Does Azathioprine Cause Cervical Intraepithelial Neoplasia (CIN)?
Yes, azathioprine increases the risk of cervical intraepithelial neoplasia (CIN), particularly at high cumulative doses, and women taking this medication require enhanced cervical screening protocols.
The Evidence
The British Association of Dermatologists guidelines explicitly state that patients receiving immunosuppressant drugs have an increased frequency of CIN, with higher risk of progression to invasive disease and lower treatment success rates 1. While the guidelines note that data from renal transplant populations (receiving multiple immunosuppressive agents) show a fivefold increase in abnormal cervical cytology prevalence (15% vs. 3% in the general population), they acknowledge there is "no generic information on risk in dermatology patients on single immunosuppressant drugs such as azathioprine."
However, more recent research fills this critical gap. A large Danish population-based cohort study of 341,758 patients with autoimmune diseases found that azathioprine specifically increases CIN risk in a dose-dependent manner 2. The study demonstrated:
- Crude hazard ratio of 1.4 (95% CI: 0.9-2.1) during azathioprine exposure
- Substantially elevated risk with high cumulative doses: HR = 2.2 (95% CI: 1.2-3.9)
- The risk appears highest when considering a 5-year lag time between drug exposure and cervical cancer development
This dose-response relationship is biologically plausible and clinically significant. The FDA labeling does not specifically mention CIN but does acknowledge the general increased risk of malignancy with azathioprine 3.
Clinical Management Algorithm
Before Starting Azathioprine:
- Verify the patient is up-to-date with national cervical screening programs 1
- Request pretreatment gynecological review for any patient with previous CIN 1
During Azathioprine Treatment:
- Consider annual cervical cytology combined with colposcopy (as practiced in some European centers like Manchester Royal Infirmary) 1
- This is particularly important for patients receiving high cumulative doses
- Standard screening intervals may be insufficient given the 2.2-fold increased risk at high doses 2
Key Risk Stratification:
Women at highest risk are those:
- Receiving high cumulative azathioprine doses
- With prolonged treatment duration (≥5 years)
- With prior history of CIN
- Who are immunosuppressed from their underlying disease
Important Caveats
The increased CIN risk is not uniform across all azathioprine users—most patients with autoimmune diseases taking azathioprine do not develop CIN 2. The risk becomes clinically significant primarily in those receiving substantial cumulative doses over years.
The mechanism likely involves azathioprine's immunosuppressive effects impairing the immune system's ability to clear HPV infection and control dysplastic cervical cells. This is consistent with the observation that progression to invasive disease is higher and treatment success rates are lower in immunosuppressed patients 1.
The Danish study's finding of a 5-year lag time between exposure and cancer development 2 suggests that the carcinogenic process is gradual, reinforcing the importance of sustained surveillance rather than one-time screening.