Patient and Therapy Characteristics
In total, 166 LDAA and 118 AZAm patients were included (Fig. 1), with a median follow-up of 25 and 27 months, respectively. Collected baseline characteristics were very similar in both cohorts (Table 1). Primary indication for thiopurines was ‘active disease’ (LDAA n = 149 [90%]; AZAm n = 109 [92%]). All patients were thiopurine-naïve and most patients were immunosuppressant-naïve (150 LDAA [90%] and 113 AZAm [97%]).
Only 14 (8%) LDAA and 3 (3%) AZAm patients used concurrent biologic. In most cases (11/14 LDAA and 2/3 AZAm patients) thiopurine and biologic therapy were commenced simultaneously because of a top-down therapeutic approach. In those with normal TPMT activity (~90%), median AZA dose was 0.54 mg/kg/day (LDAA) and 1.83 mg/kg/day (AZAm).
Clinical benefit rates are summarized in Figs. 2 and 3, and Table 2. Clinical benefit was more frequently observed in LDAA than AZAm patients at 6 months (116/156 [74%] vs. 59/111 [53%], p = 0.0003) and 12 months (74/138 [54%] vs. 38/103 [37%], p = 0.01). Furthermore, 51/138 (37%) LDAA compared to 25/103 (24%) AZAm subjects demonstrated sustained clinical benefit during a median of 36 (IQR 20–44) and 33 (IQR 22–44) months, respectively (p = 0.04).
A Kaplan–Meier curve (Fig. 4) demonstrates that more LDAA than AZAm patients were having clinical benefit during the entire study period (p = 0.003). Throughout follow-up, AZAm individuals were 60% more likely to fail therapy (95%-CI 1.16–2.14). Moreover, median duration of beneficial response from commencement of therapy was 17 months in the LDAA cohort (95%-CI 9–25) compared to 6 months in the AZAm cohort (95%-CI 1–11).
A multivariable analysis on the association between patient characteristics and clinical benefit in LDAA-treated patients (Table S1, Supplementary Material) demonstrated that stricturing Crohn’s disease was inversely correlated with clinical benefit (hazard ratio 2.09, 95%-CI 1.02–4.28). No difference in response to LDAA was found between Crohn’s disease and ulcerative colitis patients, nor between patients with and without concurrent biologic therapy.
Secondary outcomes are summarized in Table 3. Steroid withdrawal within 6 months occurred in approximately 90% of both cohorts. In the LDAA cohort, 65% (69/106) demonstrated clinical remission (SCCAI ≤ 2 or HBI ≤ 4) at last review, compared to 58% (45/78) in the AZAm (p = 0.31). Biochemical remission (CRP ≤ 10 mg/L) was observed in 93/158 (59%) and 59/94 (63%) of LDAA and AZAm patients, respectively (p = 0.54).
Sixty-eight of the 116 AZAm (58%) and 80/166 (48%) LDAA patients experienced adverse events during a median follow-up of 27 and 25 months, respectively (p = 0.12, Table 4). Adverse events were the main reason for discontinuing either LDAA or AZAm. However, a greater proportion of AZAm patients discontinued due to adverse events (AZAm: 53/118 [45%]; LDAA: 43/166 [26%]; p = 0.001). LDAA withdrawal due to intolerance did not depend on gender, age, IBD-type or TPMT level.
No malignancies were reported in either cohort and the incidence of pancreatitis was low.
Liver Enzyme Abnormalities
Liver enzyme abnormalities occurred equally in both cohorts: 11 (7%) patients reported hepatotoxicity and 13 (8%) elevated liver function tests (LFTs) without hepatotoxicity in the LDAA cohort, compared to 8 (7%) and 10 (8%) AZAm patients, respectively. Upon more detailed review of LDAA patients, 4/11 reporting hepatotoxicity and 5/13 reporting elevated LFTs without hepatotoxicity had liver disease prior to LDAA initiation (fatty liver n = 7; focal nodular hyperplasia n = 1; primary sclerosing cholangitis n = 1). In contrast, 1/18 AZAm patients with liver enzyme abnormalities had prior liver disease (fatty liver).
Hepatotoxicity led to LDAA discontinuation in two (1%) patients as did elevated LFTs without hepatotoxicity in one patient (0.6%). In six other patients with hepatotoxicity, allopurinol dose was increased to 200–300 mg/day. Consequently, the abnormal LFTs resolved in 4/6, improved in 1/6 and persisted in the remaining patient (who had primary sclerosing cholangitis). All six patients continued LDAA until final follow-up and did not experience further side effects on the escalated allopurinol dose.
AZAm was discontinued due to hepatotoxicity and elevated LFTs without hepatotoxicity in three (3%) and two (2%) patients, respectively.
Incidence of myelotoxicity was similar in both cohorts (LDAA: 18/166 [11%]; AZAm: 11/118 [9%], p = 0.17). One patient in each cohort required hospital admission related to myelotoxicity (LDAA: respiratory tract infection, AZAm: CMV reactivation).
Regarding the LDAA cohort, 2/21 (10%) with heterozygous TPMT activity developed myelotoxicity, whereas 16/137 (12%) patients with wild-type TPMT (p = 0.77). Additionally, myelotoxicity was not related to gender, age or IBD-type.
Upon minor AZA dose reduction in 5/12 LDAA patients with leukopenia, leukocyte count normalized in three patients. All three were able to continue therapy until final follow-up, without loss of response. Myelotoxicity resulted in permanent LDAA withdrawal in 3/166 (2%) patients.
None of the AZAm patients had a dose reduction after myelotoxicity was detected and 5/118 (4%) permanently discontinued AZAm due to myelotoxicity.