similar severe acute reaction, while the other two had no recurrences. This study also suggested that acute infusion reactions are probably not IgE-mediated, as tryptase and IgE serum concentrations were not raised. Of 86 patients with Crohn’s disease receiving infliximab 14% of patients experienced severe systemic reactions, with a significant difference between adults (21%) and children (3%), the reason for which was unclear (30). There were severe infusion reactions, defined by any significant change in vital signs or the development of chest pain, wheeze, dyspnea, vomiting, abdominal pain, or rash, in 16 of 100 patients with refractory Crohn’s disease (31). Half of them occurred during the first infusion, and the rate of infusion reactions was similar in patients taking concurrent immunosuppressants or glucocorticoids compared with those who were not. One patient had anaphylactic shock, five had significant hypotension, six had acute pulmonary symptoms, two had pruritus, flushing, or rash, and one had vomiting. The final patient, who had a previous history of chronic pancreatitis, had acute pancreatitis within 1 hour of treatment. Immediate hypersensitivity reactions Acute hypersensitivity reactions can mimic an anaphylactic reaction, but specific IgE antibodies have not so far been identified. A dose-escalation protocol has been proposed to desensitize patients who have had acute systemic reactions (32), but this has not always been successful (33). Although most reported anaphylactic reactions to infliximab have been mild, severe reactions can occur.
Incidence Immediate hypersensitivity reactions to infliximab occur in 6–19% of adults. In a retrospective evaluation of 165 patients (479 infliximab infusions) with Crohn’s disease, the overall incidence of infusion reactions was 6.1% (29 episodes) (29). Acute infusion reactions within 24 hours of infusion were the most frequent (26 episodes) and delayed infusion ª 2006 Elsevier B.V. All rights reserved.
A 36-year-old man with Crohn’s disease became refractory to standard anti-inflammatory treatment (glucocorticoids, mercaptopurine, methotrexate, ciclosporin, tacrolimus) (33). Remission over 8 months was achieved with a single infusion of infliximab. With the onset of relapse he was given another infusion of infliximab and had an anaphylactic-like reaction within 1 minute. A 35-year-old woman with known hypersensitivity to mesalazine had severe symptoms, namely chest pain, dyspnea, productive cough, skin rash, and hypotension, during a third infusion of infliximab, and died 6 hours later from refractory hypotension and respiratory failure (34). Specific IgE or human antichimeric antibodies were not checked. A 33-year-old man with a 3-year history of Crohn’s disease had previously received a well-tolerated single infusion of infliximab. When, 14 months later, he received a second infusion for exacerbation of the disease he had no immediate adverse effects, but complained of myalgia, arthralgia, nausea, and vomiting 7 days later and received diphenhydramine. After 3 days he had dyspnea, fever, and chills. An open lung biopsy showed features of eosinophilic pneumonia and no
infections or other obvious causes were found. He subsequently worsened and required intubation and mechanical ventilation for 13 days. He was given glucocorticoids and quadruple antituberculosis drug therapy and recovered completely within 2 months. Human antichimeric antibodies were raised (13 times normal). A 73-year-old woman had three separate episodes of vascular purpura (with leukocytoclastic vasculitis during the third episode) during each sequence of treatment with etanercept; she later developed similar cutaneous lesions after a third injection of infliximab (35).
