SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To study whether premedication with an oral antifebrile agent (acetaminophen) and antihistamine (cetirizine) could decrease the frequency of acute infusion reactions in pediatric patients.

Methods

All pediatric patients scheduled for infliximab infusions at the Helsinki University Central Hospital, a tertiary care center, were prospectively introduced to a standard oral premedication of acetaminophen (20 mg/kg) and cetirizine (10 mg) prior to infliximab infusions for a period of 1 year. All acute adverse events related to infliximab infusions given according to the guidelines of pediatric rheumatologists or gastroenterologists were registered for this time period and retrospectively during the preceding year.

Results

During the study period, infliximab infusions with premedication were given to 64 pediatric patients (48 with rheumatic disease and l6 with inflammatory bowel disease, mean age 13 years, n = 34 boys, and n = 30 girls). Infliximab was introduced to 14 children; the rest were on maintenance therapy. Twelve infusion reactions, 4 mild and 8 severe, were observed in 8 (12.5%) of the 64 subjects, and in 1 subject 4 times. During the preceding year, 60 pediatric patients had received infliximab infusions without premedication. In this latter group, infusion reactions occurred in 5 children (8.3%; P > 0.05). The presentation of an acute infusion reaction was not related to the sex or diagnosis of the patient.

Conclusion

In pediatric patients, acute infusion reactions related to infliximab could not be prevented with premedication with oral acetaminophen and cetirizine.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

During recent years, tumor necrosis factor (TNF) modulators have become an essential part of the therapy for children with severe gastrointestinal or rheumatologic inflammatory diseases. Infliximab, one of the commercially available anti-TNF antibodies, has been used successfully in patients with juvenile idiopathic arthritis (JIA) (1, 2), uveitis associated with JIA (3, 4), and inflammatory bowel disease (IBD) refractory to conventional medication (5). So far, the responders to this therapy cannot be foreseen, but it has been estimated that approximately 70% of patients experience an initial therapeutic response (1, 2, 5). According to current guidelines, induction therapy with infliximab at weeks 0, 2, and 6 is used. Because the majority of patients will relapse if not retreated, long-term treatment every 4–10 weeks is usually maintained if there is objective initial response (6, 7).

Among the most important side effects of the therapy are increased risk for infections and development of malignancies (8, 9). However, in clinical practice, acute infusion reactions are the most frequent cause that limits the use of this biologic therapy in children (10).

Acute infusion reactions related to infliximab are considered to reflect a serum sickness–type reaction. There is some evidence that antibody formation to infliximab increases the probability of an acute infusion reaction, and reintroduction of the therapy after a long interval is potentially risky (11). To this end, it is evident that acute reactions are not IgE mediated, but generally the underlying mechanisms are poorly understood (12). Concomitant immunosuppressive medication has been advised to decrease antibody formation against infliximab, but, although immunosuppressants may have been in regular use for several months, acute infusion reactions may still appear (10, 13, 14). Likewise, administration of glucocorticoids does not seem to prevent acute reactions in pediatric patients (10, 13), although in some adult studies of patients with IBD, premedication with hydrocortisone seemed to be effective in preventing infusion reactions (12, 15).

The most common acute reactions include flushing, urticaria, dyspnea, and feverish sensation (16–18). To prevent these acute reactions, rheumatologists and gastroenterologists in our pediatric clinic introduced a routine premedication with an oral antihistamine and an antifebrile agent prior to all infliximab infusions. Here we report the results after a period of 1 year and compare the frequency of acute infusion reactions with those from the preceding year.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

All patients were treated with infliximab infusions in the Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. The hospital is a tertiary referral center with a catchment area of 29% of the pediatric population in Finland. All pediatric patients with IBD or a significant pediatric rheumatic disease in this catchment area are diagnosed and followed up in this hospital. Further, all infliximab infusions are given on a single ward by trained personnel. Intravenous (IV) infusions of infliximab at a dose of 4–8 mg/kg were given at 0, 2, and 6 weeks, and thereafter usually at 4–8-week intervals depending on the inflammatory condition of the patient.

