Management of Inflammatory Bowel Diseases

Oral-Administered Therapies

Sulfasalazine and various oral mesalamine derivatives have demonstrated efficacy for induction and maintenance of remission in mildly to moderately active UC ( Fig. 116.2 ). They have not been evaluated in a randomized, controlled fashion in patients with severely active disease. At a dose of 3 to 6 g/day, sulfasalazine induces remission in 39% to 62% of patients with mildly to moderately active UC, about twice the remission rate of placebo-treated patients. Meta-analyses have demonstrated that the mesalamines are as efficacious as sulfasalazine, and the various mesalamine preparations appear to be comparable in efficacy. A Cochrane review of oral 5-ASA for induction of remission included a total of 53 studies comprising 8548 patients. In the induction studies, 29% of patients treated with 5-ASA entered clinical remission compared with 17% of patients given placebo. There was no difference in efficacy between patients who received the conventional dosing in 2 to 4 split doses daily compared with those who received once daily dosing (relative risk [RR] 0.94, 95% confidence interval 0.83 to 1.07) suggesting that the latter may be more effective from the standpoint of patient adherence because of increased convenience.

More important than the specific 5-ASA preparation is the dose-dependent response when 5-ASA is used as an induction therapy for active UC. For this indication, mesalamine is not effective at doses less than 2 g daily, and there may be an increased response at doses of 4 to 4.8 g daily for some patients. The ASCEND I and II trials showed that mesalamine at doses of 2.4 and 4.8 g/day had similar efficacy for patients with mildly active disease, but that the higher dose (4.8 g/day) led to significantly higher response rates, but not remission rates, in patients with moderately active disease. The ASCEND III trial reported that patients with moderately active UC treated with Asacol 4.8 g/day had significantly higher remission rates but not response rates than those treated with 2.4 g/day. Also, data from ASCEND III and the Lialda trials showed that the 4.8 g/day dosing was more effective than 2.4 g/day dosing in patients previously treated with mesalamines or for those who did not achieve clinical remission after 8 weeks of therapy. The 4.8 g/day dose of mesalamine is comparable to 12 g/day of sulfasalazine, which is impractical in clinical practice because of the high pill burden and dose-dependent intolerance.

Once remission is achieved, sulfasalazine and other 5-ASAs are effective in maintaining it. This benefit appears to be dose-dependent for sulfasalazine, with a dose of 2 g/day often used to balance efficacy and AEs. Such a dose-dependent response, however, has not been found with the other 5-ASA preparations, and doses of 1.5 to 4.8 g/day maintain remission in more than 50% of patients. A similar review of 41 studies demonstrated that 5-ASAs were superior to placebo for maintaining both clinical and endoscopic remission. Fewer patients (41%) on 5-ASA therapy relapsed when compared with those receiving placebo (58%, RR 0.69, 95% CI 0.62 to 0.77) with a trend toward lower rates of relapse with higher doses of mesalamines. Compared to less than 1 g/day, patients receiving 1 to 1.9 g/day (RR 0.65, 95% CI 0.56 to 0.76) and more than 2 g/day (RR 0.73, 95% CI 0.60 to 0.89) had fewer relapses. Although there was no difference between agents in induction of remission, sulfasalazine was found to be modestly superior to the other 5-ASAs for maintenance of remission (RR 1.14, 95% CI 1.03 to 1.27). Other meta-analyses have suggested that the superiority of sulfasalazine lasts for only 6 months, and when the trial was extended to 12 months, this statistically significant benefit was lost. A double-blind randomized controlled trial (RCT) comparing 2 doses of balsalazide (1.5 g twice daily and 3 g twice daily) with mesalamine 0.5 g 3 times daily for 6 months reported a remission rate of 77.5% with the higher dose of balsalazide compared with remission rates of 56.8% and 43.8% with mesalamine and the lower dose of balsalazide, respectively. The dose of 5-ASA that induces remission is recommended for maintenance, although this has not been formally tested in a randomized placebo-controlled fashion. In the multicenter MOMENTUM trial, patients with mildly to moderately active UC who achieved complete remission after 8 weeks of therapy with 4.8 g daily of MMX mesalazine were more likely to remain in remission after dose reduction to 2.4 g daily for 1 year compared to those who achieved only partial remission, suggesting that complete remission should be the target before considering dose reduction in mildly to moderately active UC.