Delayed hypersensitivity reactions Delayed hypersensitivity reactions were mostly observed in patients with Crohn’s disease who received episodic treatment. In one patient, this complication was associated with acute respiratory distress syndrome, which became evident only 10 days after retreatment (22). Susceptibility factors Susceptibility factors for the development of severe systemic reactions after infliximab retreatment have been analysed in 52 adults and 34 children with Crohn’s disease (30). Acute severe systemic reactions were defined by symptoms of anaphylactic reactions that required pharmacological treatment, and delayed severe systemic reactions were defined by the occurrence of arthralgia and joint stiffness (that is serum sickness-like symptoms) requiring glucocorticoids in the days after infliximab retreatment. According to these definitions, severe systemic reactions developed in 14% of patients (four acute and eight delayed) during retreatment. They were significantly more frequent in adults than in children (21 versus 3%), and delayed systemic reactions were observed exclusively in adults. These reactions mostly occurred during the second infusion of infliximab, and particularly when retreatment was distant from the first infusion, that is beyond a 20-week interval. This suggested a higher potential for delayed hypersensitivity reactions when repeated doses are given within a longer time interval, and led the authors to recommend multiple early infusions if future infliximab retreatment is anticipated. In a retrospective review of 361 infliximab infusions in 57 children with inflammatory bowel disease there were 35 episodes of infusion reactions (36). Female sex, previous episodes of infusion reactions, and the use of immunosuppressive therapy for less than 4 months were significant predictors of subsequent infusion reactions. Infection risk Infliximab can increase the susceptibility of patients to severe infections, and in particular opportunistic infections (SEDA-26, 402). In patients who received repeated infusions of infliximab, infections requiring antimicrobial treatment occurred in about 30% of patients and severe infections in 4% (20). Bacterial infections Blockade of tumor necrosis factor alfa impairs resistance to infections with intracellular pathogens such as mycobacteria, Pneumocystis jiroveci, Listeria monocytogenes, ª 2006 Elsevier B.V. All rights reserved.
and Legionella pneumophila (37,38). Severe streptococcal and staphylococcal infections have also been observed. Case reports with very severe or fatal outcomes have usually been reported in patients taking concomitant immunosuppressants and have included:
necrotizing fasciitis due to streptococcal infection (39) septicemia due to Staphylococcus aureus (40) Listeria monocytogenes infection (41) disseminated tuberculosis (42) listeriosis (37).
The safety and efficacy of infliximab have been assessed in 40 patients with severe active spondylarthropathy in a double-blind, randomized, placebo-controlled trial (43). One 65-year-old patient improved but 3 weeks after the third infusion developed a systemic illness. He had enlarged mediastinal lymph nodes and nodular lesion of the liver and spleen. Biopsy of the mediastinal lymph nodes showed tuberculosis, which was confirmed by culture. He was treated and recovered slowly. Reactivation of latent tuberculosis is a major concern with infliximab (SEDA-26, 402), and accounts for about one-third of infections in these patients. According to data from the manufacturers, 130 cases of active tuberculosis were notified up to October 2001. Many of the cases were disseminated or extrapulmonary tuberculosis, and several patients died. Several case reports have provided detailed information in at least seven other patients, including three who developed miliary tuberculosis and one who developed Mycobacterium tuberculosis enteritis (44–48). A detailed analysis of 70 cases of tuberculosis reported to the FDA has been published (49). Two-thirds of the cases were noted after three or fewer infusions and 57% of the patients had extrapulmonary disease. There were 64 cases from countries with a low incidence of tuberculosis. From these reports and the number of patients treated with infliximab, the estimated rate of tuberculosis in patients with rheumatoid arthritis treated with infliximab was four times higher than the background rate. Patients with evidence of active infection should not receive infliximab until the infection is under control; all should be screened for tuberculosis before starting infliximab (50). From these and other data it has been estimated that the risk of tuberculosis in the first year of infliximab treatment is 0.035 in US citizens and 0.2% in non-US citizens. Further investigations, such as a chest X-ray and a Mantoux test, and prophylactic treatment with isoniazid, will show whether the incidence can be reduced in patients taking anti-TNF treatment (51). In a multicenter trial in 70 patients with ankylosing spondylitis given infliximab, treatment had to be withdrawn in three patients because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leukopenia; after withdrawal all three recovered (8). However, the allergic granulomatosis of the lung was probably due to a hypersensitivity reaction.
An 11-year-old boy with Crohn’s disease received infliximab and 3 days later developed fever, signs of cardiac failure, and S. aureus sepsis (52). At surgery an intramyocardial para-aortic abscess with destruction of the aortic valve was found, suggesting chronic infection, possibly activated by the use of infliximab.