Because several acute infusion reactions during a short period of time were experienced (10), clinicians introduced a routine premedication protocol for all children receiving infliximab infusions, launched on June 13, 2007. Premedication included oral acetaminophen 20 mg/kg (maximum 1,000 mg) and cetirizine 10 mg (in children <5 years of age, 0.3 mg/kg) given 30–60 minutes prior to infusion.

During a period of 1 year (until June 12, 2008), 65 children received infliximab infusions. Of these, 49 children had rheumatic disease (20 with JIA and 29 with chronic uveitis associated with JIA; mean age 12 years [range 3–18 years], n = 25 boys, and n = 24 girls), and 16 children had IBD (13 with Crohn's disease and 3 with ulcerative colitis; mean age 15 years [range 7–19 years], n = 10 boys, and n = 6 girls). The majority of the children were on maintenance therapy, but 4 children with rheumatic disease and 10 children with IBD were introduced to the infusions for the first time during the study period. Of the 65 children on infliximab treatment, 64 took the premedication as described.

During the preceding year (June 13, 2006 through June 12, 2007), 60 children received infliximab infusions at our hospital. Of these, 54 children had rheumatic disease (26 with JIA and 28 with chronic uveitis associated with JIA; mean age 12 years [range 2–18 years], n = 27 boys, n = 27 girls), and 6 children had IBD (5 with Crohn's disease and 1 with ulcerative colitis; mean age 16 years [range 12–18 years], n = 5 boys, n = 1 girl). However, worthy of remark is that several children were on maintenance infliximab therapy and therefore were treated during both periods. In total, during these 2 years, infliximab was administered to 77 children (58 with rheumatic disease and 19 with IBD). In the analysis of both the premedication group and the group without premedication, 48 patients were overlapping.

We registered all adverse events during these treatment periods. Statistical comparisons were performed with Fisher's exact test or Wilcoxon's rank test as appropriate.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

During the period of premedication with acetaminophen and cetirizine, acute infusion reactions were observed in 9 children (13.8%), 8 with and 1 without premedication (Table 1). Because 1 child presented with acute reactions during 4 separate infusions, the total number of infusion reactions was 12. The number of infusion reactions per premedicated children was 8 (12.5%) of 64. Of the 8 children, 3 had presented with an infusion reaction also earlier when no premedication was given (patients 3, 6, and 8 in Table 1 correspond to patients 4, 3, and 1, respectively, in Table 2).

Table 1. Acute adverse reactions associated with infliximab infusions in pediatric patients during a 1-year period of routine oral premedication with acetaminophen (acet.) and cetirizine (Z)*
Patient numberDiagnosisAge, yearsSexMaintenance therapyPremedicationWeeks from previous infusionNo. of infliximab infusions (dose, dose/kg)Adverse reactionActions due to adverse reaction
  • *

    JIA = juvenile idiopathic arthritis; LEF = leflunomide; IVMP = intravenous methylprednisolone; MTX = methotrexate; CATCH22 = 22q11.2 deletion syndrome; AZA = azathioprine.

