Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases

Azathioprine (AZA) is a cornerstone immunosuppressive therapy for patients with inflammatory bowel disease (IBD) [1, 2]. It improves important outcomes such as hospitalization, surgery, steroid use and colorectal cancer risk [3‐7]. Moreover, AZA has been used for over 50 years in millions of patients worldwide and hence common as well as rare adverse events are well documented. As IBD most commonly affects patients during their reproductive years, the well-established safety of AZA during pregnancy and breastfeeding is an important advantage, as compared to newer biologics and small-molecule drugs [8‐10].

Unfortunately, AZA is limited by adverse events with the tolerated dose often being well below the effective dose [11, 12], resulting in 55% of patients discontinuing therapy within 5 years due to intolerance or ineffectiveness [13]. Consequently, a shift towards early therapy with biologics has occurred in those in more affluent countries. Whilst biologics can be transformative, they do have limitations: poor long-term effectiveness (related to antibody formation) [14]; parenteral administration, which affects quality of life [15]; infusion reactions (occasionally life-threatening) [16]; and high costs [17]. To address some of these concerns, new small-molecule drugs are being developed. However, the potential to optimize established small-molecule drugs like the thiopurines, and subsequently reduce the number of patients escalated to treatments like biologics, is often overlooked. Since thiopurines are affordable this strategy also reduces healthcare costs, which is particularly pertinent for developing countries and uninsured patients in higher-income countries [18].

One such optimization strategy for patients with IBD is to combine low-dose thiopurine with allopurinol, which was first described in 2005 [19]. Despite the fact that switching AZA monotherapy (AZAm) to low-dose AZA with allopurinol co-therapy (LDAA) improves tolerability and efficacy [19‐26], LDAA remains underreported in current literature [27], not mentioned in most IBD guidelines [1, 2] and hence underutilized. Moreover, most studies restricted LDAA to patients both failing AZA (due to intolerance or inefficacy) and showing aberrant metabolism i.e. hypermethylation (production of toxic 6-MMPs at the expense of therapeutic 6-TGNs). Conversely, several studies have demonstrated a poor predictive value of metabolites with regard to clinical outcomes. For instance, 52% of the patients resistant [28] and up to 50% of the patients intolerant to AZAm [26, 29] were non-hypermethylators. Of those with high 6-MMP levels, nearly 90% did not show hepatotoxicity [29, 30]. Only using LDAA in patients showing hypermethylation thus excludes a large number of patients who could benefit from LDAA. Furthermore, this approach hinders LDAA use in less affluent institutions/countries without access to metabolite measurements.

Apart from being a valuable option for all patients with IBD who have failed AZAm, LDAA might be beneficial as first-line immunosuppressive therapy [24]. Using LDAA as first-line therapy in daily practice (rather than AZAm) could reduce delay in reaching an effective treatment, and could eliminate complex drug dosing and extra monitoring typically needed with AZAm (LDAA can be initiated and maintained at the target/effective dose in most patients). This would improve both patient and clinician experience.

Hence, we sought to evaluate the long-term effectiveness and safety of first-line LDAA therapy in a large IBD cohort undirected by 6-TGNs/6-MMPs, and to compare outcomes with a similar AZAm cohort.

This is the largest study with the longest follow-up evaluating first-line LDAA for IBD to date, and the first study comparing safety and effectiveness of LDAA (n = 166) with AZAm (n = 118) in two very similar cohorts. Ongoing therapy without need for steroids, biologics or surgery was more frequently observed in LDAA compared to AZAm patients at 6 months (74% vs. 53%), 12 months (54% vs. 37%) and in the long-term (median 36 months, 37% vs. 24%). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%).

Direct comparison of our results with others is challenging since most studies have evaluated either effectiveness or tolerability of thiopurines, whereas our primary outcome assessed both elements. Nevertheless, high success rates have been reported for low-dose thiopurine with allopurinol therapy, but not for AZAm (see next paragraphs).

Two well-known randomized, double-blind trials evaluated the efficacy of 2.5 mg/kg/day AZAm: steroid-free remission was seen in 30% (51/170) of Crohn’s patients at 6 months [32] and 24% (18/76) of ulcerative colitis patients at 4 months [33]. The lower response rates compared to our study are likely due to the fact that endpoints of a randomized trial are more difficult to achieve, and that intention-to-treat analysis was used (while we used per-protocol analysis). Recently, long-term effective thiopurine monotherapy was observed in 4995/11928 (42%) subjects, but analysis did not include initiation of steroids [6].

