Normal response to vaccines in inflammatory bowel disease patients treated with thiopurines

Abstract

Background: Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients are appropriately vaccinated, and data on their ability to mount an immune response are vague. We evaluated the effects of the thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), on cellular and humoral immune responses in IBD patients.

Methods: A prospective clinical investigation was conducted on IBD patients referred for thiopurine treatment. Immune competence was evaluated by assessing lymphocyte counts and phenotype, response to mitogen and antigen stimulation, immunoglobulin levels, and response to pneumococcal and tetanus vaccines (before treatment, week 0), and to Haemophilus influenza type b vaccine (at week 24).

Results: Thirty-one Crohn's disease and 12 ulcerative colitis patients who completed at least 24 weeks of therapy were included. The posttherapy average 6-MP dose was 1.05 ± 0.30 mg/kg, and white blood cell counts had decreased significantly from baseline values (P < 0.002). The posttreatment response to mitogens and antigens and the immunoglobulin levels were unchanged. Responses to vaccines were normal both in thiopurine-naïve and thiopurine-treated patients, suggesting that these patients were immunologically intact while on thiopurine therapy and capable of generating normal immune responses in vivo.

Conclusions: There is no evidence for any intrinsic systemic immunodeficiency in IBD patients. Thiopurines at the doses used for treating IBD showed no significant suppressive effect on the systemic cellular and humoral immune responses evaluated. Thiopurine-treated IBD patients can be safely and efficiently vaccinated.

FIGURE 1

Lymphocyte subpopulations during the course of thiopurine therapy. Lymphocyte subpopulations were assessed at week 0, 12, and 24. Lymphocytes were incubated with directly conjugated antibodies against CD3, CD4, CD8, CD20, CD14, CD56 as well as relevant isotype controls. Gating on mononuclear cells or CD3+ populations, the percentage of positive cells was measured by flow cytometry. Values are percent ± SE. n = 22–33, P = 0.05 CD3 24 weeks versus 0, P = 0.025 CD4 week 24 versus 0.

FIGURE 2

Proliferative responses to mitogens and antigens. Peripheral venous blood was obtained before (time 0) and during (12 and 24 weeks) thiopurine therapy. Lymphocyte proliferative responses to mitogens (MG): Con A, PHA (panel A) and antigens (Ag): candida, tetanus (panel B) were determined after 72 and 96 hours of incubation, respectively, assessed by thymidine incorporation detected by a β-counter, and compared to the proliferative response at baseline and to that of healthy volunteers. Values are fold increase (FI) ± SE compared to the patient’s nonstimulated PBMCs. At week 24 versus baseline: P = 0.23 and P = 0.85 for tetanus and candida stimulation, respectively. P = 0.22 and P = 0.10 for Con A and PHA stimulation, respectively. At week 24 versus healthy controls: P < 0.001 and P = 0.20 for tetanus and candida stimulation, respectively. P = 0.21 and P < 0.001 for Con A and PHA stimulation, respectively.

FIGURE 3

Response to HIB vaccine in thiopurine-naïve and thiopurine- treated IBD patients. IBD patients were vaccinated with HIB vaccine either at baseline (thiopurine-naïve, n = 9, left bars) or after 6 months of therapy (thiopurine-treated, n = 19, right bars). Serum antibody titers before and 3 weeks after vaccination were detected. Values are mean IU/mL ± SE. P = 0.009 for pre- versus postvaccination in thiopurine-naïve patients, P = 0.008 for pre- versus postvaccination in thiopurine-treated patients.