Infliximab Crohn’s disease can lead to vasculitic changes of the aorta, which may have favored the development of the intramyocardial abscess in this case. The size of the abscess suggested persistence for several weeks. Severe necrotizing fasciitis has been reported in a patient who was given infliximab (39).
A 54-year-old man with rheumatoid arthritis for 12 years was given infliximab, with remission. He then developed a painful, confluent, erythematous, pustular rash over his trunk and limbs. Skin biopsy showed an acute pustular dermatitis. Five hours later he collapsed with a tachycardia (140/minute) and a blood pressure of 120/70 mmHg. He was apyrexial. His left leg was very tense, painful, and swollen, and he had a disseminated intravascular coagulopathy. There was marked necrosis of his adductor compartment and fascia of his left thigh and necrotic muscles were debrided. Blood cultures and skin swabs grew group A hemolytic streptococci. He then became unstable and died, despite efforts at resuscitation.
Viral infections Infliximab can compromise antiviral defence mechanisms. There have been detailed reports of cytomegalovirus retinitis (53) and life-threatening disseminated cytomegalovirus infection (54). Most of these patients were taking concomitant immunosuppressants at the time of diagnosis.
A 67-year-old woman with a 5-year history of rheumatoid arthritis, who had taken prednisone and methotrexate, was given infliximab (55). Her rheumatoid arthritis improved, but she developed multiple bilateral lesions of molluscum contagiosum on the upper and lower eyelids, despite normal CD4 and CD8 counts. She had had similar lesions during a previous course of infliximab. Excision biopsy confirmed the diagnosis.
Protozoal infections There has been a detailed report of P. jiroveci pneumonia (56). Fungal infections In a review of 10 cases of histoplasmosis in patients treated with infliximab (n ¼ 9) or etanercept (n ¼ 1) the infection occurred within 1 week to 6 months after the first dose (57). Of these 10 patients, nine required treatment in an intensive care unit and one died. All lived in regions in which histoplasmosis was endemic. It was not possible to determine which patients had new infections or reactivation of previous infections. In 41 patients with rheumatic disease who received a total of 300 infusions of infliximab over 9 months there were severe adverse effects in 15%, one of which was a case of histoplasmosis (58).
A 28-year-old woman with unresponsive rheumatic disease developed histoplasmosis after a second infusion of infliximab. She had pet birds, and the authors thought that she had had reactivation of an infection rather than a new infection.
There have been other reports of histoplasmosis (59), invasive pulmonary aspergillosis (60), and extensive pulmonary coccidioidomycosis (61). ª 2006 Elsevier B.V. All rights reserved.
A 64-year-old man without heart failure was found dead 18 hours after a single infusion of infliximab for rheumatoid arthritis (62). No obvious cause was found at autopsy, except that the patient was known to have had frequent intervention by a pacemaker that had been implanted for several years.
Long-Term Effects Tumorigenicity There is great concern about the potential development of malignancy after blockade of tumor necrosis factor alfa, and it is biologically plausible. However, it is unclear whether this is a drug-related or a disease-related phenomenon. There have been several cases of lymphoproliferative disease (B cell non-Hodgkin’s lymphoma and nodular sclerosing Hodgkin’s disease) in the 9 months after infliximab infusion in patients with Crohn’s disease (63). The FDA received reports of 26 cases of lymphoproliferative disorders in patients treated with etanercept (n ¼ 18) or infliximab (n ¼ 8) over 20 months (64). Although this reporting rate does not exceed the ageadjusted incidence of lymphomas in the USA, spontaneous reporting underestimates the true incidence. In addition, several findings were similar to those reported in patients taking immunosuppressive drugs after transplantation. For example, 81% of the reported cases were non-Hodgkin’s lymphomas. Also, the median time to occurrence after the start of anti-TNF-alfa treatment was only 8 weeks. Finally, lymphoma regressed in two patients after withdrawal and without specific cytotoxic therapy. Although the actual incidence of neoplasia was low, additional long-term data that take into account concomitant or previous immunosuppressive treatment are needed before firm conclusions can be reached.
