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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Aliment Pharmacol Ther 2010; 32: 1017–1022

Summary

Background  Patients with ulcerative colitis often receive thiopurines as immunomodulators (IMs) to maintain remission and avoid corticosteroids. If unresponsive or intolerant to these agents, patients are treated with methotrexate, an antimetabolite never assessed in paediatric ulcerative colitis.

Aim  To describe the experience with methotrexate in children with ulcerative colitis.

Methods  Thirty-two patients (median age 13.9 years) received methotrexate. Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months.

Results  Indications to methotrexate were azathioprine unresponsiveness in 18 patients, azathioprine intolerance/toxicity in 10 and spondyloarthropathy in four. Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P: 0.03). At the beginning of methotrexate, 16 patients (50%) received corticosteroids that were discontinued in 13 of them (81%) by 6 months. At the end of the study, 11 patients (33%) needed short courses of corticosteroids for disease relapse.

Conclusions  Methotrexate may be useful in treating children with ulcerative colitis, although large, controlled trials are warranted to define better its effectiveness.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory disorders of the gut characterized by recurrent exacerbations intermingled with phases of quiescence.1, 2 Most patients with active UC respond to aminosalicylates (5-ASA) or corticosteroids. The latter are highly effective in inducing remission; however, a considerable group of patients relapse when steroids are withdrawn.3 Moreover, children on long-term corticosteroids exhibit serious adverse effects, among which linear growth delay, osteopaenia and infections are the most cumbersome.3, 4 Corticosteroids sparing while maintaining remission is a tricky therapeutic strategy in the management of IBD: for this purpose, IMs have successfully been introduced into the therapeutic armamentarium of this disorder.5, 6 The most commonly used IMs for IBD are thiopurine analogues such as azathioprine (AZA) and mercaptopurine (MP);7 however, serious adverse events may lead to cessation of therapy in up to 25% of patients, whereas unresponsiveness occurs in 15–20% of them.8, 9 Thiopurine intolerant or unresponsive patients are usually treated with alternative IMs or biological therapy. Recently, there has been a great concern due to a reported increase in the risk of lymphoma in IBD patients chronically treated with AZA.10 The chronic use of thiopurine analogues has been also challenged following publication of cases of hepato-splenic T cell lymphoma in young adults receiving them in association with biologics.11 Thus, paediatric gastroenterologists commonly consider alternative IMs.

Methotrexate (MTX), a potent folic acid antagonist, causes a decrease in purine production at the cellular level.12, 13 A direct anti-inflammatory effect of MTX (i.e. inhibition of cellular proliferation, decrease in the formation of antibodies and in the production of inflammatory mediators, induction of apoptosis) has also been demonstrated13 leading to its use in several inflammatory disorders, such as psoriasis and rheumatoid arthritis.14, 15 However, the role of MTX in IBD remains somewhat unclear, although it has been shown to be effective both for induction and maintenance of remission in adults with CD.16–18 Although very few reports have shown the effectiveness and safety of MTX in children with CD,19, 20 reports in UC are lacking and confined to adult patients.21–23 Thus, the aim of this study was to report the experience of a tertiary referral Centre for Pediatric Gastroenterology in the use of MTX in children with UC.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

This is a retrospective longitudinal study conducted at a single tertiary referral Centre for Pediatric Gastroenterology. The Department database was screened for all children diagnosed with UC by 2004, and those treated with MTX were identified. Diagnosis of UC was based on widely agreed endoscopic and histological criteria,24 after excluding infectious and systemic disease, food allergies and malabsorption syndromes. All patients underwent ileocolonoscopy with a paediatric videocolonoscope (Olympus, PCF Q 180 I) following conscious sedation with i.v. pethidine (1–2 mg/kg) and midazolam (0.1 mg/kg) or under general anaesthesia. Endoscopic criteria for UC were diffuse continuous inflammation extending from the rectum proximally and characterized by granularity, friability, small diffuse superficial ulcers superimposed on a background of loss of vascular mucosal pattern and normal appearing distal ileal mucosa. Histological features for UC included a continuous intense mixed acute and chronic inflammatory infiltrate of the lamina propria, distortion of crypt architecture and/or crypt atrophy, basal plasmacytosis, cryptitis and crypt abscesses, Paneth cell metaplasia distal to the ascending colon. The behaviour of disease activity, measured through PUCAI25 and the use of corticosteroids (evaluated baseline and at 3, 6, 12 months post-MTX) were the main outcomes. PUCAI is a validated, non-invasive, multi-item measure of disease activity with established cut-off values for remission (<10 points), mild (10–34 points), moderate (35–64 points) and severe disease (65–85 points), developed in 2007.25–27 Clinical remission was defined as a PUCAI score <10 and clinical response as a decrease in the PUCAI of at least 20 points as compared with baseline.25 Medical records of patients evaluated before 2007 were retrospectively reviewed by an experienced physician unaware of medical therapy, and PUCAI sub-domain scores were attributed. The use of corticosteroids, adverse effects and surgical procedures during the study period were the secondary outcomes recorded. Thiopurine intolerance was defined as a requirement to discontinue thiopurine because of side effects. Thiopurine refractoriness was defined as no clinical improvement to a trial of at least 12 weeks’ therapy. MTX was given weekly by intramuscular injection at the dose of 15 mg/m2 body surface area. All children received 5 mg of intramuscular folic acid weekly, 6 h after MTX. To detect potential hepatic, renal or haematological side effects of MTX therapy, patients were monitored every 2 weeks during the first 2 months and every 8–12 weeks thereafter.28 Laboratory tests included full blood count, inflammatory, renal and liver function parameters, serum albumin, electrolytes, lipase and amylase. Liver ultrasound was performed if liver function tests were abnormal, whereas chest X-ray was performed in all patients before starting MTX to rule out pulmonary fibrosis.