The high incidence of intolerance to AZAm in our study is in keeping with other studies, in which 30–40% of patients withdrew AZAm due to adverse events [11, 12, 34, 35]. Additionally, it is worth noting in these studies that tolerability came at the expense of a sub-therapeutic AZA dose. In our study inability to tolerate an effective AZAm dose (i.e. 2.5 mg/kg/day for patients with normal TPMT activity [36]) was also observed: only a median dose of 1.83 mg/kg/day was achieved, which is 73% of the effective dose. Conversely, LDAA could be initiated and maintained at the target dose in most patients, with a better response rate. Hence, using LDAA as first-line therapy in clinical practice (instead of AZAm) would likely reduce periods of active disease, improve patient experience and eliminate the time and costs associated with managing poor treatment effectiveness and intolerance.

In a previous study, positive response to low-dose thiopurine with allopurinol (AZA in > 50% of patients, mercaptopurine in the rest) at 12 months was seen in 62% of patients failing thiopurine monotherapy and/or showing hypermethylation [25]. Another study showed thiopurine-allopurinol continuation in 78% (n = 145) and 66% (n = 83) of patients at 12 months and 2 years, respectively [37]. The possible explanation for the greater effectiveness in their study might be a twofold lower incidence of patients with active disease at initiation, and that initiation of steroids, biologics or surgery was not considered treatment failure. In a recent randomized trial, 73% of patients on thiopurine and allopurinol (AZA in 50%) were in steroid-free remission at 6 months according to per-protocol analysis [20]. Lastly, another study showed clinical benefit during at least 12 months in 38% of the optimized thiopurine cohort (co-administration of allopurinol in 40%) [23]. The results of these studies are in line with our outcomes.

To date, effectiveness of thiopurine-allopurinol co-therapy in thiopurine-naive patients has only been assessed by our study group [24]. An improvement in IBD activity scores in the absence of steroid use was observed in 79/110 (72%) patients after a median treatment duration of 12 months [24].

Our study has limitations which need to be acknowledged. First, allocation to LDAA or AZAm was not randomized. However, collected baseline characteristics in both cohorts were very similar. Another limitation is the retrospective design, which could have led to information bias. The influence of this was minimized by comparing two treatment groups, with a single researcher collecting all of the data. A further limitation concerns sampling bias, as the cohorts were restricted to patients in a single centre. Finally, we were not able to comment on mucosal response or draw firm conclusions regarding CRP level and IBD activity scores due to incomplete data.

Although myelotoxicity is a common concern during LDAA therapy, only 12 (7%) LDAA patients developed leukopenia during a median follow-up of 25 months. This incidence is comparable to our AZAm cohort, to other thiopurine monotherapy studies [12, 38], and also to two large studies using low doses of AZA during co-therapy [26, 37]. The lack of correlation between myelotoxicity and heterozygous TPMT activity in our study can be explained by dose adjustment for weight and TPMT activity.

Elevated LFTs occurred in 14% (24/166) of LDAA and 15% (18/118) of AZAm patients during our study, of which 7% of both cohorts had hepatotoxicity. Nine of twenty-four patients with elevated LFTs in the LDAA cohort had a pre-existing liver disorder, which is the likely explanation in these patients. In contrast, the liver injury in the AZAm patients was more likely to be drug-induced as only one patient had a pre-existing liver condition. Previous studies described hepatotoxicity in 5% of LDAA patients [24] and de-novo elevated LFTs in 14% [37], which is in line with our results. Interestingly, we showed that increasing the allopurinol dose can be a beneficial strategy to treat hepatotoxicity. On increasing allopurinol to 200–300 mg/day, LFTs fell significantly in 5/6 patients and stabilized in a patient with primary sclerosing cholangitis. These findings are in concordance with our previous study, in which an escalated allopurinol dose of 300 mg/day led to normalization of LFTs in 8/11 patients, with the remaining three patients having primary sclerosing cholangitis [24]. The biochemical mechanism for this phenomenon may be that allopurinol reduces methylated metabolites and reactive oxidative free radicals, both of which are thought to be hepatotoxic [19, 29, 39].

Although myelotoxicity and elevated LFTs were relatively common in our study, they only resulted in LDAA withdrawal in 2% for either abnormality. Recently, Kreijne et al. reported the same phenomenon in a cohort of 221 patients: myelotoxicity and elevated LFTs led to LDAA cessation in only 4% and 1%, respectively [37].

In conclusion, this large study demonstrates that optimization of AZA is needed, as poor outcomes were observed in our AZAm cohort. We have shown that first-line co-administration of allopurinol is a long-term effective and safe optimization strategy, even without metabolite monitoring. Although patients may still experience mild laboratory abnormality, we confirmed that myelotoxicity and elevated liver enzymes rarely necessitate LDAA withdrawal if closely monitored and adequately treated. Using LDAA as first-line therapy for IBD (rather than AZAm) would likely reduce periods of active disease, improve patient experience and reduce the number of patients escalated to more expensive treatments like biologics. Hence, LDAA may be considered as standard first-line immunosuppressive.