Conventional Medical Management of Crohn’s Disease: Methotrexate

Fig. 31.1

Methotrexate (MTX) metabolism . MTX and its polyglutamate metabolites (MTXPG) potently inhibit dihydrofolate reductase (DHFR), impairing the conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4). MTXPG also inhibit folate-dependent enzymes distal to DHFR such as thymidylate synthase (TS). 5,10, methylenetetrahydrofolate polyglutamate (5,10 methylene THFPG)

At the cellular level, MTX has been observed to induce apoptosis and clonal deletion of activated T-lymphocytes in a mechanism that is independent of the APO-1/Fas (CD95) receptor/ligand system [13]. MTX also acts as a strong differentiation factor for immature monocytes which in vitro is associated with natural cytokine inhibitor release and a simultaneous down-regulation of interleukin (IL)-1β effects [14].

MTX decreases the production of the pro-inflammatory cytokines IL1, IL6 [15–17], IL2, interferon-γ [18], and tumor necrosis factor (TNF)-α [14] and increases IL4 and IL10 gene expression, both of which have anti-inflammatory effects [18]. MTX was shown to inhibit IL-1 activity by blocking the binding of IL-1 to its receptor [19]. There is evidence in patients with rheumatoid arthritis that MTX indirectly inhibits COX-2 synthesis [20] and neutrophil chemotaxis [21]. It is likely that the anti-inflammatory effects of MTX in IBD are underpinned to an extent by combinations of these different actions.

Methotrexate Use in Crohn’s Disease

The treatment of steroid-dependent IBD is problematic. In a population-based study on the natural history of corticosteroid therapy for IBD [22], 58 % of patients with Crohn’s disease treated with corticosteroids were in complete remission after 30 days of therapy and one year outcomes revealed that 28 % of patients were steroid dependent. Corticosteroids are not indicated in the maintenance of IBD because of their side effect profile with 32 % of patients on high dose and 26 % on prophylactic dose requiring withdrawal or dose reduction of therapy secondary to side effects [23].

MTX has been studied for both induction and maintenance of remission in patients with chronic active Crohn’s disease. There have been five randomized controlled trials reported on the use of MTX for induction of remission in refractory Crohn’s disease.

Randomized Controlled Trials

The largest trial, by Feagan et al. in 1995, reported substantial benefit [24]. This trial used intramuscular administration of MTX 25 mg once weekly in patients with chronic active, steroid-dependent Crohn’s disease. After 16 weeks, 39.4 % of patients were in clinical remission compared to 19.1 % with placebo. MTX also induced a substantial benefit in quality of life in these patients, as well as lower requirements for corticosteroid administration.

A study of 54 patients with chronic active Crohn’s disease by Ardizzone et al. compared using intravenous MTX 25 mg once weekly for 3 months, followed by 3 months of oral therapy at the same dose, to therapy with oral azathioprine [25]. The study showed no significant difference in induction of remission between MTX and azathioprine [25]. Adverse reactions resulting in withdrawal of therapy were the same in both treatment groups (11 %) but more adverse effects that did not require withdrawal of therapy occurred in the MTX group (44 % versus 7 %).

Several trials have evaluated the oral administration of MTX at lower doses. Oren et al. compared oral MTX 12.5 mg once weekly to oral 6-mercaptopurine (6-MP) in chronic steroid-dependent Crohn’s disease [26]. There was no statistically significant difference between the drugs for induction or maintenance of remission.

Mate-Jimenez et al. evaluated the efficacy and tolerance of oral MTX 15 mg once weekly to 6-MP and 5-aminosalicylic acid (5-ASA) [27]. This study similarly failed to show a benefit with oral MTX compared to 6-MP in inducing or maintaining remission in chronic active Crohn’s disease. It did show a statistically significant benefit over therapy with 5-ASA. A study by Arora et al. which also investigated using 15 mg oral MTX once weekly in steroid-dependent Crohn’s disease similarly failed to show a benefit [28]. This suggests that lower doses of 12.5–15 mg MTX per week and oral route of administration may be less effective than higher, parenterally administered doses. However, no firm conclusions can be drawn from these studies as the numbers involved were small and failure to respond may have been due to inadequate dose and oral route being utilized [26–28].