1Uveitis with JIA11F      
 Reaction 1   LEF 10 mg/dayAcet. + Z2.02 (200 mg, 5 mg/kg)Headache, flush, dizzinessFollowup
 Reaction 2   LEF 10 mg/dayAcet. + Z + IVMP4.04 (200 mg, 5 mg/kg)HeadacheFollowup
 Reaction 3   LEF 10 mg/dayAcet. + Z + IVMP5.05 (200 mg, 5 mg/kg)DizzinessFollowup
 Reaction 4   LEF 10 mg/dayAcet. + Z + IVMP4.67 (200 mg, 5 mg/kg)Dyspnea, flushDiscontinued infusion, IVMP
2Uveitis with JIA7MMTX 15 mg/weekNo10>10 (100 mg, 4 mg/kg)Dyspnea, cough, flush, urticariaDiscontinued infusion, IVMP, oxygen
3Uveitis with JIA7MMTX 10 mg/weekIV acet. + Z + IVMP3.64 (100 mg, 4 mg/kg)Headache, dyspneaDiscontinued infusion, IV fluid, oxygen
4Uveitis with JIA8FMTX 10 mg/weekAcet. + Z12>10 (200 mg, 6 mg/kg)Dyspnea, cough, vomitingDiscontinued infusion, IVMP, adrenaline
5Uveitis with JIA6MMTX 10 mg/weekAcet. + Z2.02 (100 mg, 4 mg/kg)Dyspnea, cough, abdominal painDiscontinued infusion, IVMP, oxygen
6JIA3FMTX 10 mg/weekAcet. + Z + IVMP4.08 (100 mg, 7 mg/kg)Cough, urticariaDiscontinued infusion, IV fluid, oxygen
7JIA15FMTX 25 mg/weekAcet. + Z8.14 (400 mg, 4 mg/kg)DyspneaDiscontinued infusion, IVMP, oxygen
8JIA and CATCH2211FMTX 15 mg/weekAcet. + Z6.0>10 (200 mg, 8 mg/kg)Flush, vomitingDiscontinued infusion, IVMP
9Ulcerative colitis12FAZA 50 mg/day, prednisolone 10 mg, clarithromycinAcet. + Z2.02 (200 mg, 5 mg/kg)UrticariaFollowup
Table 2. Acute adverse reactions associated with infliximab infusions in pediatric patients during a period of 1 year when no regular premedication protocol was used*
Patient numberDiagnosisAge, yearsSexMaintenance therapyPremedicationWeeks from previous infusionNo. of infliximab infusions (dose, dose/kg)Adverse reactionActions due to adverse reaction
  • *

    SSZ = sulfasalazine. See Table 1 for additional abbreviations.

  • Nine-month interval from the preceding infliximab infusion.

1JIA and CATCH2210F      
 Reaction 1   MTX 10 mg/weekNone8.014 (100 mg, 4 mg/kg)Flush, vomitingDiscontinued infusion
 Reaction 2   MTX 10 mg/weekNone8.015 (100 mg, 4 mg/kg)Flush, vomitingAntihistamine, acet., IV fluid
 Reaction 3   MTX 15 mg/weekAcet. + Z8.316 (200 mg, 8 mg/kg)Transient nauseaSlowing down the infusion rate
2Uveitis with JIA9FMTX 5 mg/week, prednisolone 10 mgNone3.413 (200 mg, 7 mg/kg)Nausea, feverDiscontinued infusion, IV fluid, acet.
3JIA3FMTX 10 mg/week, prednisolone 2.5 mgNone6.05 (100 mg, 7 mg/kg)Cough, vomiting, urticariaDiscontinued infusion, IV fluid
4Uveitis with JIA7MMTX 10 mg/weekNone2.02 (100 mg, 4 mg/kg)Dyspnea, cough, nauseaDiscontinued infusion, prednisolone, antihistamine, oxygen
5Crohn's disease16MMTX 25 mg/week, prednisolone 40 mg, SSZ, ciprofloxacillin     
 Reaction 1    Hydrocortisone 100 mg IV48.31 (300 mg, 6 mg/kg)ItchingPrednisolone, antihistamine
 Reaction 2    Hydrocortisone 100 mg IV2.42 (300 mg, 5 mg/kg)FeverDiscontinued infusion, acet.

During the preceding year when premedication was not routine, acute infusion reactions were observed in 5 children (8.3%) (Table 2). Of these, 1 girl presented with acute infusion reactions during 3 separate infusions, and 1 boy presented with acute infusion reactions during 2 separate infusions. Therefore, the total number of infusion reactions was 8. In the patient who had reactions during 3 consecutive infusions, premedication with acetaminophen and cetirizine was tried prior to the third infusion. Another child was premedicated with IV hydrocortisone.