References 1. Bell S, Kamm MA. Antibodies to tumour necrosis factor alpha as treatment for Crohn’s disease. Lancet 2000;355 (9207):858–60. 2. Wall GC, Heyneman C, Pfanner TP. Medical options for treating Crohn’s disease in adults: focus on antitumor necrosis factor-alpha chimeric monoclonal antibody. Pharmacotherapy 1999;19(10):1138–52. 3. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354(9194):1932–9. 4. Keeling S, Oswald A, Russell AS, Maksymowych WP. Prospective observational analysis of the efficacy and safety of low-dose (3 mg/kg) infliximab in ankylosing spondylitis: 4-year follow up. J Rheumatol 2006;33(3):558–61. 5. Bickston SJ, Lichtenstein GR, Arseneau KO, Cohen RB, Cominelli F. The relationship between infliximab treatment
and lymphoma in Crohn’s disease. Gastroenterology 1999;117(6):1433–7. Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000;95(3):841–2. Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol Suppl 2002;65:33–8. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359(9313):1187–93. Baig I, Storch I, Katz S. Infliximab induced eosinophilic pleural effusion in inflammatory bowel disease. Am J Gastroenterol 2002;97(Suppl):177. Marotte H, Charrin JE, Miossec P. Infliximab-induced aseptic meningitis. Lancet 2001;358(9295):1784. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, Richert JR, Siegel JN. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44(12):2862–9. Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44(9):1977–83. ten Tusscher MP, Jacobs PJ, Busch MJ, de Graaf L, Diemont WL. Bilateral anterior toxic optic neuropathy and the use of infliximab. BMJ 2003;326(7389):579. Foroozan R, Buono LM, Sergott RC, Savino PJ. Retrobulbar optic neuritis associated with infliximab. Arch Ophthalmol 2002;120(7):985–7. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135(1):27–31. Menghini VV, Arora AS. Infliximab-associated reversible cholestatic liver disease. Mayo Clin Proc 2001;76(1):84–6. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol 2002;138(9):1258–9. Kent PD, Davis JM 3rd, Davis MD, Matteson EL. Bullous skin lesions following infliximab infusion in a patient with rheumatoid arthritis. Arthritis Rheum 2002;46(8):2257–8. Griffin SP, Selby WS. Poor wound healing following surgery in three patients who received infliximab for Crohn’s disease. J Gastroenterol Hepatol 2000;15(Suppl):78. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359(9317):1541–9. Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348(7):601–8. Riegert-Johnson DL, Godfrey JA, Myers JL, Hubmayr RD, Sandborn WJ, Loftus EV Jr. Delayed hypersensitivity reaction and acute respiratory distress syndrome following infliximab infusion. Inflamm Bowel Dis 2002;8(3):186–91. Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebocontrolled trials. Arthritis Rheum 2000;43(11):2383–90.
ª 2006 Elsevier B.V. All rights reserved.