A randomized trial by Egan et al. investigated the optimum dose of MTX for induction of remission in patients with steroid-dependent IBD [29]. Of these patients, 80 % were refractory to corticosteroid therapy and 70 % had previously failed adequate therapy with 6-MP or azathioprine. Overall, 17 % of IBD patients investigated entered remission and there was no benefit to 25 mg over 15 mg of weekly subcutaneous MTX. The likely explanation for the low level of response seen in this group of IBD patients is the refractory nature of their disease. Interestingly, 11 of the patients who did not respond to treatment with 15 mg weekly after 16 weeks subsequently had their dose escalated to 25 mg weekly MTX and 36 % of these patients had an improvement in clinical status although there was no increase in the rate of remission. Toxicity was not different between the two groups [29].

A large trial by Feagan et al. in 2000 examined maintaining remission using intramuscular MTX 15 mg once weekly in patients with chronic active Crohn’s disease who had already achieved remission after 14–24 weeks treatment with intramuscular MTX 25 mg once weekly [30]. This study showed that relapse occurred in 35 % after 40 weeks of therapy with MTX compared to 61 % with placebo. The number needed to treat to prevent one relapse was 4. The mean time to relapse was >40 weeks compared to 2 weeks with placebo [30]. This study followed on to treat 22 of the 36 patients who relapsed (14 in the MTX group and 22 in the placebo group) with 25 mg intramuscular MTX for 40 weeks. Of this group, 55 % were in remission at 40 weeks compared to 14 % of the remainder of the group not treated with MTX [30].

Concomitant immunosuppressive therapy has been shown to reduce the magnitude of the immunogenic response of infliximab (IFX) [31]. Feagan et al. compared MTX plus IFX to IFX monotherapy in a placebo controlled trial involving 126 patients to maintain remission in Crohn’s disease [32]. Primary outcome was defined as treatment failure, i.e., lack of prednisone free remission at week 14, or failure to maintain remission by week 50. Steroid free remission was 76 % in the dual therapy group at week 14 as opposed to 78 % in the IFX monotherapy group. Remission was maintained in 56 % at week 50 in the dual therapy group verses 57 % with IFX alone. Combination therapy was well tolerated but not superior to IFX monotherapy in induction or maintenance of remission [32], indicating that MTX does not confer any additional benefit in IFX treated Crohn’s disease patients. However, the remarkably high and prolonged remission rate in IFX monotherapy patients in this trial may have compromised the ability to detect any advantages of MTX.

For an overview of MTX clinical trials in Crohn’s disease , see Table 31.1.

Table 31.1

Evidence base for MTX in Crohn’s disease

Study	Methods	Patient selection	Category	Intervention	Primary endpoint	Outcome
Feagan (1995) [24]	Randomized, double-blind placebo-controlled, multicenter study	Chronic active CD despite minimum 3 months therapy with prednisone. n = 141	Induction of remission CD	IM MTX at 25 mg per week versus placebo for 16 weeks	Clinical remission at 16 weeks defined as off corticosteroids and CDAI < 150 [33]	39.4 % remission with MTX versus 19.1 % with placebo
Feagan (2000) [30]	Randomized, double-blind placebo-controlled, multicenter study	Chronic active CD previously achieving remission (CDAI ≤ 150) with MTX 25 mg per week IM for 16–24 weeks. n = 76	Maintenance of remission CD	IM MTX 15 mg per week versus placebo for 40 weeks. Relapsed patients subsequently treated with MTX 25 mg IM per week for 40 weeks	Occurrence of a relapse at 40 weeks (increase of 100 in CDAI above baseline or initiation of prednisone or an antimetabolite)	Relapse in 35 % MTX group, 61 % placebo group. Relapsed patients treated with 25 mg MTX per week, 55 % achieved remission versus 14 % in untreated group
Mate Jimenez (2000) [27]	Randomized, controlled unblind single center, three-arm study	Induction arm: Steroid-dependent CD and UC Maintenance arm: Achieved remission at 30 weeks on MTX from induction arm of study n = 72 (38 CD)	Induction and Maintenance of remission CD and UC	Oral MTX 15 mg per week 6-MP 1.5 mg/kg/day 5-ASA 3 g/day Induction: 30 weeks Maintenance: if achieved, MTX 10 mg once per week given for 76 weeks	Clinical remission at 30 weeks, CDAI < 150 Maintenance of remission at 76 weeks	Differences not statistically significant
Egan (1999) [29]	Randomized, single-blind study	Steroid-dependent IBD resistant to azathioprine and 6-MP n = 32 ( 22 CD)	Induction of remission CD and UC	Compared 25 and 15 mg once weekly subcutaneous MTX for 16 weeks. Non responders in 15 mg group escalated dose to 25 mg for 16 weeks	Compare clinical remission (IBDQ < 170 [34]) at 16 weeks between 15 and 25 mg once weekly dose of MTX	No significant difference between different doses of MTX. 17 % from each group achieved remission. Dose escalation did not improve remission or increase toxicity
Arora (1999) [28]	Randomized, double-blind placebo-controlled trial	Steroid-dependent CD n = 33	Induction and maintenance of remission CD	Oral MTX 15 mg once weekly for 1 year. Nonresponders had MTX titrated up to 22.5 mg/weekly	Remission (CDAI < 150) and reduction in corticosteroid use	Nonsignificant trend towards fewer flares and increased side effects in MTX group
Oren (1997) [26]	Randomized, double-blind placebo-controlled, multicenter trial	Chronic active, steroid-dependent CD (Harvey–Bradshaw Index ≥7 [35]) n = 84	Induction and maintenance of remission CD	Three arms: Oral MTX 12.5 mg weekly Oral 6-MP 50 mg daily Placebo	Induction of remission and not receiving corticosteroids	No statistically significant difference between the groups
Feagan (2014) [32]	Randomized, double-blind, placebo-controlled, multicenter trial	Active Crohn’s disease on steroids n = 126	Induction and maintenance of remission of CD	IM MTX weekly, 10 mg initially uptitrating to 25 mg/week plus infliximab (5 mg/kg) at weeks 1, 3, 7, 14, and every 8 weeks thereafter for 50 weeks. Placebo plus infliximab (5 mg/kg) at weeks 1, 3, 7, 14, and every 8 weeks thereafter for 50 weeks. Prednisone was tapered to stop by week 14	Failure to enter prednisone free remission (CDAI < 150) at week 14, or failure to maintain remission at week 50	Combination therapy was well tolerated but not superior to infliximab monotherapy in induction or maintenance of remission