There was no statistically significant difference in the frequency of infusion reactions during the period of premedication with acetaminophen and cetirizine when compared with that during the period with no such premedication (by Fisher's exact test, P = 0.364). Except for fever, the premedication with cetirizine and acetaminophen did not have any effect on the type of adverse reactions (Tables 1 and 2).

The total number of infliximab infusions given during the study year (premedication with acetaminophen and cetirizine) and the previous year (no premedication) were 383 and 376, respectively, and the mean doses of infliximab infusions were comparable (243 mg and 209 mg, respectively). In those with no infusion reactions, the mean doses were 236 mg (n = 371) and 210 mg (n = 368) during the period of premedication and the previous year, respectively. Further, among those with infusion reactions, the infliximab doses were comparable (mean 183 mg [n = 12] and 175 mg [n = 8] during the period of premedication and the previous year, respectively).

During the whole 2-year study period, the frequency of acute infusion reactions did not differ between children with rheumatic disease or IBD (in total, 8 of 58 and 3 of 19, respectively; P > 0.7 by Fisher's exact test). The sex of the patients was not associated with the presentation of an acute infusion reaction. Younger children tended to have more infusion reactions (P = 0.089 by Wilcoxon's rank test), and the majority of children with infusion reactions (8 [72%] of 11) were younger than the mean age of the patient groups. The lower absolute amounts of infliximab doses in those with infusion reactions compared with those without such reactions were related to the younger age of the subjects.

Erythrocyte sedimentation rate (ESR; mean 14 mm/hour, range 2–37) or hemoglobin level (mean 120 gm/liter, range 112–142) values did not differ by the time of acute infusion reaction when compared with the preceding infusion (ESR mean 11 mm/hour, range 3-26; hemoglobin level 128 gm/liter, range 119–138). Further, absolute and relative counts of eosinophils were similar at presentation of an acute reaction (mean of 0.26 × 109/liter, range 0.01–0.52, in 18 reactions; not determined in 2 cases) and at the preceding infusion (mean of 0.25 × 109/liter, range 0.01–0.47).

Remarkably, infusion reactions tended to cluster. Prior to systematic premedication, 6 of 8 reactions occurred within 1.5 months. During the premedication period, 2 reactions occurred within the same day, and 1 reaction 2 weeks later. The practical matters of infusion equipment, including tubes and filters, were carefully monitored, and all infusions were given according to the established instructions.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Infliximab, a chimeric IgG1 monoclonal antibody specific for human TNFα, has emerged as a novel therapy for a variety of inflammatory pediatric diseases. However, in clinical practice, adverse reactions during infusions are common, occurring in up to 17–22% of pediatric patients with IBD (10, 13, 14) or rheumatic disease (7). So far, it has been impossible to stratify patients prone to acute adverse events at the time of the introduction of the infliximab therapy. Because flush, urticaria, dyspnea, and feverish sensation are the most frequently encountered acute reactions, we chose to give antihistamine and antifebrile premedication prior to all infliximab infusions. Disappointingly, after a period of 1 year, it was evident that this premedication did not reduce such acute infusion reactions in pediatric patients.

The rate of acute infusion reactions that we observed during the two 12-month periods (8.3% with no premedication and 12.5% with premedication) is in line with the figures previously reported in children (1, 5, 16) and adults (18, 19). It has been suggested that prostaglandins may play a role in these conditions, particularly in the vasodilatation, resulting in flushing (20). The antifebrile agent we used was acetaminophen, which has inhibitory activity to prostaglandins and cyclooxygenase isoform 3 (21, 22). The dose of cetirizine, a second-generation H1 antihistamine, in this study was high (10 mg) when compared with the recommended dosage of 5 mg/day for allergic symptoms (23). Intriguingly, substitution of acetaminophen for acetylsalicylic acid in the premedication protocol for infliximab infusions was reported to abolish acute infusion reactions in 3 children with systemic JIA (20).