Statistical analysis for the comparison of the qualitative variables was carried out by chi-square test or Fisher’s exact test (where appropriate). Continuous variables were compared using the Mann–Whitney nonparametric U-test. A P value less than or equal to 0.05 was considered as significant. Data were given as median (and ranges) and as mean ± s.d.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Of the 38 children with active UC treated by MTX with a follow-up of at least 12 months, 32 (16 male children) provided complete data on all items of the PUCAI with a valid total score (median age: 14.0 years; range: 8.3–19.8; IQR 12.5). The mean age at diagnosis of UC was 10 ± 4.3 years, and MTX was commenced 23.4 ± 12.3 months after diagnosis. Table 1 summarizes baseline clinical characteristics of the patients. At the introduction of MTX, an extensive colitis (pancolitis) was present in 24 (75%), a left-sided colitis in five (16%), and a proctitis in three (8%). AZA had been introduced in all, but four patients as first-line IM agent. Thiopurine therapy was discontinued because of primary nonresponse or relapse in 18 patients (56%), and intolerance/toxicity in 10 (31%). In four patients, MTX had been introduced as the first-line IM because of coexisting joint disease (spondyloarthropathy). MTX was administered parenterally in all patients with a mean dose of MTX for patient of 13.7 ± 3.6 mg/m²/week. All patients were on chronic treatment with mesalazine (mesalamine) (75–100 mg/kg/day) that was maintained in addition to MTX during the entire observation period.

Table 1.   Clinical characteristics of 32 patients with ulcerative colitis treated with methotrexate
Age (years)Median14.0
Range8.3–19.8
Gender 12M,12F
Age at diagnosis (years)Mean ± s.d.10 ± 4.3
Disease locationProctitis3 (8%)
Left-sided colitis5 (16%)
Pancolitis24 (75%)
Previous therapy with AZA 28 (87%)
Indication to MTX therapyAZA intolerance/toxicity10 (31%)
Nonresponse/relapse on AZA18 (56%)
Spondyloarthropathy4 (12%)
Corticosteriods at the introduction of MTX 16 (50%)

Of the 32 children on MTX, a clinical improvement (response or remission) was seen in 72%, 63% and 50% at 3, 6, and 12 months respectively (Figure 1): this included six of 10 with AZA intolerance or toxicity and 14 of 18 with AZA refractoriness. Remission was observed in 10 patients at 3 months, and in nine at both 6 and 12 months; response was observed in 13, 11 and 7 patients at 3, 6, and 12 months, respectively. Mean PUCAI 6 months before the introduction of MTX was 40.5 ± 23.6 (moderate disease), 49.5 ± 23.3 at the introduction of MTX, and 32.9 ± 21.9, 29.5 ± 22.8, 29.4 ± 25.9 (mild disease) at 3, 6 and 12 months post-MTX respectively (P: 0.03). At the beginning of MTX, 16 patients were receiving oral prednisolone with a mean dose of 1.24 mg/kg/day (range 0.2–3.2 mg): tapering of corticosteroids was possible in 14 (87.5%), with complete discontinuation in 11 (68.7%) within the first 3 months, and in other two patients after 6 months of MTX. At 12 months, eight children were receiving short courses of corticosteroids because of disease relapse. At the end of the study period, eight patients had a sustained steroid-free clinical remission.

image

Figure 1.  Rate of clinical remission/response and relapse/intolerance to methotrexate in paediatric patients with ulcerative colitis over the 1-year study period. Pts, paediatric patients.