CD Crohn’s disease, UC ulcerative colitis, 6-MP 6-mercaptopurine, 5-ASA 5-aminosalicylic acid, IM intramuscular, MTX methotrexate, IFX infliximab, IBD inflammatory bowel disease, CDAI Crohn’s disease activity index, IBDQ inflammatory bowel disease questionnaire

Published Clinical Data: Comparative Analysis of Methotrexate and Other Treatment Options

Harper et al. assessed dual therapy of azathioprine/6-MP or MTX in patients starting anti-TNF therapy for induction of disease remission. This study showed azathioprine/6-MP and MTX performed similarly in this treatment group with regard to maintaining response to infliximab [36]. Diaz-Saa et al. studied methotrexate monotherapy as a third line option after thiopurine and anti-TNF failure in Crohn’s disease. They reported remission rates of 28 % at month four, and 22 % at month twelve of treatment. MTX was well tolerated in this difficult to treat group [37].

Margien et al. assessed the efficacy and tolerability of MTX use in Crohn’s Disease. 63 % of patients discontinued MTX after a mean of 33 weeks for various reasons, primarily due to ineffectiveness (39 %) and side effects (35 %). At 12 months 59 % were maintained on MTX, while this number had fallen to 9 % after 5 years [38]. Similarly a study looking at tolerability of MTX monotherapy after thiopurine failure found a clinical benefit was maintained in 63 % at year 1. This number had fallen to 20 % at 5 years. 26 % stopped MTX due to intolerances primarily in the first 6 months of treatment but adverse events were generally minor suggesting this treatment is safe [39].

Methotrexate and Its Role in the Formation of Antibodies to Infliximab

Vermeire assessed the formation of antibodies to IFX when combined with azathioprine, MTX or placebo and reported a lower incidence of antibodies to IFX in the group receiving either azathioprine or MTX [40]. In the dual treatment groups (azathioprine/MTX plus IFX) 46 % of patients developed antibodies to IFX compared to 73 % on IFX alone. There was no significant difference in the incidence of antibodies between the MTX and azathioprine groups (44 % vs 48 % respectively). The formation of antibodies to IFX >8 μg/ml is associated with lower serum levels of IFX [40]. Feagan et al. measured serum antibody levels in their two study groups (IFX + MTX and IFX + placebo). Patients who received methotrexate were significantly less likely to develop antibodies to IFX than those who received IFX alone (4 % compared to 20 %). Serum trough IFX levels were higher in the MTX treatment group but were not significant. This was not explored beyond 50 weeks, and it is possible the effects of MTX on antibody formation would result in benefit in the long term however this would need to be studied further [32].