In our patient series, concomitant immunosuppressive therapies, e.g., methotrexate in JIA and azathioprine in IBD, were used. This therapy is known to decrease the development of drug-specific antibodies to infliximab and, therefore, may reduce but not necessarily abolish the risk for acute infusion reactions (24). In line with this, we did not observe elevated levels of antinuclear or anti-DNA antibodies in any patient (data not shown). Further, concomitant glucocorticoid administration does not exclusively prevent the occurrence of acute reactions (10, 13, 25). Daily low-dose glucocorticoids may reduce the risk of treatment-limiting infusion reactions to infliximab in adult patients with rheumatoid arthritis (26). However, some of our pediatric patients with acute infusion reactions were on low-dose oral steroids during the period of no regular premedication, and some of them, when we tried to prevent infusion reactions even more rigorously, received IV glucocorticoid in addition to oral acetaminophen and cetirizine prior to infliximab infusions. This is in line with the poor preventive effect of glucocorticoids in clinical practice in children receiving infliximab.

All of our patients with infusion reactions had concomitant immunosuppressive therapy that had been ongoing for several months. Likewise, the majority of patients with acute reactions were on continuous infliximab therapy and followed the regular dosing schemes with infusion intervals of ≤8 weeks. Therefore, the presentation of infusion reactions was not due to reintroduction of the therapy after a longer infusion interval (27). In the prospective study by Ruperto et al (2), a lower dose of infliximab seemed to be associated with a higher frequency of adverse events. In the present study, such an association was not evident.

Unexpectedly, several infusion reactions prior to regular premedication occurred within a short period of 1 month (10). Therefore, the practical matters were carefully monitored and the administration of the infusions was confirmed to be of lege artis. At our hospital, all of the infliximab infusions are given on a single ward under the surveillance of trained personnel, reducing the risk for unforced errors. At the moment, the background and significance of the clustering of infusion reactions remain unclear.

The obvious limitations of the present and previous studies dealing with acute infusion reactions associated with infliximab (10, 12–15) are that they are mostly retrospective, lack adequate control groups, and that the effect of premedication has not been studied in a proper randomized fashion. The present study was not randomized and used historic controls. Therefore, we cannot provide definite proof that such infusion reactions cannot be prevented. However, it seems quite unlikely that oral acetaminophen and cetirizine are effective.

Taken together, acute infusion reactions hamper the use of infliximab therapy in pediatric rheumatology and gastroenterology. Disappointingly, premedication with an oral antihistamine and an antifebrile agent could not reduce the frequency of acute adverse events in pediatric patients. To improve the care of the infliximab-treated patients and to avoid acute reactions, further studies are warranted on the mechanisms underlying the presentation of the acute reactions and on other effective premedications.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Lahdenne had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Lahdenne, Wikström, Aalto, Kolho.

Acquisition of data. Lahdenne, Wikström, Aalto, Kolho.