Common AEs of sulfasalazine include fever, rash, nausea, vomiting, and headache. Other less common but important AEs of sulfasalazine include hypersensitivity reactions, reversible sperm abnormalities, and impairment of folate absorption (by competitively inhibiting the jejunal enzyme, folate conjugase); folate supplementation (≥1 mg/day) should be prescribed to patients receiving sulfasalazine. Approximately 15% of patients taking sulfasalazine develop significant AEs that require discontinuing the medication. Up to 90% of patients who are intolerant to sulfasalazine, however, can tolerate mesalamine. In clinical trials, the newer 5-ASA preparations and balsalazide have been shown to be better tolerated than sulfasalazine. Oral mesalamine preparations do not appear to have significant dose-dependent toxicity. Olsalazine is associated with drug-induced diarrhea in up to 10% of patients, which often limits its use. Oral mesalamine therapy rarely has been associated with reversible acute kidney injury due to interstitial nephritis. Routine measurement of a serum creatinine level every 6 to 12 months is recommended for all patients receiving mesalamines. Up to 5% of patients receiving 5-ASA may develop paradoxical worsening of their colitis symptoms, often within the first few days or weeks of initiating therapy. This may recur with use of other drugs within the same class and even with topical therapy and requires a high index of suspicion to diagnose and appropriately cease the drug.

Orally-Administered Therapies

At doses equivalent to 40 to 60 mg/day of oral prednisone, glucocorticoids are effective first-line therapy for moderately to severely active UC. Use of doses higher than 60 mg/day is associated with increased AEs without appreciable clinical benefit and thus should be avoided. Although no study has directly compared the efficacy of oral and parenteral glucocorticoids, the latter commonly are used in severely active disease. Options for IV glucocorticoid formulation include hydrocortisone (100 mg IV every 8 hours), prednisolone (30 mg IV twice daily), or methylprednisolone (16 to 20 mg IV every 8 hours). Hydrocortisone can cause slightly more salt retention and sodium wasting, but it is likely to be equally effective. In a randomized double-blind trial with UC patients, continuous infusion was no better than divided dosing for efficacy and safety. The use of ACTH has been suggested as an alternative to conventional glucocorticoid therapy of active UC in small studies. One double-blind RCT suggested that IV ACTH was more effective than IV hydrocortisone for the treatment of severely active UC only in steroid-naïve patients ; this observation has not been confirmed. Because most patients with severely active disease have been treated previously with glucocorticoids, ACTH rarely is used in clinical practice. A noteworthy complication of ACTH therapy is bilateral adrenal hemorrhage.

As in CD, glucocorticoids have no maintenance benefits in patients with UC. Steroid-dependent patients, or patients who are unable to taper off glucocorticoids without experiencing disease exacerbation, benefit from the addition of steroid-sparing agents. There has been no trial to date assessing the efficacy of mesalamine therapy and its efficacy in maintaining remission induced with glucocorticoids. The long-term remission rate in patients who require parenteral glucocorticoids for severe UC is approximately 50%. Immunomodulatory or biologic agents should be considered in patients who are steroid-dependent, who require 2 courses of glucocorticoids for induction of clinical response or remission within 1 year, or who require parenteral glucocorticoids to induce remission.

Although a controlled study did not show benefit of conventional oral budesonide for the treatment of active UC, an oral formulation of MMX budesonide (Uceris) that provides optimal release characteristics throughout the length of the colon has been shown to be efficacious for the induction of remission in mildly to moderately active UC. Patients in this study were treated with MMX budesonide at doses of 9 mg or 6 mg once daily, Asacol at 800 mg 3 times daily, or placebo, for 8 weeks; the authors noted remission rates of 18%, 13%, 12%, and 7.4%, respectively (P = 0.014 for MMX budesonide 9 mg vs. placebo) at week 8. For this reason, the use of MMX budesonide at a dose of 9 mg daily for 8 weeks was approved by the FDA for the treatment of mildly to moderately active UC. Just as with other steroid formulations, there are no data supporting a role for budesonide MMX in maintaining remission in UC. Pooled safety analysis from the clinical trials demonstrated fewer AEs (including steroid-related AEs) in patients receiving budesonide MMX than in those receiving systemic steroids. In addition, the mean morning plasma cortisol was similar to that with placebo for the duration of the induction period in the clinical trials.