24. Mikuls TR, Moreland LW. Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. Drug Saf 2003;26(1):23–32. 25. Ali Y, Shah S. Infliximab-induced systemic lupus erythematosus. Ann Intern Med 2002;137(7):625–6. 26. Klapman JB, Ene-Stroescu D, Becker MA, Hanauer SB. A lupus-like syndrome associated with infliximab therapy. Inflamm Bowel Dis 2003;9(3):176–8. 27. Hanauer SB, Rutgeerts PJ, D’Haens G, Targan SR, Kam L, Present DH, Wagner C, LaSorda J, Sands B, Livingstone RA. Delayed hypersensitivity to infliximab (Remicade) re-infusion after a 2-4 year interval without treatment. Gastroenterology 1999;116:A731. 28. Favalli EG, Sinigaglia L, Varenna M, Arnoldi C. Druginduced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 2002;11(11):753–5. 29. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98(6):1315–24. 30. Kugathasan S, Levy MB, Saeian K, Vasilopoulos S, Kim JP, Prajapati D, Emmons J, Martinez A, Kelly KJ, Binion DG. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002;97(6):1408–14. 31. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, Peppercorn MA. Clinical experience with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000;95(12):3490–7. 32. Puchner TC, Kugathasan S, Kelly KJ, Binion DG. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Inflamm Bowel Dis 2001;7(1):34–7. 33. O’Connor M, Buchman A, Marshall G. Anaphylaxis-like reaction to infliximab in a patient with Crohn’s disease. Dig Dis Sci 2002;47(6):1323–5. 34. Lankarani KB. Mortality associated with infliximab. J Clin Gastroenterol 2001;33(3):255–6. 35. McCain ME, Quinet RJ, Davis WE. Etanercept and infliximab associated with cutaneous vasculitis. Rheumatology (Oxford) 2002;41(1):116–17. 36. Crandall WV, Mackner LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 2003;17(1): 75–84. 37. Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002;34(4):410–12. 38. Shanahan JC, St Clair W. Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. Clin Immunol 2002;103(3 Pt 1):231–42. 39. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J 2002;78(915):47–8. 40. Matzkies FG, Manger B, Schmitt-Haendle M, Nagel T, Kraetsch HG, Kalden JR, Schulze-Koops H. Severe septicaemia in a patient with polychondritis and Sweet’s syndrome after initiation of treatment with infliximab. Ann Rheum Dis 2003;62(1):81–2. 41. Gluck T, Linde HJ, Scholmerich J, Muller-Ladner U, Fiehn C, Bohland P. Anti-tumor necrosis factor therapy and Listeria monocytogenes infection: report of two cases. Arthritis Rheum 2002;46(8):2255–7. 42. Liberopoulos EN, Drosos AA, Elisaf MS. Exacerbation of tuberculosis enteritis after treatment with infliximab. Am J Med 2002;113(7):615. 43. Van Den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F, Mielants H, Veys EM. Randomized doubleblind comparison of chimeric monoclonal antibody to
tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002;46(3): 755–65. Mayordomo L, Marenco JL, Gomez-Mateos J, Rejon E. Pulmonary miliary tuberculosis in a patient with anti-TNFalpha treatment. Scand J Rheumatol 2002;31(1):44–5. Nunez Martinez O, Ripoll Noiseux C, Carneros Martin JA, Gonzalez Lara V, Gregorio Maranon HG. Reactivation tuberculosis in a patient with anti-TNF-alpha treatment. Am J Gastroenterol 2001;96(5):1665–6. Roth S, Delmont E, Heudier P, Kaphan R, Cua E, Castela J, Verdier JM, Chichmanian RM, Fuzibet JG. Anticorps anti-TNF alpha (infliximab) et tuberculose: a` propos de 3 cas. Rev Med Interne 2002;23(3):312–16. Rovere Querini P, Vecellio M, Sabbadini MG, Ciboddo G. Miliary tuberculosis after biological therapy for rheumatoid arthritis. Rheumatology 2002;41(2):231. Wagner TE, Huseby ES, Huseby JS. Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn’s disease after treatment with a tumor necrosis factor-alpha inhibitor. Am J Med 2002;112(1):67–9. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345(15):1098–104. Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol 2002;97(12):2962–72. Antoni C, Braun J. Side effects of anti-TNF therapy: current knowledge. Clin Exp Rheumatol 2002;20(6 Suppl 28):S152–7. Reichardt P, Dahnert I, Tiller G, Hausler HJ. Possible activation of an intramyocardial inflammatory process (Staphylococcus aureus) after treatment with infliximab in a boy with Crohn disease. Eur J Pediatr 2002;161(5): 281–3. Haerter G, Manfras B, Schmitt M, Wendland T, Moch B. Severe CMV retinitis in a patient with HLA-B27 associated spondylarthropathy following immunosuppressive therapy with anti-TNF alpha (infliximab). Infection 2003;31(Suppl 1):150. Helbling D, Breitbach TH, Krause M. Disseminated cytomegalovirus infection in Crohn’s disease following antitumour necrosis factor therapy. Eur J Gastroenterol Hepatol 2002;14(12):1393–5. Cursiefen C, Grunke M, Dechant C, Antoni C, Junemann A, Holbach LM. Multiple bilateral eyelid molluscum contagiosum lesions associated with TNFalphaantibody and methotrexate therapy. Am J Ophthalmol 2002;134(2):270–1. Tai TL, O’Rourke KP, McWeeney M, Burke CM, Sheehan K, Barry M. Pneumocystis carinii pneumonia following a second infusion of infliximab. Rheumatology (Oxford) 2002;41(8):951–2. Lee JH, Slifman NR, Gershon SK, Edwards ET, Schwieterman WD, Siegel JN, Wise RP, Brown SL, Udall JN Jr, Braun MM. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002;46(10):2565–70. Fitzcharles MA, Clayton D, Menard HA. The use of infliximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002;29(12):2525–30. Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002;112(1):78. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001;344(14):1099–100.
ª 2006 Elsevier B.V. All rights reserved.
61. Ramzan NN, Shapiro MS, Robinson E, Smilack JD. Use of infliximab leading to extensive pulmonary coccidioidomycosis. Am J Gastroenterol 2002;97(Suppl):157. 62. de’ Clari F, Salani I, Safwan E, Giannacco A. Sudden death in a patient without heart failure after a single infusion of 200 mg infliximab: does TNF-alpha have protective effects on the failing heart, or does infliximab have direct harmful cardiovascular effects? Circulation 2002;105(21):E183. 63. Drewe E, Powell RJ. Clinically useful monoclonal antibodies in treatment. J Clin Pathol 2002;55(2):81–5. 64. 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(12):3151–8.
Influenza vaccine See also Vaccines
General Information Influenza vaccine viruses are propagated in embryonated chicken eggs. The virus-containing extra-embryonic fluid is harvested, purified, and inactivated with formalin. Inactivated flu vaccine is produced either as whole virus vaccine or ether-disrupted split or subunit preparations. However, many other new or modified influenza vaccines are already available or are expected to appear in the near future, for example vaccines containing new adjuvants, live attenuated vaccines, and vaccines administered by alternative routes. Comparisons of reactogenicity (and immunogenicity) of different vaccine types have been provided (SEDA-8, 299) (SEDA-10, 290) (SEDA-11, 290) (SEDA-12, 282) (SEDA-13, 286) (SEDA-14, 284) (SEDA-15, 351) (SEDA-16, 386) (SEDA-17, 375) (SEDA-18, 335) (1). In most of these trials the investigators found little difference in reactogenicity between the various vaccines. The safety and immunogenicity of an inactivated subunit influenza vaccine containing MF59 (oil-in-water emulsion, squalene, and Tween 80 and sorbitan trioleate as stabilizers) as an adjuvant has been described in two studies of 92 and 211 elderly persons (65 years of age and over) (2,3). Investigations were carried out during three consecutive influenza seasons. Compared with a commercial non-adjuvant subunit vaccine containing the same influenza strains recommended by the World Health Organization, geometric mean titers and seroconversion rates were higher after the use of the newly developed vaccine. The adjuvant vaccine caused more local reactions than the conventional vaccine. However, the reactions were mild and limited to the first 2–3 days after immunization. Systemic reactions were not significantly different, except for mild transient malaise. Considering the better immunogenicity of the adjuvant vaccine, the authors recommended it particularly for elderly people, who are at greatest risk of developing severe influenza disease. The vaccine manufactured by Chiron Behring has been already licensed for persons of 65 years of age and over in Italy and Germany.