Analysis and interpretation of data. Lahdenne, Kolho.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We thank Anne Nikkonen, RN, for her excellent help in collecting the patient data, and Marjo Sinisalo, RN, for her assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  • 1
    Lahdenne P, Vahasalo P, Honkanen V. Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis 2003; 62: 2457.
  • 2
    Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, et al, for the Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007; 56: 3096106.
  • 3
    Foeldvari I, Nielsen S, Kummerle-Deschner J, Espada G, Horneff G, Bica B, et al. Tumor necrosis factor-α blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol 2007; 34: 114650.
  • 4
    Tynjala P, Lindahl P, Honkanen V, Lahdenne P, Kotaniemi K. Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007; 66: 54850.
  • 5
    Lamireau T, Cezard JP, Dabadie A, Goulet O, Lachaux A, Turck D, et al. Efficacy and tolerance of infliximab in children and adolescents with Crohn's disease. Inflamm Bowel Dis 2004; 10: 74550.
  • 6
    Ruemmele FM, Lachaux A, Cezard JP, Morali A, Maurage C, Ginies JL, et al. Efficacy of infliximab in pediatric Crohn's disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm Bowel Dis 2009; 15: 38894.
  • 7
    Tynjala P, Vahasalo P, Honkanen V, Lahdenne P. Drug survival of the first and second course of anti-TNF agents in juvenile idiopathic arthritis. Ann Rheum Dis 2009; 68: 5527.
  • 8
    D'Haens G. Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut 2007; 56: 72532.
  • 9
    Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 227585.
  • 10
    Kolho KL, Ruuska T, Savilahti E. Severe adverse reactions to infliximab therapy are common in young children with inflammatory bowel disease. Acta Paediatrica 2007; 96: 12830.
  • 11
    Ebert EC, Das KM, Mehta V, Rezac C. Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-α antibodies. Clin Exp Immunol 2008; 154: 32531
  • 12
    Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98: 131524.
    Direct Link:
  • 13
    Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing experience using infliximab for Crohn's disease at a pediatric inflammatory disease center. Am J Gastroenterol 2003; 98: 10411.
    Direct Link:
  • 14
    Jacobstein DA, Markowitz JE, Kirschner BS, Ferry G, Cohen SA, Gold BD, et al. Premedication and infusion reactions with infliximab: results from a pediatric inflammatory bowel disease consortium. Inflamm Bowel Dis 2005; 11: 4426.
  • 15
    Bermejo F, Lopez San Roman A, Algaba A, van Domselaar M, Carneros JA, Rivero M, et al. Efficacy of premedication with intravenous corticosteroids and antihistaminics in preventing infusion reactions to infliximab. Gastroenterol Hepatol 2008; 31: 62932.
  • 16
    Crandall WV, Mackner LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 2003; 17: 7584.
  • 17
    Duburque C, Lelong J, Iacob R, Seddik M, Desreumaux P, Fournier C, et al. Successful induction of tolerance to infliximab in patients with Crohn's disease and prior severe infusion reactions. Aliment Pharmacol Ther 2006; 24: 85188.
  • 18
    Lequerre T, Vittecoq O, Klemmer N, Goeb V, Pouplin S, Menard JF, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol 2006; 33: 130714.
  • 19
    Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 15419.
  • 20
    Becker M, Rose CD, McIlvain-Simpson G. Niacin-like reaction to infliximab infusion in systemic juvenile rheumatoid arthritis [letter]. J Rheumatol 2004; 31: 252930.
  • 21
    Graham GG, Day RO, Milligan MK, Ziegler JB, Kettle AJ. Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs. Inflammopharmacology 1999; 7: 25563.
  • 22
    Rezende RM, Franca DS, Menezes GB, dos Reis WG, Bakhle YS, Francischi JN. Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain. Br J Pharmacol 2008; 153: 7608.
  • 23
    Chen C. Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine. Curr Med Chem 2008; 15: 217391.
  • 24
    Antoni C, Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor α antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: S737.
  • 25
    Sany J, Kaiser MJ, Jorgensen C, Trape G. Study of the tolerance of infliximab infusions with or without betamethasone premedication in patients with active rheumatoid arthritis. Ann Rheum Dis 2005; 64: 16479.
  • 26
    Augustsson J, Eksborg S, Ernestam S, Gullstrom E, van Vollenhoven R. Low-dose glucocorticoid therapy decreases risk for treatment-limiting infusion reaction to infliximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 146266.
  • 27
    Baraliakos X, Listing J, Rudwaleit M, Brandt J, Alten R, Burmester G, et al. Safety and efficacy of readministration of infliximab after longterm continuous therapy and withdrawal in patients with ankylosing spondylitis. J Rheumatol 2007; 34: 5105.