Rectally-Administered Therapies

Topical glucocorticoids in liquid and foam formulations are effective short-term therapy for active UC distal to the splenic flexure. Foam preparations often are tolerated better by patients and may be easier to retain than liquid preparations. Topical glucocorticoids have been found to be less effective than topical mesalamine for inducing remission of distal UC, however, the combination of topical corticosteroids and topical mesalamine has been more efficacious than either alone in the short-term treatment of distal UC. Whereas systemic absorption of glucocorticoids with topical therapy is significantly less than that with oral administration, prolonged treatment with topical glucocorticoids still may be associated with steroid-related AEs and should be avoided. Budesonide foams and enemas have been shown to be effective for the treatment of active distal UC in several controlled trials. In a double-blind RCT of patients with active distal UC, budesonide, 2 mg/100 mL for 6 weeks resulted in a remission rate of 19% compared with 4% in patients receiving placebo therapy (P < 0.05). Subsequent trials have shown budesonide enema to be as efficacious as or even superior to prednisolone enema without resultant depression of endogenous cortisol levels. Budesonide enema perhaps is inferior in efficacy to mesalamine enema, but it clearly presents an alternative topical glucocorticoid for treatment of distal UC. The optimal dose for budesonide enema consistently has been shown to be 2 mg/100 mL once daily. Budesonide foam is available at a similar dose and is effective in inducing clinical remission and complete mucosal healing. Additional studies are needed to determine the effect of longer-term topical budesonide use. As with other glucocorticoids, budesonide enema is not effective for maintaining remission in UC.

Thiopurine Treatment of Crohn Disease

AZA and 6-MP have been used to treat CD since the initial report of Brooke and colleagues describing healing of fistulas with AZA. Another decade would pass, however, before the efficacy of this class of drugs was demonstrated in an RCT by Present and colleagues ; earlier studies were marred by either insufficient power or incomplete understanding of adequate dosing and the slow onset of action of these agents. A Cochrane meta-analysis of studies of AZA and 6-MP in CD has provided the best summary of the effects of these drugs. For active disease, thiopurine treatment produced a remission rate of 47% compared with a 37% placebo rate, but this corresponded to a non-significant Odds Ratio of 1.23 (95% CI, 0.97 to 1.55). The outcome of remission or clinical response similarly yielded a higher but not statistically significant result compared with placebo (48% vs. 36%; RR 1.26; 95% CI, 0.98 to 1.62). The odds ratio for response increases after 17 weeks of therapy, suggesting the minimum duration for a trial of 6-MP or AZA. A steroid-sparing effect was significant (RR, 1.34; 95% CI, 1.02 to 1.77), and the number needed to treat (NNT) was about 6. Only 18 patients with fistulas were included in the original study, but a 54% rate of fistula response was noted, compared with a 29% healing rate on placebo; this, however, was not statistically significant (RR, 2.00; 95% CI, 0.67 to 5.93). There is more convincing evidence of the benefit of thiopurines for maintenance of remission. The OR for maintenance of remission with AZA was 2.32 (95% CI, 1.55 to 3.49; NNT = 6) and with 6-MP 3.32 (95% CI, 1.40 to 7.87; NNT = 4). The OR for AZA maintaining remission increased from 1.20 at 1 mg/kg up to 4.13 (95% CI, 1.59 to 10.71) at 2.5 mg/kg, demonstrating the importance of appropriate dosing.

Overall, approximately one half of patients may respond to thiopurine therapy; once in remission, about half to two thirds of patients will maintain that response. In earlier studies, mucosal healing was seen in approximately half of the patients who received thiopurines, however, in a more recent large study, mucosal healing was seen in only 16.5% of patients at 26 weeks. In children, early administration of 6-MP soon after diagnosis was associated with steroid sparing and maintenance of remission ; however, this was not reproduced in adults in a recently published trial. In clinical practice, AZA and 6-MP are used virtually interchangeably, with the exception of dosing. AZA generally is used in doses of 2 to 2.5 mg/kg/day, and 6-MP is given in doses of 1 to 1.5 mg/kg/day. The introduction of thiopurine medications should be timed with their slow onset of action in mind; many patients require a long, tapering regimen of glucocorticoids to bridge the time period until the thiopurines have taken effect.

