Are there problems with wound healing during treatment with azathioprine? Is it possible/nto operat

Fråga: Are there problems with wound healing during treatment with azathioprine? Is it possible

to operate during ongoing azathioprine therapy?

Background: Rheumatic patient requiring hand surgery.

Sammanfattning: Azathioprine in combination with corticosteroids (prednisone or methylprednisolone) has

been shown in some, but not all, animal studies to impair the wound healing process. The

results of these studies are difficult to interpret in view of the fact that corticosteroids impair

wound healing. Relevant studies in humans are not available, either for azathioprine alone or

in combination with other agents. Azathioprine, administered alone, is not expected to cause

clinically significant wound healing impairment.

Svar: A variety of chemotherapeutic agents, such as corticosteroids, doxorubicin, methotrexate,

cyclophosphamide and nitrogen mustard, has been implicated with impairment of wound

healing (1).

Azathioprine is an immunosuppressive agent that is also used in the treatment of severe

rheumatoid arthritis. Published data on the relation between azathioprine and wound healing

are limited to studies in animals (dogs and rats).

Employing the wound breaking strength method (WBS) for assessing wound healing,

Arumugon et al (2) found no defect in rat abdominal wall wound healing with a wide range of

intraperitoneal doses (4, 8, 16 and 32 mg/kg/d) beginning either two days before injury or at

the time of injury.

In another study, azathioprine (1.5 mg/kg/d) in combination with methylprednisolone (2

mg/kg/d) was shown to decrease the breaking strength of skin incisions in dogs at 9, 16, and

23 days postoperatively (3). As corticosteroids are generally considered to impair wound

healing, it is not possible to arrive at conclusions regarding the contribution of azathioprine

alone to these findings due to the lack of a comparison group treated with azathioprine alone.

Eisinger and Sheil (4) found highly significant weakness of incisions in rats that received

azathioprine (3 mg/kg/d) in combination with prednisone (1 mg/kg/d) compared to the control

and another treatment (cyclosporin A) groups at postoperative day 8. However, at

postoperative day 15 there were no differences in WBS among the three comparison groups.

Other studies have also reported contradictory findings. Hansen and Loreazen (5) reported

increased deposition of dry tissue in polyvinyl sponges implanted in rats receiving

azathioprine 1, 6, or 10 mg/kg/d intraperitoneally and removed at either 14 or 42 days.

St Muller et al reported a decrease in sulfomucopolysaccharide deposition in a cotton pellet

implanted subcutaneously in rats receiving a single 100 mg/kg injection of azathioprine four

days prior to wounding (quoted in ref 1).

The above studies have all been conducted in animals. As the process of wound healing is

similar from species to species, this is not an obstacle in the interpretation of the results. The

main difficulty in interpreting these studies relate to correlating the dosage in animals to its

corresponding dose in humans. Moreover, in all of these studies, azathioprine has been

administered in combination with corticosteroids (prednisone or methylprednisolone).

Steroids are considered to impair wound healing and these agents may be the main

determinants of the reported results.

Thus, there is no evidence that azathioprine impairs wound healing. Limited clinical

experience in surgery at Huddinge Hospital is in agreement with this conclusion (6). 1 Shamberger RC, Devereux DF, Brennan MF: The effect of chemotherapeutic agents in wound healing. Int Adv Surg Oncol 1981; 4: 15-58 2 Arumugam S, Nimmannit S, Enquist IF: The effect of immunosuppression on wound healing. Surg Gynecol Obstet 1971; 133: 72-74 3 Lima O, Cooper JD, Peters WJ, Ayabe H, Townsend E, Luk SC, Goldberg M: Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. J Thorac Cardiovasc Surg 1981; 82: 211-215 4 Eisinger DR, Sheil AGR: A comparison of the effects of cyclosporin A and standard agents on primary wound healing in the rat. Surg Gynecol Obstet 1985; 160: 135-138 5 Hansen TM, Lorenzen I: The effects of cyclophosphamide and azathioprine on collagen in skin and granulation tissue in rats, and the effects of cyclophosphamide on collage in human skin. Acta Pharmacol Toxicol 1975; 36: 448-461 6 Anders Lindholm, personal communication