Administration of Methotrexate

Subcutaneous administration of MTX has been shown to have similar pharmacokinetics compared to the intramuscular route [41, 42]. Bioavailability approaches 100 % with parenteral administration in contrast to oral route which has shown 50–90 % bioavailability in other chronic inflammatory conditions [43–45]. The subcutaneous route has been shown to be well tolerated by patients and to have few local complications at the injection site [41, 46, 47].

Adverse Effects

Adverse effects experienced with MTX can be categorized as being due to bone marrow suppression [48], idiosyncratic reactions such as rash or pneumonitis [49]; or secondary to MTX-induced fibrosis, e.g., pulmonary fibrosis or hepatic fibrosis.

There is evidence that the anti-inflammatory effect of MTX may be offset at higher doses by MTX-induced enterotoxicity [50, 51]. MTX causes morphological and functional abnormalities of the small intestinal mucosa [52, 53]. Two studies reporting on jejunal biopsies taken from children with acute lymphoblastic leukemia treated with MTX revealed striking structural abnormalities of the Paneth cells with marked vacuolar dilatation of the cytoplasm [51] and striking distension of the lateral basal intercellular spaces, cell vacuolation, and patchy necrosis [50]. This effect may have been due to a direct toxic effect of MTX therapy or interference with crypt cell generation [50]. There are also several case reports of MTX itself (or aminopterin, a related anti-folate compound) causing severe colitis [54–58].

Up to 18 % of patients in IBD trials discontinue the drug due to MTX related toxicity [24, 59]. In the largest study by Feagan et al., side effects were observed in similar frequency at 45 % in the MTX treated group versus 42 % in placebo group, however 17 % withdrew from treatment because of adverse events (including nausea and asymptomatic elevation in serum aminotransferase) compared to 2 % in the placebo group [24]. The patients who withdrew secondary to adverse effects improved after withdrawal of MTX.

The Oren 1997 study found that there was no statistically significant difference in withdrawals and adverse events between patients treated with MTX and 6-MP [26].

A similar small study looked at MTX use in patients who developed Azathioprine or 6 MP induced pancreatitis. Of the five patients who were started on MTX none had a recurrence of pancreatitis but in one patient MTX was stopped due to a rise in transaminases. Another patient developed a localized reaction at the site of drug administration but continued successfully on MTX after a brief course of antihistamines [60].

Chen et al. assessed frequency of adverse events (reactivation of Varicella Zoster Virus, Squamous Cell Carcinoma, non-dermatologic malignancies, and drug-induced pancreatitis) in patients on either MTX or Thiopurine monotherapy for their Crohn’s disease. Of 852 patients, 105 had complications, 5.29 % in MTX group verses 13.77 % in the thiopurine group indicating adverse events were less numerous in the MTX group. Similarly being cognizant of gender, age, and length of treatment the probability of AEs were less in the MTX group. No notable differences were established between the groups with respect VZV reactivation and non dermatological malignancies [61].

Importantly, liver fibrosis and cirrhosis can develop in some patients that are treated chronically with weekly MTX. MTX polyglutamates accumulate in hepatocytes and hepatotoxicity with MTX is thought to be due to the direct toxic and steatogenic effects of MTX on the liver [62, 63].

Patients with psoriasis treated with MTX appear to be at the highest risk of developing hepatic toxicity. In that disease, liver biopsies are typically performed at cumulative MTX doses of 1.5 g [64, 65]. In contrast, patients with rheumatoid arthritis seem to be at a lower risk with the risk of cirrhosis after 5 years of continuous therapy estimated at only 1/1000 [63, 66].

Studies have suggested that patients with IBD appear to be at a lower risk of developing MTX induced hepatic toxicity than patients with psoriasis [67, 68]. Te et al. showed that cumulative doses of up to 5410 mg MTX given for up to 281 weeks in patients with IBD were associated with minimal hepatotoxicity, and that abnormal liver function tests did not identify patients with fibrosis [67]. They suggested that surveillance liver biopsies based on cumulative MTX doses are not warranted in patients with IBD [67]. However, it is the practice of other authors to perform biopsies at cumulative doses of 1.5 g MTX [29]. Whether or not IBD patients on chronic MTX should undergo liver biopsies remains controversial.

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