When a patient is not responding to thiopurine therapy after 3 to 4 months of therapy, it is useful to measure metabolite levels to identify individuals who are noncompliant, under-dosed, or shunting (see later). Although mixed results have been reported of the correlation between 6-TGn nucleotide levels and response to therapy, a meta-analysis of 6 studies did find an overall significant relationship. A threshold of 230 to 260 pmol/8 × 10 ¹⁰ red blood cells corresponded to a 62% rate of remission, compared with a rate of 36% in those with lower levels (OR, 3.27; 95% CI, 1.71 to 6.27) of 6-TGn. Correlations between higher levels of 6-TGn nucleotides and leukopenia, and between metabolite levels and response to therapy, might explain the clinical observation that patients who achieve mild leukopenia are more likely to respond to such therapy. Conversely, however, leukopenia is not necessary to achieve a therapeutic response. Further, it is not clear if routine measurement of thiopurine metabolite levels and directed dose adjustment would contribute to improved management of Crohn disease, as opposed to the standard weight-based dose approach. Shunting refers to high TPMT activity that results in low 6-TGn levels and high 6-MMP levels (see Fig. 116.3 ); a 6-MMP:6-TGn ratio of >10 has been suggested as a profile of metabolism that is unlikely to lead to clinical benefit. In these patients, it may be possible to add allopurinol and take advantage of the drug interaction noted earlier. A study testing this hypothesis showed that by decreasing the thiopurine dose to 25% to 50% of the original dose and adding a low (100 mg daily) dose of allopurinol, 6-TGn levels rose significantly, with a coincident drop in 6-MMP levels and an improvement in clinical outcomes. Although this strategy requires careful following of the WBC count, it has been shown to be well tolerated and safe in one study with a median follow-up period of 19 months.

In addition to its role as monotherapy for CD, emerging evidence suggests that thiopurines may have an additional important role in combination therapy with a biologic agent. This hypothesis is supported by analysis of clinical trial data in which individuals on combination therapy with an anti-TNF biologic and a thiopurine have lower rates of anti-drug antibody and higher serum trough levels of the biologic agent. A large clinical trial, the Study of Biologic and Immunomodulator Naïve Patients with Crohn’s Disease (SONIC) study, randomized 508 thiopurine- and biologic agent-naïve adults with moderately to severely active CD to receive either AZA alone, infliximab alone, or a combination of both drugs. At week 26, the combination of AZA with infliximab resulted in superior clinical efficacy and mucosal healing compared with those receiving infliximab alone, or AZA alone. A similar benefit has also been noted in moderately to severely active UC. When used as combination therapy, one may observe a benefit even with lower doses of thiopurine, though this has not been prospectively studied. In a retrospective study, a 6-TGn trough level of 125 pmol/8 × 10 ⁸ RBCs was sufficient to achieve a higher infliximab trough level.

