Is there an increased risk of postoperative infections and/or impaired wound healing, after treatme

Fråga: Is there an increased risk of postoperative infections and/or impaired wound healing, after treatment with Remicade (infliximab)?

Background: A 35-year-old woman with Crohn´s disease is planned for bowel surgery (intestinal resection) in two weeks time, because of persistent bleeding and stenosis. She received a single course of infliximab (5 mg/kg) 2-3 weeks ago in an attempt to reduce disease activity. At present, she is not taking any medication and is otherwise in good condition.

Sammanfattning: Infliximab is a novel drug and the picture of adverse reactions is not clear. It appears that the risk of infections may be increased during infliximab-therapy, and this must be considered carefully before and after surgery. Sporadic reports have also indicated a potential risk of impaired wound healing. However, the risk of complications should be lower in the present case of a relatively young patient in good condition without any other immunosuppressants, and where more than four weeks have passed since she received a single course of infliximab.

Svar: Infliximab was very recently introduced in the treatment of Crohn´s disease (1, 2). The drug has showed promising effects in patients with moderate to severe Crohn´s disease, and is considered to be a useful alternative in patients who have failed to respond to other immunosuppressants (2). The active substance of infliximab is a monoclonal antibody which neutralises tumour necrosis factor alpha (TNFa) by specific binding to soluble or cell-attached TNFa polypeptide. TNFa is an important pro-inflammatory cytokine produced locally in the inflamed mucosa of Crohn´s disease, where it plays an active role in disease progression, for instance by recruiting inflammatory cells (3). Infliximab is given as a single infusion at intervals ranging from 2 to 6 weeks in Crohn´s disease (2). The plasma half-life of antibodies is approximately three weeks. However the inhibitory effect on TNFa is not directly proportional to plasma antibody levels (4).

Considering the physiological role of TNFa in upregulation of the immune response, treatment with TNFa-inhibitors results in a selective immunosuppression with an assumed increased susceptibility to infections (4).

Indeed, clinical trials with infliximab in patients with Crohn´s disease and rheumatoid arthritis have showed that upper respiratory tract infections appear to be more frequent in infliximab-treated patients than placebo (13-18.5 versus 7-11.5 per cent, respectively) (1, 2, 5, 6). This was evident at a dose of 10 mg/kg, ie higher than the currently recommended dose in Crohn´s disease which is 5 mg/kg. The risk of serious infections was not different between infliximab-treated and placebo (6, 7), whereas patients also receiving other immunosuppressants (corticosteroids, cyclosporine, methotrexate) not surprisingly showed a higher frequency of serious infections compared to patients on infliximab monotherapy (7.7 versus 0.7 per cent) (2). The response to antibiotic therapy was normal. Sporadic cases of opportunistic infections have been described in infliximab-treated patients (eg disseminating tuberculosis, aspergillosis, coccoidomycosis, listeriosis). In the described case of listeriosis, the patient was also on immunosuppression by prednisone and azathioprine (8), but no information was given on possible co-medication in the other cases of opportunistic infections (2).

Infliximab is contraindicated in patients with manifest infection or abscesses. However, symptoms of infection, such as fever, might be masked by anti-TNFa-therapy, further underscoring the need for increased clinical alertness in infliximab-treated patients (9).

Not much is known about possible effects of anti-TNFa-agents on wound healing in humans. Increased TNFa levels have been found in chronic venous leg ulcers (10), but if this is causally related to impaired healing is not clear. Interestingly, data from rat models indicated that an induced expression of TNFa in sepsis mediates impaired healing of cutaneous wounds, but healing of intestinal incisions was not affected by sepsis (11). In fact, peritoneal TNFa levels rise postoperatively in humans and a role for TNFa in peritoneal tissue repair has been proposed (12). Taken together, anti-TNFa-therapy could perhaps have differential effects on wound healing in different organ systems.

Interestingly, impaired wound healing is listed as a rare adverse reaction to infliximab in the Swedish Catalogue of Approved Medical Products (FASS 2000). This is based on two American cases but no further details could be provided by the manufacturer (13). However, one Swedish case of impaired wound healing is listed in Swedis (14). It describes a 54-year-old female with Crohn´s disease who underwent plastic surgery because of a recto-vaginal fistula, two months after the last in a series of three infliximab doses. She was also on azathioprine and prednisolone. At a follow-up one week after surgery, pronounced secretion was found and it was evident that no wound healing had taken place. The reaction was considered possible by the Swedish Adverse Drug Reaction Advisory Committee (SADRAC).

No cases of impaired wound healing were found in the international WHO-database (15). Here, of all 23 reports on different adverse drug reactions to infliximab, perhaps five could be related to infections, including pneumonia (2), fever (2), and dyspnoea (1), but clinical details are lacking.

There are no general guidelines concerning surgery in infliximab-treated patients. However, nine cases were reported from the USA, where infliximab (5 mg/kg) was given 1-2 weeks before or concomitant with surgery, and continued 1-2 weeks thereafter, without adverse events (13). In Huddinge University Hospital, the Rheumatology division has introduced a policy to postpone surgery at least four weeks, if possible, after the last infliximab dose. Also a new infusion would not be given until two weeks have passed postoperatively (16). Even though this choice of time frame is admittedly not based on hard data (16), it was also considered reasonable by the in-house Surgery division, where the possibility to give antibiotic prophylaxis 24h before surgery was discussed (17). 1 European Agency for the Evaluation of Medicinal Products (EMEA), Committee for Proprietary Medicinal Products, European Public Assessment Report CPMP/1901/99, Remicade, 13 Aug. 1999, http://www.eudra.org/emea.html (as of June 5th, 2000)

2 Medical Products Agency (Sweden), Remicade monograph, http//www.mpa.se/mono/remicade.html (as of June 5thd, 2000)
3 Van Deventer SJH: Immunotherapy of Crohn´s Disease. Scand J Immunol 2000; 51: 18-22
4 Lars Klareskog, Professor in Rheumatology, Karolinska Institutet, personal communication

5 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. Lancet 1999; 354: 1932-39 6 Hanauer SB: Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 1999; 13(suppl.4): 16-22 7 Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJH: Infliximab for the treatment of fistulas in patients with Crohn´s disease. N Engl J Med 1999; 340: 1398-405 8 Morelli J, Wilson FA: Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000; 95: 841-2 9 Furst DE, Keystone E, Maini RN, Smolen JS: Recapitulation of the round-table discussion-assessing the role of anti-tumour necrosis factor therapy in the treatment of rheumatoid arthritis. Rheumatology 1999; 38(suppl 2): 50-3 10 Wallace HJ, Stacey MC: Levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in chronic venous leg ulcers - correlations to healing status. J Invest Dermatol 1998; 110: 292-6 11 Maish GO, Shumate ML, Ehrlich HP, Cooney RN: Tumor necrosis factor binding protein improves incisional wound healing in sepsis. J Surgical Res 1998; 78: 108-117 12 Holmdahl L, Ivarsson M-L: The role of cytokines, coagulation, and fibrinolysis in peritoneal tissue repair. Eur J Surg 1999; 165: 1012-9 13 Thomas Fockter, Regulatory Affairs Manager, AB (Sweden), personal communication, and data on file Schering-Plough and Centocor Inc

14 Swedis (The Swedish Drug Information System)
15 Intdis (International Drug Information System): WHO:s adverse drug reactions database
16 Johan Bratt, Consultant in Rheumatology, Huddinge University Hospital, personal communication

17 Jan-Erik Åkerlund, Consultant in Bowel Surgery, Huddinge University Hospital, personal communication