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No surgery was performed during the observation period. There were adverse reactions in eight patients within the first 3 months of therapy: asymptomatic elevation of alanine aminotransferase (ALT 3 to 4 times the upper limit of normal) in four, with normalization in all after dose reduction of MTX and four needed to discontinue the drug because of intractable nausea. No haematological or infectious complications were observed in this case series.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The natural history of UC is characterized by phases of remission intermingled with recurrent flare-ups that occur in an unpredictable fashion and impair the quality of life of the patients. The main goals in the management of paediatric UC are to control disease exacerbations and avoid prolonged use of corticosteroids.1 The classical medical armamentarium for UC includes anti-inflammatory drugs, corticosteroids and IMs. Although corticosteroids have short-term clinical efficacy, they do not change the natural history of the disease and cause a number of troublesome side effects. The IMs are considered as steroid sparing agents, when a long-term remission is attainable.29 Although thiopurines are the most commonly used IMs, some patients exhibit unresponsiveness or intolerance to them and MTX has been proposed as an alternative immunomodulatory therapy.1, 2 Although there are few retrospective reports on MTX in patients with CD, there are no data on the effectiveness and safety of MTX in paediatric UC. Our study shows that children with UC may benefit from MTX, both to induce and to maintain remission, as well as in reducing corticosteroids exposure. Of the 32 treated patients, we observed an overall clinical improvement in 23, 20 and 16 at 3, 6 and 12 months respectively. Comparable high response rates are reported in adult studies. A recent retrospective study in 32 adults nonresponsive or intolerant to thiopurines reported a clinical response of 68% using either oral or parenteral MTX at an induction dose of 25 mg/week.30 Previously, a response rate of 72% and a remission rate of 42% had been reported in adults with active UC formerly treated with thiopurines.23 The evidence for using MTX in UC is restricted to observational studies, whereas the only randomized, placebo-controlled trial in adults found no efficacy; however, it was underpowered and a low oral dose of MTX (12.5 mg weekly) was used.21 In our study, the majority of patients started MTX during a flare-up of the disease, thus it is conceivable that a ‘regression to the mean phenomenon’ might contribute to the clinical response to the therapy, leading to a lower disease activity just by chance. However, as shown by longitudinal assessment of disease activity, our patients had highly active disease already 6 months before starting MTX (i.e. medium PUCAI 40.5 ± 23.6), thus reducing the likely impact of this phenomenon.

We gave MTX intramuscularly as it has previously shown that this way of administration may be more useful due to the variable oral bioavailability of the drug.31 Subcutaneous injection is an alternative method of parenteral administration as, compared with intramuscular injection, it produces similar pharmacokinetics and leads to greater patient comfort by reducing local complication rate at the injection site.22 The majority of our patients improving on MTX achieved clinical remission within 10–12 weeks (range, 6–12), thus indicating that MTX is clinically efficacious earlier than thiopurines, which have a delayed onset of action, usually 2 or 3 months after commencement of administration.29

The anti-inflammatory effect of MTX at low doses has not clearly been defined. Although MTX at high doses has an antiproliferative and cytotoxic effect, by inhibiting the enzyme dihydrofolate reductase and leading to defective DNA synthesis and cell death,12 at low doses, it acts mainly as an IM.32 The immunomodulatory effect of MTX is poorly understood, but it involves increased concentrations of adenosine,33 inhibition of cellular proliferation and induction of apoptosis,34 and decreased production of inflammatory mediators, such as interleukins and eicosanoids.13

The safety of MTX has been extensively studied in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. In the short-term, the most common side effects are of gastrointestinal type, in particular nausea, vomiting and diarrhoea, and asymptomatic elevation of transaminases. Longer term safety concerns include bone marrow suppression, opportunistic infection due to immune suppression, pneumonitis, teratogenicity and cirrhosis.29 The supplementation of folates during MTX therapy seems to reduce the risk of cytopaenia and the severity of gastrointestinal symptoms without reduction in efficacy and bioavailability of the drug.35 Majority of our patients preferred folic acid intramuscularly despite the latter being widely known to be very effective by oral route.36

In our study, MTX was well tolerated and safe. Four children needed to discontinue the drug due to intractable nausea unresponsive to folic acid and antiemetics; in four patients, there was a transient abnormality in liver function tests, which resolved with MTX dose reduction. Due to the rarity of severe chronic liver disease related to MTX therapy and according to recent recommendations37, 38 a conservative approach was adopted and no patient underwent liver biopsy.

It is still unsettled whether MTX may be considered as a first-line IM agent in the treatment of UC. Indeed, there are no head-to-head studies comparing MTX and AZA in IBD and no data are available on MTX as first-line therapy, whereas it is commonly reported in patients unresponsive or intolerant to thiopurines. In our study, only four patients with UC and spondyloarthopathy received MTX as first-line IM agent: they improved both in intestinal and articular symptoms without adverse reactions.

Although this study has some limitations such as the small sample size, lack of controls and being retrospective in nature, it suggests that MTX can be a useful agent for the management of paediatric UC patients, unresponsive or intolerant to thiopurines. Large, controlled prospective trials are warranted to define better the role and the place of MTX in the treatment of paediatric UC.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References