AEs are frequently noted in patients receiving thiopurines. In a Cochrane analysis, AEs severe enough to result in drug withdrawal were seen in 10% of patients. AEs that lead to drug discontinuation typically occur soon after drug initiation, with a median time of 1 month. Nausea within the first few weeks of treatment is reported in approximately 8% of patients, but typically will subside gradually. Allergic reactions consisting of fever, rash, or arthralgias are seen in 1% to 2% of patients, also usually within a few weeks of introducing the drug. Pancreatitis, observed in 3% to 4% of patients, is another idiosyncratic reaction and usually occurs in the first month of therapy. The presentation is typically classic with epigastric pain that radiates to the back, but may be atypical and subtle, with nausea and vague dyspepsia. When symptoms are recognized promptly, discontinuation of the drug leads to resolution of pancreatitis. Rechallenge with either drug, AZA or 6-MP, should not be attempted, because recurrent pancreatitis is certain to occur. Elevated serum aminotransferase levels develop in approximately 3% of patients and have been correlated with the presence of very high levels of 6-MMP. Mild elevations of liver biochemical tests can often revert to normal without any intervention, or with dose reduction. An exception is in the rare occurrence of cholestatic hepatitis or nodular regenerative hyperplasia, in which case thiopurine therapy should be withdrawn. Bone marrow suppression is another concern with thiopurine agents. A 27-year, retrospective, single-center study of 739 IBD patients treated with AZA found 28 patients (3.8%) developed leukopenia (WBC count <3 × 109 cells/L [<3000 cells/mm ³ ]), 9 of whom (1.2%) had severe leukopenia (WBC count <2 × 109 cells/L [<2000 cells/mm ³ ]); 3 of these patients became pancytopenic, and 2 died of sepsis. A review of 66 studies that included more than 8000 patients had a similar rate of myelotoxicity and, fortunately, a low risk (<0.1%) of death attributable to treatment. Although leukopenia occurs early among patients with low TPMT activity, it might not be related solely to TPMT genotype and can occur at any time during therapy. For this reason, it is advisable to continue monitoring the CBC every 1 to 3 months for the duration of therapy and more frequently (every 2 weeks if TPMT activity is normal, weekly if it is heterozygous) in the 8 to 12 weeks after introducing the drug or increasing dosage. Temporary cessation of therapy for a week or 2 and an adjustment in dose usually suffice to bring the leukocyte count back within normal range. Careful monitoring of the leukocyte count also should be performed during a tapering regimen of glucocorticoids. Concurrent treatment with glucocorticoids can raise the leukocyte count, but as the glucocorticoid is discontinued, leukopenia can develop.

Infections can occur in the setting of thiopurine therapy. Serious infections are reported to occur approximately 2% to 6% of the time, not necessarily in the setting of leukopenia. Treatment should be interrupted when serious infections occur, although the effect of the drug will endure for weeks. Systemic viral infections are of particular concern in thiopurine users. Patients treated concurrently with glucocorticoids also are at greater risk of serious infection, including CMV. Case series suggested that thiopurine users who develop primary Epstein-Barr virus (EBV) infection are at a higher risk for aggressive lymphoproliferative diseases including hemophagocytic lymphohistiocytosis leading a few to recommend routine screening for EBV seropositivity, particularly in young men and avoiding thiopurines in seronegative patients. The routine benefit of this, however, has not been established and nearly 100% of IBD patients are seropositive for EBV by age 26.

Malignancy associated with thiopurines has been a longstanding concern of patients and providers. Immunosuppressive regimens given to patients after organ transplantation and for other immune-mediated conditions are associated with an excess risk of malignancy, particularly non-Hodgkin lymphoma (NHL). Such regimens have included AZA, often administered in higher doses than for IBD and in conjunction with other immunosuppressive agents. In IBD, there does appear to be an association between thiopurine exposure and lymphoma, specifically NHL. The rate of NHL is reported to be approximately 4 to 9 per 10,000 patient-years. Data suggest that once stopping thiopurines, the risk of lymphoma returns to the patient’s baseline risk. NMSC appears to have a clear association with thiopurine exposure, but not melanoma. Multiple prospective cohort studies have suggested a 4- to 6-fold increase in risk of NMSC in patients who continue thiopurine therapy; this risk appears lower in those who are past users. Whereas the relative risk is highest in younger individuals, the absolute increase in likelihood of NMSC is significant in older adults and requires close dermatologic follow-up. Thiopurine use has also been linked to increase in risk of cervical neoplasia in some cohort studies. No other solid tumors have been found to be consistently associated with thiopurines when used for the treatment of IBD and use of thiopurines appears to be safe in individuals with prior solid-organ cancer. Continued thiopurine use, however, is associated with increased risk of recurrence of NMSC.

Once treatment with a thiopurine agent has proved to be effective, the question inevitably arises of how long to continue such therapy. One RCT demonstrated a clinical relapse rate of 21% 18 months after withdrawal of AZA in patients who had been in remission for at least 3.5 years on the drug, compared with a relapse rate of only 8% in the group who continued AZA. The authors concluded, and most authorities agree, that AZA maintenance therapy should be continued for more than 3.5 years. The decision to withdraw thiopurine therapy should only be undertaken after discussion between doctor and patient of possible risks and benefits.

Thiopurine Treatment of UC

There are less robust data supporting the efficacy of AZA in the treatment of UC, although it remains widely used for this indication. Four RCTs have evaluated AZA for inducing remission in active UC ( Table 116.3 ), all of which were small, heterogeneous in design, used different outcome definitions for response, and reached different conclusions. Two of the studies involved steroid-dependent patients, one study used steroids for induction, and 2 studies used 5-ASAs as a comparator group rather than placebo. Only one study showed a significant benefit with AZA compared with 5-ASA for induction therapy in steroid-dependent disease. With respect to the use of AZA for maintenance of remission in UC, 4 RCTs have been performed. Just as with studies of induction therapy, these 4 studies also had small sample sizes, used heterogeneous designs with different outcome definitions of response, allowed for various co-therapies, and again reached different conclusions. One of the studies was in steroid-dependent disease, another allowed the use of steroids for relapse, one study used 5-ASA as a comparator group rather than placebo, and another included patients who were mostly taking 5-ASAs and was actually a study of AZA withdrawal. Only this withdrawal study showed a benefit with continued AZA. Thus, for the purpose of induction or maintenance therapy for UC, the use of AZA is largely based on its established efficacy in CD rather than any proved benefit in UC. One subset of patients, however, has been shown to obtain benefit with the use of AZA: patients who have severely active UC and who are able to attain induction of remission with cyclosporine. In these patients, maintenance therapy with AZA has been reported to decrease colectomy rates (see later). A single RCT has also demonstrated benefit of AZA when used in combination with infliximab. Among 239 patients with moderately to severely active UC, corticosteroid-free remission was achieved at week 16 more frequently in the combination therapy group (40%) than in those receiving infliximab monotherapy (22%, P = 0.017). Mucosal healing was also more common with combination therapy than with each agent alone and no additional safety concerns were noted with combination therapy.

Methotrexate Treatment of Crohn Disease

Methotrexate (MTX) has long been used to treat psoriasis and rheumatoid arthritis. Although the cytotoxic effect of MTX is attributed to inhibition of DNA and RNA synthesis through inhibition of dihydrofolate reductase, its efficacy in immune-mediated diseases may be due to inhibition of other folate-dependent enzymes, inhibition of pro-inflammatory cytokines, and increased production of regulatory cytokines. In an RCT, patients were studied who had chronically active CD despite at least 3 months of prednisone (at least 12.5 mg/day) and with at least one failed attempt to taper off treatment. All patients were brought to a 20 mg/day dose of prednisone to standardize therapy, with separate stratification for patients in whom the dose of prednisone was increased and for those in whom the dose had been reduced to 20 mg before entry. Subjects then received either weekly injections of MTX 25 mg intramuscularly or placebo while executing a tapering prednisone regimen over 16 weeks. Overall, 39.4% of patients assigned to MTX achieved remission off prednisone compared with 19.1% of placebo-treated patients. Most patients responded by the eighth week of treatment. A follow-up study randomized patients who achieved remission by week 16 on MTX 25 mg intramuscularly once weekly to receive either weekly injections of placebo or MTX at a dose of 15 mg. At week 40, 65% of patients treated with MTX were still in remission, compared with 39% of placebo-treated patients (P = 0.04). Thus, MTX has been shown to be beneficial at inducing and maintaining remission

Among patients who relapsed on the maintenance dose, more than half were able to achieve remission again by resuming a 25 mg dose. If the 16 weeks of induction therapy were included, the combined duration of therapy was nearly 1 year, with some patients in selected practices treated successfully for more than 4 years. Although 15 mg intramuscular dosing was studied for maintenance, many patients continue on 25 mg weekly without dose reduction. Pharmacokinetic studies in RA have shown equivalency for subcutaneous and intramuscular dosing, and therefore most gastroenterologists administer MTX subcutaneously. Although oral dosing would be more convenient for long-term administration, a Cochrane review did not find evidence of efficacy when oral dosing was compared to placebo. This may be explained by the variable intestinal absorption of MTX, particularly in the presence of more extensive small intestinal disease.

In addition to its role in monotherapy, like thiopurines, the role of MTX as co-therapy with a biologic agent has been examined under the hypothesis that it suppresses immunogenicity. A 50-week RCT compared the combination of MTX and infliximab to infliximab alone in 126 patients initiated on prednisone within 6 weeks prior to the study. At the end of the study, there was no difference in steroid-free remission between the 2 groups. However, patients on combination therapy had higher trough infliximab levels than those receiving biologic monotherapy. There are fewer studies, particularly in IBD, on whether dosing of MTX influences its benefit when used in combination with an anti-TNF biologic agent. A single-center study examining dosing in patients on remission with combination anti-TNF therapy and MTX found that MTX dose greater than 12.5 mg weekly was associated with higher rates of clinical remission. A prospective 24-week trial in patients with RA who had previously failed MTX suggested slightly higher adalimumab trough levels in patients on high-dose MTX (20 mg/week) compared with low-dose MTX (7.5 mg/week), although there was no statistically significant difference in the rate of anti-drug antibody positivity.

MTX is given with folic acid (1 to 2 mg/day) to prevent folate deficiency (through inhibition of dihydrofolate reductase) as well as symptoms of nausea and stomatitis; diarrhea, hair loss, and mild leukopenia also can occur with MTX. Elevation of serum aminotransferase levels sometimes occurs, but correlate poorly with the complication of hepatic fibrosis. Liver biopsy is performed routinely in patients with psoriasis after cumulative doses of 1.5, 3, and 5 g have been administered, but these guidelines have not been widely adopted in patients with RA or IBD, in whom the risk of hepatic fibrosis appears to be lower. In one series of IBD patients who received a mean cumulative dose of MTX >2.5 g and had liver biopsy, only minimal hepatic toxicity was evident; obesity, diabetes, and alcohol intake, however, correlate with hepatic fibrosis. In clinical practice, liver biopsy is usually performed in those with persistently elevated liver enzymes or likelihood of an alternate cause of liver abnormality. MTX interacts with sulfa medications and with AZA and 6-MP to cause severe leukopenia. Rarely but potentially life-threatening, interstitial pneumonitis can manifest as cough and dyspnea of insidious onset. Early detection, cessation of MTX, and prompt treatment with glucocorticoids is essential. MTX is a potent abortifacient and is strongly teratogenic. Women of childbearing capacity must use MTX only with highly effective contraception and must cease therapy 3 to 6 months prior to planned conception. There are less data on the safety of MTX in men contemplating conceiving, although emerging data in patients with RA and IBD suggest that paternal exposure to MTX before conception is not associated with increased risk of congenital malformation, still births, or preterm birth. However, many physicians still consider cessation 3 months before planned conception in men.

Methotrexate Treatment of UC

MTX long lacked data supporting its use in UC with the first randomized, placebo-controlled trial failing to demonstrate efficacy for the treatment of active UC. In one study of 67 patients with chronic active UC, oral MTX at 12.5 mg/wk for 9 months was comparable to placebo therapy in the rate of achieving first remission, time to first remission, relapse following remission, and the mean glucocorticoid dose. Given the difference in dose and route of administration from the more successful trial in CD, however, it was unknown if a higher dose of parenteral administration would be of benefit in UC. Two recent RCTs provide more answers to the question. The METEOR study randomized 111 patients with steroid-dependent UC to receiving either parenteral MTX 25 mg weekly or placebo for 24 weeks. At the end of the trial, there was no statistically significant difference in steroid-free remission or endoscopic healing between the 2 groups. However, patients were more likely to be in clinical remission with MTX when compared to placebo (42% compared to 24%, P = 0.04). The subsequently completed multi-center MERIT-UC study did not show benefit of parenteral MTX 25 mg weekly for induction and maintenance of remission. The study design included a 16-week open label treatment with MTX, followed by a 32-week double blind, placebo-controlled maintenance period. Although 51% of patients responded in the open-label portion of the study, there was no difference between active treatment and placebo in maintenance, with 60% of patients in the placebo group and 66% in the MTX group relapsing (P = .75).